Allergy and Allergic Diseases, 2 Volume Set

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Allergy and Allergic Diseases

Allergy and Allergic Diseases, 2nd edition. Edited by A.B. Kay, A.P. Kaplan, J. Bousquet, P.G. Holt. © 2008 Blackwell Publishing. ISBN: 978-1-405-15720-9.

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To our wives: Rosemary, Lee, Hélène and Barbara

Commissioning Editor: Maria Khan Development Editor: Jennifer Seward Production Controller: Debbie Wyer CD produced by: Meg Barton and iBooks Production Services

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Allergy and Allergic Diseases Editor-in-Chief

A. Barry Kay MD, PhD, FRCP, DSc, FRSE, FMedSci Emeritus Professor of Allergy and Clinical Immunology, National Heart and Lung Institute, London, UK

Editors

Allen P. Kaplan MD The National Allergy, Asthma, and Urticaria Centers of Charleston; Professor, Department of Medicine Medical University of South Carolina, Charleston, South Carolina, USA

Jean Bousquet MD, PhD CHU Montpellier, Service des Maladies Respiratoires, Hôpital Arnaud de Villeneuve, Montpellier, France

Patrick G. Holt DSc, FRCPath, FAA Head, Division of Cell Biology, TVW Telethon Institute for Child Health Research, West Perth, Western Australia, Australia

SECOND EDITION

FOREWORD BY K. FRANK AUSTEN, MD

In two volumes Volume 1

A John Wiley and Sons, Ltd., Publication

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This edition first published 2008, © 1997, 2008 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Allergy and allergic diseases / edited by A.B. Kay . . . [et al.]; foreword by K. Frank Austen. – 2nd ed. p. ; cm. Includes bibliographical references and indexes. ISBN 978-1-4051-5720-9 (alk. paper) 1. Allergy. I. Kay, A.B. [DNLM: 1. Hypersensitivity–immunology. 2. Allergens–immunology. 3. Asthma–immunology. 4. Immunotherapy. WD 300 A4326 2008] RC584.A348 2008 616.97–dc22 2008000958 ISBN: 978-1-4051-5720-9 A catalogue record for this book is available from the British Library. Set in 9/12pt Meridien by Graphicraft Limited, Hong Kong Printed & bound in Singapore by Fabulous Printers Pte Ltd. 1 2008

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Contents

List of Contributors, ix

Part 2 Inflammatory Cells and Mediators

Foreword, xvii

11 Mast Cells: Biological Properties and Role in Health and Allergic Diseases, 217 Peter Bradding and Glenn Cruse

Preface, xviii

VOLUME 1 The Scientific Basis of Allergy Part 1 Immunology of the Allergic Response 1 Allergy and Hypersensitivity: History and Concepts, 3 A. Barry Kay 2 Development of Allergy and Atopy, 23 Catherine Thornton and Patrick G. Holt 3 T Cells and Cytokines in Asthma and Allergic Inflammation, 48 Chris Corrigan 4 Regulatory T Cells and Other Tolerogenic Mechanisms in Allergy and Asthma, 83 Catherine Hawrylowicz and Cezmi A. Akdis 5 IgE and IgE Receptors, 103 Brian J. Sutton, Andrew J. Beavil, Rebecca L. Beavil and James Hunt 6 Immunoglobulin Gene Organization and Expression and Regulation of IgE, 119 Hannah J. Gould and David J. Fear 7 Environmental Factors in IgE Production, 141 Anne Tsicopoulos, Catherine Duez and Andrew Saxon 8 Antigen-presenting Dendritic Cells and Macrophages, 166 Bart N. Lambrecht and Hamida Hammad 9 Innate Immunity in Allergic Disease, 187 Ian Sabroe 10 Signal Transduction in Allergic and Inflammatory Cells, 203 Rafeul Alam

12 Eosinophils: Biological Properties and Role in Health and Disease, 258 Simon P. Hogan, Helene F. Rosenberg, Redwan Moqbel, Simon Phipps, Paul S. Foster, Paige Lacy, A. Barry Kay and Marc E. Rothenberg 13 Neutrophils: Biological Properties and Role in Health and Allergic Diseases, 295 Alison M. Condliffe, Andrew S. Cowburn and Edwin R. Chilvers 14 Basophils: Biological Properties and Role in Allergic Diseases, 320 Gianni Marone, Giuseppe Spadaro and Arturo Genovese 15 Leukocyte Adhesion in Allergic Inflammation, 337 Michelle J. Muessel and Andrew J. Wardlaw 16 Airway Epithelium, 366 Pedro C. Avila and Robert P. Schleimer 17 Airway Vascularity in Asthma, 398 John W. Wilson 18 Fibroblasts and the Extracellular Matrix, 412 Lynne A. Murray, William G. Glass, Anuk M. Das and Geoffrey J. Laurent 19 Immune Complexes and Complement: Their Role in Host Defense and in Disease, 436 Michael M. Frank and C. Garren Hester 20 Bradykinin Pathways and Allergic Disease, 451 Allen P. Kaplan 21 Chemokines, 471 James E. Pease and Timothy J. Williams 22 Neurotrophins, 494 Wolfgang A. Nockher, Sanchaita Sonar and Harald Renz 23 Neuropeptides, 511 David A. Groneberg and Axel Fischer

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Contents 24 Late-phase Allergic Reactions in Humans, 524 Yee-Ean Ong and A. Barry Kay

41 Airway Smooth Muscle, 874 Stuart J. Hirst

Part 3 Pharmacology

Part 5 Allergens

25 Antihistamines, 551 F. Estelle R. Simons and Keith J. Simons

42 Biochemistry of Allergens and Recombinant Allergens, 895 Rudolf Valenta

26 Lipid Mediators: Leukotrienes, Prostanoids, Lipoxins, and Platelet-activating Factor, 566 Sophie P. Farooque, Jonathan P. Arm and Tak H. Lee 27 Theophylline and Isoenzyme-selective Phosphodiesterase Inhibitors, 634 Mark A. Giembycz 28 Adrenergic Agonists and Antagonists, 668 Tony R. Bai 29 Cholinergic Antagonists, 683 Nicholas J. Gross 30 Antileukotriene Agents, 694 Graeme P. Currie and Brian J. Lipworth 31 Glucocorticosteroids, 715 Peter J. Barnes 32 Immunomodulating Drugs, 732 Iain A.M. MacPhee

Part 4 Physiology 33 Physiologic Aspects of Asthma, 749 Philip W. Ind and Neil B. Pride 34 Aerosol Delivery Systems, 768 Thomas G. O’Riordan and Gerald C. Smaldone 35 Bronchial Hyperresponsiveness, 783 Guy F. Joos 36 Exercise-induced Bronchoconstriction: Animal Models, 794 Arthur N. Freed and Sandra D. Anderson 37 Exercise-induced Bronchoconstriction: Human Models, 808 Arthur N. Freed and Sandra D. Anderson

43 Host Responses to Allergens, 913 Wayne R. Thomas and Belinda J. Hales 44 Allergen Extracts and Standardization, 928 Ronald van Ree 45 Grass, Tree, and Weed Pollen, 942 Jean Emberlin 46 Fungi as Allergens, 963 Cathryn C. Hassett, W. Elliott Horner, Estelle Levetin, Laurianne G. Wild, W. Edward Davis, Samuel B. Lehrer and John Lacey 47 Dust Mites and Asthma, 984 Thomas A.E. Platts-Mills and Judith A. Woodfolk 48 Animal Allergens, 997 Adnan Custovic and Angela Simpson 49 Airborne Allergens and Irritants in the Workplace, 1017 Xaver Baur 50 Allergens from Stinging Insects: Ants, Bees, and Vespids, 1123 Te Piao King and Rafael I. Monsalve 51 Cockroach Allergens, Environmental Exposure, and Asthma, 1131 Martin D. Chapman and Anna Pomés 52 Food Allergens, 1146 Ricki M. Helm and A. Wesley Burks 53 Latex Allergy, 1164 Robyn E. O’Hehir, Michael F. Sutherland, Alexander C. Drew and Jennifer M. Rolland

Part 6 Animal Models of Asthma

39 Mucus and Mucociliary Clearance in Asthma and Allergic Rhinitis, 840 Duncan F. Rogers

54 Primate Models of Allergic Asthma, 1187 Charles G. Plopper, Suzette M. Smiley-Jewell, Lisa A. Miller, Michelle V. Fanucchi, Michael J. Evans, Alan R. Buckpitt, Mark V. Avdalovic, Laurel J. Gershwin, Jesse P. Joad, Radhika Kajekar, Shawnessy D. Larson, Kent E. Pinkerton, Laura S. Van Winkle, Edward S. Schelegle, Emily M. Pieczarka, Reen Wu and Dallas M. Hyde

40 Biology of Vascular Permeability, 857 Peter Clark

55 Airway Remodeling in Small Animal Models, 1202 Clare M. Lloyd

38 Sensory and Autonomic Nervous System in Asthma and Rhinitis, 823 Bradley J. Undem and Kevin Kwong

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Contents 56 Are Animal Models of Asthma Useful?, 1214 Reinhard Pabst

69 Management and Treatment of Allergic Rhinitis, 1430 Jean Bousquet and Michael A. Kaliner

Index

70 Nasal Polyps and Rhinosinusitis, 1454 Wouter Huvenne, Paul Van Cauwenberge and Claus Bachert

VOLUME 2 Allergic Diseases: Etiology, Diagnosis and Treatment Part 7 Etiology and Pathology 57 Genetics of Asthma and Atopic Dermatitis, 1225 Saffron A.G. Willis-Owen, Miriam F. Moffatt and William O.C. Cookson 58 Epidemiology of Asthma, Atopy, and Atopic Disease, 1239 Debbie L. Jarvis, Seif O. Shaheen and Peter Burney 59 The Allergy March, 1259 Ulrich Wahn

71 Ocular Allergy, 1482 Avinash Gurbaxani, Virginia L. Calder and Susan Lightman 72 Mechanisms in Allergen Injection Immunotherapy, 1510 Stephen J. Till and Stephen R. Durham 73 Allergen Injection Immunotherapy: Indications and Practice, 1522 Hans-Jørgen Malling 74 Sublingual Immunotherapy, 1543 G. Walter Canonica and Giovanni Passalacqua 75 Novel Approaches to Allergen Immunotherapy, 1555 Mark Larché

60 Outdoor Air Pollution and Allergic Airway Disease, 1266 Gennaro D’Amato

Part 10 Asthma and its Treatment

61 Indoor Air Pollution, 1279 Paul Harrison, Rebecca Slack and Sanjeev Bagga

76 Definition, Clinical Features, Investigations, and Differential Diagnosis of Asthma, 1567 Piero Maestrelli, Gaetano Caramori, Francesca Franco and Leonardo M. Fabbri

62 Molecular Immunopathology of Allergic Disease, 1290 Susan Foley and Qutayba Hamid

77 Asthma in Infancy and Childhood, 1591 John O. Warner

Part 8 Diagnosis of Allergic Disease 63 Principles and Practice of Diagnosis and Treatment of Allergic Disease, 1321 Anthony J. Frew and A. Barry Kay 64 Skin Testing in Diagnosis and Management of Respiratory Allergic Diseases, 1335 Pascal Demoly, Anaïs Pipet and Jean Bousquet 65 Allergy Testing in the Laboratory, 1346 Steven O. Stapel and Jörg Kleine-Tebbe 66 Measurement of Markers of Inflammation in Induced Sputum and Exhaled Air, 1368 Ian D. Pavord and Dominick E. Shaw

Part 9 Allergic Rhinoconjunctivitis and Immunotherapy 67 Definition and Classification of Allergic Rhinitis and Upper Airways Diseases, 1383 Wytske Fokkens and Jean Bousquet 68 Pathophysiology of Allergic Rhinitis, 1402 Peter H. Howarth

78 Pathogenesis of Asthma, 1608 Stephen T. Holgate 79 Pathology of Asthma, 1632 Peter K. Jeffery, A. Barry Kay and Qutayba Hamid 80 Management of Chronic Asthma, 1650 Peter J. Barnes 81 Anti-IgE in Persistent Severe Allergic Asthma, 1661 Marc Humbert, Stephen T. Holgate, Howard Fox and Jean Bousquet 82 Occupational Asthma, 1687 Paul Cullinan and Anthony J. Newman Taylor 83 New Drugs for the Treatment of Allergy and Asthma, 1712 Trevor T. Hansel, Ed Erin,Onn Min Kon and Peter J. Barnes

Part 11 Eosinophil-associated Disease and Hypersensitivity Pneumonitis 84 Allergic Bronchopulmonary Aspergillosis, 1743 André-Bernard Tonnel, Stéphanie Pouwels-Frys and Isabelle Tillie-Leblond

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Contents

85 Extrinsic Allergic Alveolitis/Hypersensitivity Pneumonitis, 1757 Michael C. Zacharisen and Jordan N. Fink 86 Pulmonary Eosinophilia, 1779 Jean-François Cordier and Vincent Cottin 87 Hypereosinophilic Syndromes, 1802 Hans-Uwe Simon

Part 12 Allergy and the Skin

93 Food Allergy and Eosinophilic Gastroenteropathies, 1921 Scott H. Sicherer and Hugh A. Sampson 94 Drug Hypersensitivity, 1943 Werner J. Pichler 95 Hypersensitivity to Aspirin and other NSAIDs, 1966 Andrzej Szczeklik, Ewa NiLankowska-Mogilnicka and Marek Sanak 96 Insect Sting Allergy, 1980 Ulrich R. Müller

88 Atopic Dermatitis, 1813 Julia D. Proelss and Thomas Bieber

Part 14 Prevention of Allergic Disease

89 Contact Dermatitis, 1831 David I. Orton and Carolyn M. Willis

97 Prevention of Allergic Disease, 1997 Susan L. Prescott and Bengt Björkstén

90 Urticaria and Angioedema, 1853 Allen P. Kaplan

98 Prevalence of Atopic Disorders in a Developing World: Pitfalls and Opportunities, 2020 Maria Yazdanbakhsh, Taniawati Supali and Laura C. Rodrigues

91 Mastocytosis, 1878 Nataliya M. Kushnir-Sukhov, Dean D. Metcalfe and Jamie A. Robyn

Index

Part 13 Anaphylaxis and Allergy to Food and Drugs 92 Anaphylaxis, 1897 M. Rosario Caballero, Stephen J. Lane and Tak H. Lee

Companion CD-ROM A companion CD-ROM is included at the end of Volume 2 with: • the complete text of both volumes • a full text search function • over 300 of the text figures in full colour

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List of Contributors

Cezmi A. Akdis

Tony R. Bai

Swiss Institute of Allergy and Asthma Research (SIAF) Davos, Switzerland

Professor of Medicine ABC Head, Respiratory Division University of British Columbia; James Hogg iCAPTURE Center St. Paul’s Hospital Vancouver, British Columbia, Canada

Rafeul Alam Professor & Head Division of Allergy & Immunology National Jewish Medical and Research Center; University of Colorado Health Sciences Center Denver, Colorado, USA

Sandra D. Anderson Principal Hospital Scientist Department of Respiratory Medicine & Sleep Medicine Royal Prince Alfred Hospital Camperdown Melbourne, New South Wales, Australia

Jonathan P. Arm Harvard Medical School; Brigham and Women’s Hospital Boston, Massachusetts, USA

Peter J. Barnes Head of Respiratory Medicine Airway Disease Section National Heart and Lung Institute Imperial College London London, UK

Xaver Baur Head of the Zentralinstitut für Arbeitsmedizin und Maritime Medizin; Chair in Occupational Medicine University Medical Center Hamburg-Eppendorf, Germany

Andrew J. Beavil

California National Primate Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Senior Lecturer in Asthma King’s College London MRC & Asthma UK Centre in Allergic Mechanisms of Asthma The Randall Division of Cells & Molecular Biophysics London, UK

Pedro C. Avila

Rebecca L. Beavil

Northwestern University Feinberg School of Medicine Department of Medicine Division of Allergy-Immunology Chicago, Illinois, USA

Postdoctoral Research Fellow King’s College London MRC & Asthma UK Centre in Allergic Mechanisms of Asthma The Randall Division of Cell & Molecular Biophysics London, UK

Mark V. Avdalovic

Claus Bachert Chief of Clinics Head, Upper Airway Research Laboratory University Hospital Ghent Ghent, Belgium

Thomas Bieber Professor and Chair Department of Dermatology & Allergy University of Bonn Bonn, Germany

Sanjeev Bagga Institute of Environment and Health Cranfield University Cranfield, UK

Bengt Björkstén The National Institute of Environmental Medicine/IMM

Division of Physiology Karolinska Institutet Stockholm, Sweden

Jean Bousquet CHU Montpellier Service des Maladies Respiratoires Hôpital Arnaud de Villeneuve Montpellier, France

Peter Bradding Professor of Respiratory Medicine University of Leicester Glenfield Hospital Leicester, UK

Alan R. Buckpitt California National Primate Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

A. Wesley Burks Professor and Chief Pediatric Allergy and Immunology Duke University Medical Center Durham, North Carolina, USA

Peter Burney Professor of Respiratory Epidemiology and Public Health National Heart and Lung Institute Imperial College of Science, Technology and Medicine London, UK

M. Rosario Caballero King’s College London; Guy’s Hospital London, UK

Virginia L. Calder Department of Clinical Ophthalmology Institute of Ophthalmology University College London London, UK

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List of Contributors

G. Walter Canonica Full Professor and Director of Allergy & Respiratory Diseases Clinic Department of Internal Medicine University of Genoa Genoa, Italy

Gaetano Caramori Centro di Ricerca su Asma e BPCO University of Ferrara Ferrara, Italy

Martin D. Chapman INDOOR Biotechnologies Inc. Charlottesville, Virginia, USA

Reference Center for Rare Pulmonary Diseases; Claude Bernard University Department of Respiratory Medicine Hospices Civils de Lyon Louis Pradel University Hospital Lyon, France

Respiratory Medicine Unit Department of Medicine University of Cambridge School of Clinical Medicine Addenbrooke’s and Papworth Hospital Cambridge, UK

Glenn Cruse

Department of Medicine University of Cambridge School of Clinical Medicine Addenbrooke’s Hospital Cambridge, UK

Postgraduate Research Student Institute for Lung Health University of Leicester Medical School Department of Infection, Immunity and Inflammation Division of Respiratory Medicine Glenfield Hospital Leicester, UK

Leukocyte Biology Section National Heart and Lung Institute Imperial College London London, UK

Alison M. Condliffe Respiratory Medicine Unit Department of Medicine University of Cambridge School of Clinical Medicine Addenbrooke’s and Papworth Hospital Cambridge, UK

William O.C. Cookson The National Heart and Lung Institute Imperial College London London, UK

Jean-François Cordier Professor of Respiratory Medicine University of Lyon; Head, Reference Center for Rare Pulmonary Diseases; Claude Bernard University Department of Respiratory Medicine Hospices Civils de Lyon Louis Pradel University Hospital Lyon, France

Paul Cullinan Consultant Physician Department of Occupational and Environmental Medicine Royal Brompton Hospital London, UK

Graeme P. Currie Department of Respiratory Medicine Aberdeen Royal Infirmary Aberdeen Scotland, UK

Adnan Custovic University of Manchester North West Lung Centre Wythenshawe Hospital Manchester, UK

Gennaro D’Amato Director Division of Respiratory and Allergic Diseases Department of Respiratory Diseases High Speciality Hospital “A. Cardarelli” Napoli, Italy

Chris Corrigan Allergy and Respiratory Science King’s College London School of Medicine; Department of Asthma, Allergy and Respiratory Science Guy’s Hospital London, UK

Anuk M. Das Immunobiology Centocor Radnor, Pennsylvania, USA

W. Edward Davis Vincent Cottin Professor of Respiratory Medicine University of Lyon;

Head, Allergy Department University Hospital of Montpellier and Hôpital Arnaud de Villeneuve Montpellier, France

Alexander C. Drew Andrew S. Cowburn

Edwin R. Chilvers

Peter Clark

Pascal Demoly

Ochsner Clinic Foundation Department of Allergy New Orleans, Louisiana, USA

Department of Allergy, Immunology and Respiratory Medicine Alfred Hospital Melbourne, Victoria, Australia

Catherine Duez Chargée de Recherche Inserm Institut Pasteur de Lille Lille, France

Stephen R. Durham Head, Section of Allergy and Clinical Immunology National Heart and Lung Institute Faculty of Medicine Imperial College London London, UK

Jean Emberlin Director National Pollen and Aerobiology Research Unit Institute of Health University of Worcester Worcester, UK

Ed Erin National Heart and Lung Institute Clinical Studies Unit Royal Brompton Hospital London, UK

Michael J. Evans California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Leonardo M. Fabbri Full Professor of Respiratory Medicine University of Modena and Reggio Emilia Modena, Italy

Michelle V. Fanucchi California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Sophie P. Farooque MRC & Asthma UK Centre in Allergic Mechanisms of Asthma King’s College London Guy’s Hospital London, UK

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List of Contributors

David J. Fear

Arturo Genovese

Trevor T. Hansel

Division of Allergy, Asthma and Lung Biology King’s College London London, UK

Professor of Medicine Division of Clinical Immunology and Allergy University of Naples Federico II Naples, Italy

Medical Director National Heart & Lung Institute Clinical Studies Unit Imperial College Royal Brompton Hospital London, UK

Jordan N. Fink Medical College of Wisconsin Departments of Pediatrics and Medicine Milwaukee, Wisconsin, USA

Axel Fischer Otto-Heubner-Centre Pneumology and Immunology Charité School of Medicine Free University Berlin and Humboldt-University Berlin Berlin, Germany

Laurel J. Gershwin California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Mark A. Giembycz Department of Pharmacology & Therapeutics Institute of Infection, Immunity and Inflammation Faculty of Medicine University of Calgary Calgary, Alberta, Canada

Susan Foley Meakins-Christie Laboratories McGill University Montreal, Quebec, Canada

Paul S. Foster Centre for Asthma and Respiratory Diseases School of Biomedical Sciences University of Newcastle Newcastle, New South Wales, Australia

Howard Fox Novartis Horsham Research Centre Horsham West Sussex, UK

Francesca Franco Section of Respiratory Disease Department of Oncology, Hematology and Respiratory Disease University of Modena and Reggio Emilia Modena, Italy

Cathryn C. Hassett

William G. Glass Immunobiology Centocor Radnor, Pennsylvania, USA

Catherine Hawrylowicz

Hannah J. Gould Professor Randall Division of Cell & Molecular Biophysics Division of Allergy, Asthma and Lung Biology King’s College London London, UK

David A. Groneberg Department of Respiratory Medicine Hannover Medical School Hannover, Germany

MRC & Asthma UK Centre in Allergic Mechanisms of Asthma King’s College London London, UK

Ricki M. Helm Project Team Manager Research Support Center Office of the Vice Chancellor for Academic Affairs and Research Administration Little Rock, Arkansas, USA

Nicholas J. Gross

C. Garren Hester

Pulmonary and Critical Care Division Hines VA Hospital Hines, Illinois, USA

Laboratory Research Analyst II Duke University Medical Center Durham, North Carolina, USA

Avinash Gurbaxani

Stuart J. Hirst

Moorfields Eye Hospital London, UK

MRC & Asthma UK Centre in Allergic Mechanisms of Asthma King’s College London London, UK

Belinda J. Hales Michael M. Frank

Institute of Environment and Health Cranfield University Cranfield, UK

Tulane University School of Medicine Department of Medicine Section of Clinical Immunology, Allergy and Rheumatology New Orleans, Louisiana, USA

Wytske Fokkens Department of Otorhinolaryngology Head and Neck Surgery Academic Medical Center Amsterdam, The Netherlands

Paul Harrison

Samuel L. Katz Professor of Pediatrics, Medicine and Immunology Duke University Medical Center Durham, North Carolina, USA

Senior Research Officer University of Western Australia Centre for Child Health Research Telethon Institute for Child Health Research Subiaco, Western Australia, Australia

Arthur N. Freed

Qutayba Hamid

Director, Department of Research Sinai Hospital of Baltimore Baltimore, Maryland, USA

Meakins-Christie Laboratories McGill University Montreal, Quebec, Canada

Anthony J. Frew

Hamida Hammad

Professor of Allergy & Respiratory Medicine Department of Respiratory Medicine Brighton General Hospital Brighton, UK

Postdoctoral Fellow University of Ghent Laboratory of Immunoregulation Ghent, Belgium

Simon P. Hogan Division of Allergy and Immunology Department of Pediatrics Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, Ohio, USA

Stephen T. Holgate Allergy & Inflammation Research Division of Infection, Inflammation & Repair School of Medicine Southampton General Hospital Southampton, UK

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List of Contributors

Patrick G. Holt Head Division of Cell Biology TVW Telethon Institute for Child Health Research West Perth, Western Australia, Australia

W. Elliott Horner Principal Consultant Air Quality Sciences Inc. Marietta, Georgia, USA

Peter H. Howarth Reader in Medicine & Hon. Consultant Physician Southampton General Hospital Southampton, UK

Marc Humbert Professor of Respiratory Medicine Université Paris-Sud II Service de Pneumologie Respiratoire Hôpital Antoine-Béclère Clamart, France

James Hunt Postdoctoral Researcher Randall Division of Cell & Molecular Biophysics; Division of Asthma, Allergy & Lung Biology King’s College London London, UK

Wouter Huvenne Upper Respiratory Laboratory ENT-Department University Hospital Ghent Ghent, Belgium

Dallas M. Hyde California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Philip W. Ind Consultant Physician Clinical Head of Department Hammersmith Hospital; Hon. Senior Lecturer National Heart & Lung Institute at Hammersmith London, UK

Royal Brompton Hospital London, UK

Jesse P. Joad California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

John Lacey Deceased

Paige Lacy

Department of Respiratory Medicine Ghent University Hospital Ghent, Belgium

Division of Pulmonary Medicine Department of Medicine University of Alberta Edmonton, Alberta, Canada

Radhika Kajekar California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Michael A. Kaliner Medical Director Institute for Asthma & Allergy Wheaton, Maryland, USA

Allen P. Kaplan The National Allergy, Asthma, and Urticaria Centers of Charleston; Professor, Department of Medicine Medical University of South Carolina Charleston, South Carolina, USA

A. Barry Kay Emeritus Professor of Allergy and Clinical Immunology National Heart and Lung Institute Imperial College London London, UK

Te Piao King Professor Emeritus Rockefeller University New York, New York, USA

Jörg Kleine-Tebbe Allergy & Asthma Center Westend Berlin, Germany

Onn Min Kon

Senior Lecturer in Public Health Respiratory Epidemiology and Public Health Group National Heart and Lung Institute Imperial College London London, UK

National Heart and Lung Institute Clinical Studies Unit Royal Brompton Hospital London, UK

Nataliya M. Kushnir-Sukhov Emeritus Professor of Lung Pathology Senior Research Investigator Honorary Consultant Imperial College London

Johns Hopkins University Johns Hopkins School of Medicine Johns Hopkins Asthma and Allergy Center Baltimore, Maryland, USA

Guy F. Joos

Debbie L. Jarvis

Peter K. Jeffery

Kevin Kwong

Laboratory of Allergic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland, USA

Bart N. Lambrecht Professor of Pulmonary Medicine Laboratory of Immunoregulation & Mucosal Immunology University Hospital Ghent Ghent, Belgium

Stephen J. Lane Consultant Respiratory Physician & Allergist Adelaide & Meath Hospital Tallaght Dublin, Ireland

Mark Larché Professor of Medicine, Canada Research Chair Clinical Immunology & Allergy Department of Medicine McMaster University Hamilton, Ontario, Canada

Shawnessy D. Larson California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Geoffrey J. Laurent Director Centre for Respiratory Research Department of Medicine Rayne Institute University College London London, UK

Tak H. Lee Professor King’s College London; Director MRC & Asthma UK Centre in Allergic Mechanisms of Asthma Guy’s Hospital London, UK

Samuel B. Lehrer Professor of Medicine Tulane University School of Medicine Department of Medicine

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List of Contributors

Section of Clinical Immunology, Allergy and Rheumatology New Orleans, Louisiana, USA

Estelle Levetin The University of Tulsa Department of Biological Science Tulsa, Oklahoma, USA

Susan Lightman Professor of Clinical Ophthamology Moorfields Eye Hospital London, UK

Brian J. Lipworth Asthma & Allergy Research Group Ninewells Hospital and Medical School Dundee, Scotland, UK

Clare M. Lloyd Leukocyte Biology Section National Heart and Lung Institute Faculty of Medicine Imperial College London London, UK

Iain A.M. MacPhee Senior Lecturer in Renal Medicine St. George’s, University of London London, UK

Piero Maestrelli Professor of Occupational Medicine Department of Environmental Medicine and Public Health University of Padova Padova, Italy

Hans-Jørgen Malling Allergy Clinic National University Hospital Copenhagen, Denmark

Gianni Marone Division of Clinical Immunology and Allergy Center for Basic and Clinical Immunology Research (CISI) University of Naples Federico II School of Medicine Naples, Italy

University of California Davis, California, USA

St George’s Hospital London, UK

Miriam F. Moffatt

Robyn E. O’Hehir

Reader in Human Genetics Molecular Genetics Group National Heart and Lung Institute Imperial College London London, UK

Professor and Director Department of Allergy, Immunology and Respiratory Medicine Alfred Hospital and Monash University Melbourne, Victoria, Australia

Rafael I. Monsalve

Thomas G. O’Riordan

Group Leader Allergen Chemistry and Biotechnology Department Research and Development ALK-ABELLÓ Madrid, Spain

Associate Professor of Clinical Medicine and Public Health Department of Medicine State University of New York at Stony Brook Stony Brook, New York, USA

Redwan Moqbel

David I. Orton

Division of Pulmonary Medicine Departments of Medicine and Medical Microbiology and Immunology University of Alberta Edmonton, Alberta, Canada

Consultant Dermatologist Environmental & Contact Dermatitis Unit Department of Dermatology and Allergy Amersham Hospital Amersham, UK

Ulrich R. Müller

Reinhard Pabst

Allergy Division Medical Department Spital Bern Ziegler Bern, Switzerland

Head, Functional & Applied Anatomy Medical School of Hannover Hannover, Germany

Michelle J. Muessel

Giovanni Passalacqua

Research Associate Glenfield Hospital Department of Respiratory Medicine Leicester, UK

Research Professor Allergy and Respiratory Diseases Department of Internal Medicine University of Genoa Genoa, Italy

Lynne A. Murray

Ian D. Pavord

Manager of Pharmacology Promedior Inc Malvern, Pennsylvania, USA

Institute for Lung Health Department of Respiratory Medicine and Thoracic Surgery Glenfield Hospital Leicester, UK

Anthony J. Newman Taylor Head, National Heart and Lung Institute Faculty of Medicine Imperial College London London, UK

Ewa Ni-ankowska–Mogilnicka Department of Medicine Jagiellonian University School of Medicine Kraków, Poland

Dean D. Metcalfe

Wolfgang A. Nockher

Laboratory of Allergic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland, USA

Department of Clinical Chemistry and Molecular Diagnostics Medical Faculty Philipps-Universität Marburg Marburg, Germany

Lisa A. Miller

Yee-Ean Ong

California National Primate Research Center and Schools of Veterinary Medicine and Medicine

Consultant Physician and Honorary Senior Lecturer

James E. Pease Leukocyte Biology Section National Heart and Lung Institute Faculty of Medicine Imperial College London London, UK

Simon Phipps Centre for Asthma and Respiratory Diseases School of Biomedical Sciences University of Newcastle Newcastle, New South Wales, Australia

Werner J. Pichler Division of Allergology Clinic for Rheumatology and Clinical Immunology/Allergology, University of Bern Bern, Switzerland

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List of Contributors

Emily M. Pieczarka

Jamie A. Robyn

Edward S. Schelegle

California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Laboratory of Allergic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland, USA

California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Kent E. Pinkerton California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Anaïs Pipet Exploration des allergies Hôpital Arnaud de Villeneuve University Hospital of Montpellier Montpellier, France

Robert P. Schleimer Laura C. Rodrigues Infectious Disease Epidemiology Unit London School of Hygiene and Tropical Medicine London, UK

Duncan F. Rogers Thoracic Medicine National Heart & Lung Institute Imperial College London London, UK

Thomas A.E. Platts-Mills Professor Emeritus Asthma and Allergic Diseases Center University of Virginia Health System Charlottesville, Virginia, USA

Jennifer M. Rolland Associate Professor and Deputy Head Department of Immunology Monash University Melbourne, Victoria, Australia

Charles G. Plopper Professor Emeritus, California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Anna Pomés INDOOR Biotechnologies Inc. Charlottesville, Virginia, USA

Stéphanie Pouwels-Frys Department of Pneumology and Immunoallergology University Hospital Lille, France

Helene F. Rosenberg Laboratory of Allergic Diseases National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda, Maryland, USA

Marc E. Rothenberg Division of Allergy and Immunology Department of Pediatrics Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine Cincinnati, Ohio, USA

Ian Sabroe Susan L. Prescott School of Paediatrics and Child Health Princess Margaret Hospital Perth, Western Australia, Australia

Academic Unit of Respiratory Medicine School of Medicine and Biological Sciences University of Sheffield; Royal Hallamshire Hospital Sheffield, UK

Neil B. Pride Emeritus Professor of Respiratory Medicine and Senior Research Investigator National Heart and Lung Institute Imperial College London, UK

Julia D. Proelss Senior House Officer Department of Dermatology and Allergy University of Bonn Bonn, Germany

Hugh A. Sampson Professor of Pediatrics and Immunobiology Dean for Translational Biomedical Sciences Chief of Pediatric Allergy and Immunology Mount Sinai School of Medicine New York, New York, USA

Marek Sanak Department of Medicine Jagiellonian University School of Medicine Kraków, Poland

Harald Renz Professor and Chairman Department of Clinical Chemistry Philipps University Marburg Marburg, Germany

Andrew Saxon Professor of Medicine UCLA School of Medicine Los Angeles, California, USA

Northwestern University Feinberg School of Medicine Department of Medicine Division of Allergy-Immunology Chicago, Illinois, USA

Seif O. Shaheen Clinical Senior Lecturer in Epidemiology, and Asthma UK Senior Research Fellow Respiratory Epidemiology & Public Health Group National Heart and Lung Institute Imperial College London London, UK

Dominick E. Shaw Specialist Registrar Department of Respiratory Medicine Nottingham City Hospital Nottingham, UK

Scott H. Sicherer Associate Professor of Pediatrics The Elliot and Roslyn Jaffe Food Allergy Institute Division of Allergy and Immunology Department of Pediatrics Mount Sinai, School of Medicine New York, New York, USA

Hans-Uwe Simon Department of Pharmacology University of Bern Bern, Switzerland

F. Estelle R. Simons Department of Pediatrics & Child Health Department of Immunology Faculty of Medicine University of Manitoba Winnipeg, Manitoba, Canada

Keith J. Simons Faculty of Pharmacy Department of Pediatrics & Child Health Faculty of Medicine University of Manitoba Winnipeg, Manitoba, Canada

Angela Simpson Senior Lecturer Respiratory Research Group Education and Research Centre University Hospital of South Manchester NHS Foundation Trust Manchester, UK

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Rebecca Slack

Wayne R. Thomas

Laura S. Van Winkle

Institute of Environment and Health Cranfield University Cranfield, UK

University of Western Australia Centre for Child Health Research Telethon Institute for Child Health Research Subiaco, Western Australia, Australia

California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Catherine Thornton

Ulrich Wahn

Senior Lecturer in Newborn Immunity Institute of Life Science School of Medicine Swansea University Swansea, UK

Professor and Director Department of Pediatric Pneumology and Immunology Charité-University Medicine Berlin, Germany

Gerald C. Smaldone Chief, Pulmonary, Critical Care and Sleep Medicine Department of Medicine State University of New York at Stony Brook Stony Brook, New York, USA

Suzette M. Smiley-Jewel

Stephen J. Till

California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Clinician Scientist Fellow (The Health Foundation) Allergy and Clinical Immunology Imperial College London London, UK

Sanchaita Sonar

Isabelle Tillie-Leblond

Department of Clinical Chemistry and Molecular Diagnostics Medical Faculty Philipps-Universität Marburg Marburg, Germany

Giuseppe Spadaro Associate Professor of Medicine Division of Clinical Immunology and Allergy University of Naples Federico II Naples, Italy

Steven O. Stapel Head, Department of Allergy Diagnostics Sanquin Diagnostic Services Amsterdam, The Netherlands

Taniawati Supali Department of Parasitology University of Indonesia Jakarta, Indonesia

Michael F. Sutherland Department of Allergy, Immunology and Respiratory Medicine Alfred Hospital and Monash University Melbourne, Victoria, Australia

Brian J. Sutton Professor of Molecular Biophysics Randall Division of Cell & Molecular Biophysics; Division of Asthma, Allergy & Lung Biology King’s College London London, UK

Department of Pneumology and Immunoallergology University Hospital Lille, France

Andrew J. Wardlaw Institute for Lung Health Department of Respiratory Medicine Glenfield Hospital Leicester, UK

John O. Warner Department of Paediatrics Division of Medicine Imperial College London London, UK

André-Bernard Tonnel Department of Pneumology and ImmunoAllergology A. Calmette Hospital Lille, France

Anne Tsicopoulos Directeur de Recherche Inserm Institut Pasteur de Lille Lille, France

Bradley J. Undem Johns Hopkins University Johns Hopkins School of Medicine Johns Hopkins Asthma and Allergy Center Baltimore, Maryland, USA

Rudolf Valenta Christian Doppler Laboratory for Allergy Research Division of Immunopathology Department of Pathophysiology Center for Physiology and Pathophysiology Medical University of Vienna Vienna General Hospital Vienna, Austria

Paul Van Cauwenberge Upper Respiratory Laboratory Department of Otorhunolaryngology Ghent University and Ghent University Hospital Ghent, Belgium

Laurianne G. Wild Ochsner Clinic Foundation Department of Allergy New Orleans, Louisiana, USA

Timothy J. Williams Leukocyte Biology Section National Heart and Lung Institute Faculty of Medicine Imperial College London London, UK

Carolyn M. Willis Research Director Department of Dermatology Amersham Hospital Amersham, UK

Saffron A.G. Willis-Owen Postdoctoral Research Associate National Heart and Lung Institute Imperial College London London, UK

John W. Wilson Department of Allergy, Immunology and Respiratory Medicine Alfred Hospital and Monash University Melbourne, Victoria, Australia

Ronald van Ree Andrzej Szczeklik Professor and Chairman Department of Medicine Jagiellonian University School of Medicine Kraków, Poland

Head, Allergy Research Department of Experimental Immunology Academic Medical Center University of Amsterdam Amsterdam, The Netherlands

Judith A. Woodfolk Associate Professor Asthma and Allergic Diseases Center University of Virginia Health System Charlottesville, Virginia, USA

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List of Contributors

Reen Wu

Maria Yazdanbakhsh

Michael C. Zacharisen

California National Primate Research Center and Schools of Veterinary Medicine and Medicine University of California Davis, California, USA

Department of Parasitology Leiden University Medical Center Leiden, The Netherlands

Medical College of Wisconsin Departments of Pediatrics and Medicine Milwaukee, Wisconsin, USA

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Foreword

The second edition of Allergy and Allergic Diseases is a timely, all-encompassing two-volume text that covers in detail the basic science at the heart of the specialty and its major and minor clinical components. The pathobiology links back to the basic sciences through both clinical findings and translational research. There is insightful emphasis not only on pathogenesis, but also on underlying genetic and environmental factors uncovered through genomics and epidemiology, respectively. Jean Bousquet of Montpellier, France; Patrick Holt of Perth, Australia; and Allen Kaplan of Charleston, USA, now join Barry Kay, the founding editor. The differing interests and expertise of this distinguished editorial group and their geographic diversity provides unusual editorial capacity in basic and clinical science. The figures, photographs, tables and diagrams reflect their editorial wisdom in their clarity and value to the text. Similarly, the sharing of editorial responsibilities has not only resulted in a thoughtful selection of the subject matter but

also in a superb selection of authors to assure that each presentation has depth and balance. These authors are international in distribution and widely acknowledged for their comprehension of their subject. Subjects are often covered in several chapters so as to provide history, preclinical knowledge, and clinical meaning in terms of pathobiology and intervention. For example, IgE is addressed from history, to crystal structure, to effects of indoor and outdoor pollution, to neutralization by monoclonal antibodies; leukotrienes are considered from history, to chemical and biological properties, to small molecule inhibitors; eosinophils are covered from discovery, to function, to monoclonal antibody neutralization of the chemokines/ cytokines that regulate function; and the pathobiology of many conditions is presented from in situ findings of cell types, pathways, and soluble effectors through analysis of animal models and the human condition. K. Frank Austen MD Harvard Medical School

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Preface

The scope and breadth of allergy and allergic diseases has increased enormously since the first edition of this textbook was published in 1997. Our present aim, as before, is to provide a detailed, up-to-date and authoritative source of information on both the scientific basis and clinical aspects of our subject. Barry Kay is delighted to be joined by Allen Kaplan, Jean Bousquet and Patrick Holt as co-editors of this two-volume work. We have attempted to cover all important aspects of the field. This includes growing areas on the immunological basis of allergy, particularly regulatory T cells, environmental factors in IgE production and innate immunity, as well as up to date accounts of the cells and mediators of allergic inflammation. Furthermore, the sections on pharmacology, physiology, allergens and animals models have all been fully revised. In Volume 2, the clinical section, we have dealt in detail with allergic conjunctivo-rhinitis, asthma, eosinophilic disorders, allergy and the skin, anaphylaxis, food and drug allergy and allergy prevention. We have also addressed current approaches to treatment with emphasis on internationally agreed guidelines and there is a substantial section on allergen immunotherapy, including recent advances. There are of course other textbooks in the field of “Allergy and Allergic Diseases”, many from the USA. However the present work, like the first edition, attempts to give an international perspective on the principles and practice of allergy and this is reflected in our worldwide authorship. As before, we have endeavoured, where possible, to adhere to the correct “allergy nomenclature” as urged by the late Professor Robin Coombs, who kindly wrote the Foreword to the first edition. As explained in Chapter 1 (Allergy and Concepts: History and Concepts) it has become increasingly difficult to use the term “allergy” in its original sense as conceived by Clemens Von Pirquet. However Von Pirquet’s concept of “altered reactivity” to describe a true allergic response, as opposed to intolerance or pseudo-allergy, remains as valid now as it did in 1906. The burden of allergic disease is sometimes underestimated. In addition to the obvious health effects, allergic disorders can make social interactions difficult as even simple everyday activities can pose a major health risk (House of Lords Science and Technology Committee Report, September 2007). On a

national scale, the treatment of allergy patients forms a significant part of the work of the health care providers and, in Western societies, the number of allergy-related work absences represents a large cost to the economy. Allergies affect all aspects of a patient’s life. Hayfever symptoms disrupt children’s sleep and often impair their performance at school and asthma has been associated with school absenteeism. Eating out can be highly stressful for patients with food anaphylaxis, especially in teenagers and young adults who may not want to draw attention to their condition. Allergy patients often find it difficult to live a normal life. This is especially apparent in children, where special care has to be taken whilst engaging in everyday activities which in turn induces anxiety and impairs the quality of life. In England approximately 3 million people (6% of the population) each year consult their primary care physician with conditions related to allergy and 72.6 million community prescriptions are issued (Department of Health 2006; Royal College of Physicians of London 2003). This included 38.9 million prescriptions for asthma, 4.5 million for nasal allergies and 20.4 million prescriptions for eczema. This amounted to a cost of £0.9 billion, which represented 11 per cent of the total drugs budget (compared to 27 per cent spent on cardiovascular diseases and 8 per cent on gastro-intestinal disorders). The prevalence of allergic disease has markedly increased over recent years. In the UK, by 2004, the scale of the “allergy epidemic” was such that 39 per cent of children and 30 per cent of adults had been diagnosed with one or more of asthma, eczema and hayfever, and 38 per cent of children and 45 per cent of adults had experienced symptoms of these disorders in the preceding 12 months (Gupta et al. 2004). In fact by the end of 2005, approximately one in nine people had a recorded diagnosis of “any allergic disease,” including any one of asthma, hayfever, eczema, anaphylaxis or peanut allergy. This figure represented a 28% increase in prevalence over a four year period. Most alarming has been the increase in food anaphylaxis, particularly peanut allergy. Thus there was a 117% increase in the prevalence of peanut allergy from 2001 to 2005, and it is estimated that 25,700 people in England are affected. Asthma, eczema and allergic rhinitis often occur together and this comorbidity, or multiple allergic disease,

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Preface often requires multiple referrals to different organ specialists. More than two million people in England are estimated to suffer from multiple allergic diseases, with an increase in the prevalence rate of 49% cent between 2001 and 2005. (QRESEARCH and The Information Centre for health and social care). The increase in allergy and atopy in the United Kingdom has been mirrored in many other developed countries in Western Europe, the United States, Canada, Australia and New Zealand. Until a few years ago developing countries in Africa and the Middle East reported a relatively low prevalence of allergy (although this situation is rapidly changing as a result of “Western Modernisation”). Nevertheless these different patterns of prevalence represented one of the origins of the “hygiene hypothesis”. Several chapters deal with aspects of the hygiene hypothesis. These include the protective effects of early childhood infection, the influence of bowel flora, farming and the proximity to animals and a “traditional” lifestyle and other factors which may explain rising trends in allergy such as changes in diet, allergen exposure, atmospheric pollution and tobacco smoke. Although the hygiene hypothesis has stimulated much debate interventions designed to reverse the rising prevalence have met with limited success and these attempts at primary prevention are also covered in the appropriate chapters. Producing a book of this size has been an enormous task but we have been very fortunate to have had critical comments from many colleagues on all the individual chapters submitted. Several authors have also acted as reviewers of other contributors’ chapters and for this we are most grateful. In particular we would like to thank Dr Graham Devereux, Prof Cezmi Akdis, Dr Peter Clark, Prof Tony Segal, Dr Bernhard Gibbs, Dr James Pease, Dr Richard Costello, Dr Lars-Olaf Cardell, Prof Andrew Wardlaw, Prof Sergio Bonini, Dr Christian Virchow, Prof Harald Renz, Dr Andreas Nockher, Prof Guy Joos, Dr Domenico Spina, Prof David Groneberg, Dr Ray Penn, Dr Sussan Nourshargh, Prof Tim Williams, Dr Paul Cullinan, Prof Clare Lloyd, Prof Tony Frew, Dr Moises

Calderon, Dr Veronica Varney, Dr Andrew Menzies-Gow, Dr Yee-Ean Ong, Dr Charles McSharry, Prof Duncan Geddes, Dr Nataliya Kushnir, Dr Shuaib Nasser, Prof John Warner. We are also grateful to Dr K. Frank Austen for kindly writing a Foreword and for his general encouragement during the preparation of this work. Wiley-Blackwell have given us constant help and guidance with the production of the textbook and we would like to thank Maria Khan and her team for the huge effort involved in seeing this task through to a successful completion. Finally we are particularly grateful to Miss Jennifer Mitchell, the Editorial Assistant, without whom the publication of “Allergy and Allergic Diseases” would not have been possible. Her untiring efforts, commitment and attention to detail cannot be overestimated. A. Barry Kay Allen P. Kaplan Jean Bousquet Patrick G. Holt

References Department of Health. July 2006. Review of Services for Allergy. (www.dh.gov.uk/publications). Royal College of Physicians of London. 2003. Allergy: the unmet need. QRESEARCH and The Information Centre for health and social care, Primary care epidemiology of allergic disorders: analysis using QRESEARCH database 2001–2006, 2007, pp. 69–70. (see also http://www.ic.nhs.uk/ work-with-us/research/qresearch/primary-care-epidemiologyof-allergic-disorders:-analysis-using-qresearch-database-20012006) Gupta et al. (2004) Burden of allergic disease in the UK: secondary analyses of national databases. Clinical and Experimental Allergy 34, 520–526. House of Lords Science and Technology Committee Report, September 2007 Allergy (http://www.publications.parliament.uk/pa/ ld200607/ldselect/ldsctech/166/166i.pdf)

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Immunology of the Allergic Response

Allergy and Allergic Diseases, 2nd edition. Edited by A.B. Kay, A.P. Kaplan, J. Bousquet, P.G. Holt. © 2008 Blackwell Publishing. ISBN: 978-1-405-15720-9.

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Allergy and Hypersensitivity: History and Concepts A. Barry Kay

Summary The study of allergy (“allergology”) and hypersensitivity, and the associated allergic diseases, have their roots in the science of immunology but overlap with many disciplines including pharmacology, biochemistry, cell and molecular biology, and general pathology, particularly the study of inflammation. Allergic diseases involve many organs and tissues such as the upper and lower airways, the skin, and the gastrointestinal tract and therefore the history of relevant discoveries in the field are long and complex. This chapter gives only a brief account of the major milestones in the history of allergy and the concepts which have arisen from them. It deals mainly with discoveries in the 19th and early 20th century, particularly the events which followed the description of anaphylaxis and culminated in the discovery of IgE as the carrier of reaginic activity. An important conceptual landmark that coincided with the considerable increase in knowledge of immunologic aspects of hypersensitivity was the Coombs and Gell classification of hypersensitivity reactions in the 1960s. This classification is revisited and updated to take into account some newer finding on the initiation of the allergic response.

The story of anaphylaxis Untoward reactions to external agents, which were harmless to most people, were recognized even in ancient times. The Egyptian pharaoh Menes (2641 BC) was reported to have died from a wasp (kehb) sting and is thus the first recorded case of anaphylactic shock (although interpretation of hieroglyphics is apparently controversial) (Avenberg & Harper 1980). Hippocrates (born 375 BC) is attributed with the first description of allergy to goats’ milk and cheese and Britannicus (born AD 41) was said to be afflicted by acute allergic reactions to horses. During the 19th century there were a number of reports describing violent or fatal reactions to repeated injections of Allergy and Allergic Diseases, 2nd edition. Edited by A.B. Kay, A.P. Kaplan, J. Bousquet, P.G. Holt. © 2008 Blackwell Publishing. ISBN: 978-1-405-15720-9.

Fig. 1.1 A commemorative postage stamp to mark the discovery of anaphylaxis by Charles R. Richet (1850–1935) and Paul J. Portier (1866–1962).

foreign proteins to various species including dogs (Magendie 1839), guinea pigs (Von Behring 1893, quoted in Becker 1999, p. 876) and rabbits (Flexner 1894, reviewed in Bulloch 1937). However it was not until the discovery of anaphylaxis by Charles R. Richet (1850–1935) and Paul J. Portier (1866– 1962) (Fig. 1.1) in 1901 that the concept of hypersensitivity reactions having a possible immunologic basis was put on a firm scientific footing. The story of the discovery of anaphylaxis is provided by Richet (1913) and goes as follows: During a cruise on Prince Albert of Monaco’s yacht, the Prince suggested to Portier and myself a study of the toxin production of Physalia (the jelly-fish known as Portuguese Man-of-War) found in the South Seas. On board the Prince’s yacht, experiments were carried out proving that an aqueous glycerine extract of the filaments of Physalia is extremely toxic to ducks and rabbits. On returning to France, I could not obtain Physalia and decided to study comparatively the tentacles of Actinaria (sea anemone) . . . While endeavouring to determine the toxic dose (of extracts), we soon discovered that some days must elapse before fixing it; for several dogs did not die until the fourth or fifth day after administration or even later. We kept those that had been given insufficient to kill, in order to carry out a second investigation upon these when they had recovered. At this point an unforeseen event occurred. The dogs which had recovered were intensely sensitive and died a few minutes after the administration of small

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Immunology of the Allergic Response ment in Vienna, he observed that some patients receiving antiserum developed a spectrum of systemic and local symptoms, notably, fever, skin rash, arthropathy, and lymph node swelling, which they termed “serum sickness” (von Pirquet et al. 1905; Wagner & von Pirquet 1968). Earlier accounts in the hospital records described similar symptoms with diphtheria and tetanus antisera. Therefore serotherapy appeared to have produced not only immunity (protection) but also hypersensitivity (or “supersensitivity” as was the then more favored word). Von Pirquet realized that in both situations an external agent had induced some form of “changed or altered reactivity” for which he proposed the term “allergy” from the Greek allos (“other”) and ergon (“work”). The critical passage from his article in Munchener Medizinische Wochenschrift (von Pirquet 1906) is as follows:

Fig. 1.2 Clemens von Pirquet (1874–1929). von Pirquet conceived the term “allergy” (see Appendix). He meant it to include any situation where there was “changed reactivity” irrespective of whether this resulted in immunity or hypersensitivity (see Chapter 2). He also introduced tuberculin skin tests in diagnosis. (From Cohen & Samter 1992, with permission.)

doses. The most typical experiment, that in which the result was indisputable, was carried out on a particularly healthy dog. It was given at first 0.1 mL of the glycerine extract without becoming ill; 22 days later, as it was in perfect health, I gave it a second injection of the same amount. In a few seconds it was extremely ill; breathing became distressful and panting; it could scarcely drag itself along, lay on its side, was seized with diarrhoea, vomited blood and died in 25 minutes.

The vaccinated person behaves toward vaccine lymph, the syphilitic toward the virus of syphilis, the tuberculous patient toward tuberculin, the person injected with serum towards this serum in a different manner from him who has not previously been in contact with such an agent. Yet, he is not insensitive to it. We can only say of him that his power to react has undergone a change.

The problem of reconciling the protective effect of antitoxin with the adverse reactions associated with the administration of foreign agents came to a climax in 1903 with three important discoveries. Firstly, Maurice Arthus (Fig. 1.3) found that repeated injections of horse serum to rabbits

It is difficult to overstate the importance and ramifications of this seminal discovery. Our present understanding of immediate-type hypersensitivity reactions, the antibody involved together with the pharmacologic mediators released, as well as the treatments for allergic diseases which have followed, have their roots in the discovery of anaphylaxis. However the concept that foreign proteins could induce hypersensitivity as well as immune reactions was difficult for early investigators to accept. It was out of this controversy that the word “allergy,” first coined by Clemens von Pirquet (Fig. 1.2) in 1906, was introduced (von Pirquet 1906).

The word “allergy” Von Pirquet and others had noticed that as well as the protective effects of passive immunotherapy with vaccinia and horse antiserum, many patients experienced adverse reactions. Thus the word “allergy” arose from his attempts to reconcile the two apparently contradictory phenomena of immunity and hypersensitivity. Working with Bela Schick in the scarlet fever wards of Escherich’s Paediatric Depart-

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Fig. 1.3 Nicholas-Maurice Arthus (1862–1945). The Arthus reaction is an experimental localized acute necrotizing vasculitis first described as local anaphylaxis. (From Cohen & Samter 1992, with permission.)

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produced hypersensitivity reactions that were antigenically specific, so challenging the currently held view that these reactions to foreign proteins were essentially toxic (Arthus 1903). Second, von Pirquet and Bela Schick (1905) observed that a child who had received a second injection of antitoxin had clinical symptoms the same day, though, on the first injection, given some time previously, her clinical symptoms appeared only after the tenth day. As a result they hypothesized that “the time of incubation is the time necessary for the formation of these antibodies.” These two observations, together with the third discovery by Hamburger and Moro (1903) of precipitating antibody in the blood during serum sickness, led von Pirquet to speculate that the diseaseproducing factor produces symptoms only when it had been changed by antibody. Thus, although not explicitly stating so in his original definition, in a later work von Pirquet (1911) made it clear that he intended the term “allergy” to be applied only to immunologic reactions. Von Pirquet also suggested that the word “allergen” should be used to describe the agent which, after one or more applications, induced this changed reactivity. Therefore von Pirquet had brilliantly laid the foundation for the modern science of immunology by appreciating that a foreign substance “sensitizes” the organism in a way that produces a different response on the second and subsequent administration. Unfortunately with the passage of time the word “allergy” became corrupted and is now used incorrectly and with a limited usage, i.e., to describe hypersensitivity mechanisms that are operative transiently, or persistently, in a limited group of conditions, particularly the IgE-mediated allergic diseases. Such a restricted meaning was not von Pirquet’s original intent and in fact it misses his point by, in a sense, merely substituting “allergy” for “hypersensitivity” (Kay 2006).

The “corruption” of allergy So why has the term “allergy” become misused, and are “allergists” themselves largely to blame? As Elmer Becker (1999) described in his erudite paper “Elements of the history of our present concepts of anaphylaxis, hay fever and asthma,” part of the confusion lay in attempts to “classify” allergy. Doerr (1914) initially divided allergy into hypersusceptibility to antigenic substances as well as altered reactivity to nonantigens in which he included morphine addiction. By 1926 Arthur Fernandez Coca (Fig. 1.4) advised the abandonment of the term “allergy” on the basis of its then numerous conflicting meanings. More confusingly he did not consider “anaphylaxis” as part of allergy because it was a phenomenon in which the antigen–antibody reaction was established. Instead Coca classified under “allergy” all those conditions where he considered an antibody mechanism had not been demonstrated, e.g., drug “idiosyncrasies,” serum sickness in

Allergy and Hypersensitivity: History and Concepts

Fig. 1.4 Arthur Fernandez Coca (1875–1959). Coca introduced the term “atopy” (now recognized as IgE-mediated hypersensitivity). (From Cohen & Samter 1992, with permission.)

man, and hay fever. In fact the view that allergy was all forms of hypersensitivity except anaphylaxis was to persist until the 1940s. By this time a medical subspecialty practiced by clinicians diagnosing and treating hay fever, asthma, serum sickness, drug reactions, etc. and involving treatment with desensitization injections was already then well established. As Becker (1999) explained: [clinicians] desired a brief, convenient, not too limiting group of terms describing what their specialty was and what it was about. As a consequence, they turned more and more to the use of “allergy”, “allergic”, etc. so that these terms became embedded in clinical usage. This was recognized by the editors of the Journal of Allergy when in the first issue they stated, “We believe that it [allergy] does not possess an established meaning in scientific usage. [They then quoted Karsner and Ecker (1921) as the source for this belief.] However, the term is very generally employed by clinicians who apply it to conditions of specific hypersensitiveness exclusive of anaphylaxis in lower animals . . . it seems the title of this journal corresponds to current medical usage.”

In hindsight the Journal of Hypersensitivity and Hypersensitivity Disorders would have been more historically correct and still have served the clinicians’ purpose. In the 1960s Robin Coombs (Fig. 1.5) and Philip Gell attempted to restore the term “allergy” to its original meaning (Coombs & Gell 1963). They pointed out that “hypersensitivity” is a general term to describe an adverse clinical reaction to an antigen (or allergen). Such an antigen could be bacterial-derived as in a classical delayed-type hypersensitivity reaction to tuberculo-protein or derived from allergen such as pollen giving rise to IgE-mediated hypersensitivity. They argued that limiting the term “allergy” to any exaggerated

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Immunology of the Allergic Response where an “immunologic” abnormality often cannot be identified (i.e., pseudoallergy). Is anything to be gained by attempting to restore von Pirquet’s word to its original meaning? Probably not. Words lose, or change, their meaning according to custom. Semantics can bury communication. We say that a T cell is “sensitized” but it would be more correct (in the von Pirquet sense) to call it an “allergized” lymphocyte. However this would only cause further confusion and so current imprecision may have to be accepted. What is important is to appreciate that von Pirquet introduced not so much a word but a fundamental biological rule which, arguably, marked the modern approach to immunology.

From reagin to IgE

Fig. 1.5 Robin A. Coombs (1921–2006). Described the antiglobulin (Coombs’) test and, with Philip Gell, classified the hypersensitivity reactions.

response of the immune system to external (antigenic or allergenic) substances was illogical as, by definition, the role of the immune system is to effect immunity. By way of example they pointed out that a deleterious effect to autoantigens should more properly be termed “autoallergic” rather than “autoimmune.” As suggested later (Kay 1997), most of this difficulty is removed if instead of “allergy” we refer to “allergic diseases” and confine the word “allergy” (as von Pirquet originally intended) to the uncommitted biological response. In the individual this uncommitted response may lead to either immunity (which is beneficial) or allergic disease (which is harmful). Therefore, the allergic response, in producing antibodies and specifically reacting (sensitized or allergized) lymphocytes, supplies a common armamentarium for both the reactions of immunity as well as those of the hypersensitivity reactions (allergic diseases). The restricted usage of the term “allergy” (allergic disease) is reflected in the practice of the clinical allergist, where physicians diagnose and treat only selected examples of hypersensitivity states rather than the wide spectrum of immunologic disorders. In many countries this is confined to the IgE-mediated (“atopic”) diseases, e.g., summer hay fever, perennial rhinitis, allergic asthma, allergy to stinging insects, food anaphylaxis, and atopic dermatitis. Other “hypersensitivity diseases” such as celiac disease and contact dermatitis are frequently managed by the relevant organ-based specialist. Furthermore, the clinical allergist also deals with patients whose signs and symptoms mimic those of true allergic disease, i.e., where there is evidence of local or generalized release of histamine and other pharmacologic reagents but

6

In the years after Portier and Richet’s discovery numerous unsuccessful attempts were made to transfer anaphylactic sensitivity to experimental animals using the serum from patients with hay fever or asthma. However in 1919, Ramirez reported that a normal nonallergic recipient of a blood transfusion 2 weeks previously from a donor sensitive to horse serum developed asthma upon being exposed to horses when riding in an open carriage in Central Park, New York (Ramirez 1919). This was the prelude to the classical experiments of Otto Carl Prausnitz and Heinz Küstner (Fig. 1.6) who, in 1921, demonstrated the presence of a tissue-sensitizing antibody in humans. Küstner was a fish-sensitive individual. When his serum was transferred to the skin of Prausnitz, a nonallergic recipient, there was a positive reaction at the skin site when this was subsequently injected with fish extract. They suggested that the sensitizing agent should be called “reagin” because they were not sure it was an antibody (Prausnitz & Küstner 1921). The eventual identification of human reagin as IgE antibody was one of the most important biological discoveries of the 20th century. For some years reaginic activity was believed to be a property of IgA that had been discovered in the 1950s. However, Mary Loveless (Fig. 1.7) in 1964 reported the presence of reagin in an individual who formed no detectable IgA (Loveless 1964). In 1966, Kimshige and Teruko Ishizaka (Fig. 1.8) (Ishizaka & Ishizaka 1966) found that reaginic activity was associated with an immunoglobulin other than IgG and IgA and went on to develop an antiserum which, after absorption with IgG and IgG subclasses, IgA, IgM, and IgD (a new immunoglobulin whose discovery had been reported by Rowe and Fahey in 1965), still precipitated protein in immunoglobulin fractions and also precipitated skin-sensitizing activity. As they stated “the results suggest the presence of a unique immunoglobulin as a carrier of reaginic activity.” The protein was tentatively designated IgE-globulin and in a series of remarkably thorough and brilliant experiments in which they laboriously checked and cross-checked their

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Fig. 1.6 (a) Otto Carl W. Prausnitz (Giles) (1876–1963) and (b) Heinz Küstner (1897– 1963). The passive transfer of immediate skin reactivity by interdermal injection of serum from an allergic patient (“reagin”) is called the Prausnitz–Küstner (or P–K) test. (From Cohen & Samter 1992, with permission.)

(a)

Allergy and Hypersensitivity: History and Concepts

(b)

findings, they finally left no doubt of the validity of their conclusions (reviewed in Ishizaka & Ishizaka 1968). Gunnar Johansson and Hans Bennich (Fig. 1.9) had used a completely different approach to arrive at the same conclusion. They discovered in 1965 (but reported in 1967) a myeloma protein (IgND) which did not belong to any of the four known immunoglobulin classes (Johansson & Bennich 1967). IgND was shown to block skin-sensitizing activity and an antiserum prepared against it had the same specificity as the anti-IgE globulin prepared by Ishizaka. At an international conference held in 1968 it was agreed to call the new class of proteins to which reagins belonged “immunoglobulin E” (IgE) (Bennich et al. 1968).

Fig. 1.8 (Left) Teruko Ishizaka (1926–) and (right) Kimshige Ishizaka (1925–). Characterized reaginic antibody as IgE.

Mediator cells and mediators

Fig. 1.7 Mary Hewitt Loveless (1899–1991). Major contributions to immunotherapy including the identification of blocking antibody (with Robert Cooke) and the use of pure venoms in Hymenoptera allergy. (From Cohen & Samter 1992, with permission.)

The mast cell was discovered by Paul Ehrlich (Fig. 1.10) while still a medical student at the University of Freiburg. He was testing a new basic synthetic dye, “dahlia,” and discovered that some connective tissue cells contained large granules which avidly took up the dye and changed its color to a reddish purple (metachromasia) (Ehrlich 1877). He named these cells “mast” cells, i.e., well-fed cells, giving them this name because he believed the cell granules were products of cell overfeeding.

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Fig. 1.9 (Left) Hans Bennich (1930–) and (right) Gunnar Johansson (1938–). Identification of IgND as IgE immunoglobulin and with L. Wide developed the radioallergosorbent technique (RAST). (Courtesy of Pharmacia, Uppsala, Sweden.)

Fig. 1.10 Paul Ehrlich (1854–1915). An exceptionally creative bioscientist who, along with many other accomplishments, described the side-chain theory of antibody formation and discovered the mast cell and the eosinophil. (From Mahmoud & Austen 1980, with permission.)

James Riley and his coworker Geoffrey West (Fig. 1.11) were the first to provide convincing evidence that tissue mast cells contained histamine (Riley & West 1952, 1953; Riley 1959), and Stuart (1952) reported that anaphylaxis in the mouse, rabbit, and guinea pig was associated with degranulation of mast cells. By approximately the mid-1950s, evidence was

8

available that mast cells contained the mediators histamine, serotonin, and heparin, and that mast degranulation was related to the release of these mediators during anaphylaxis in several species. By that time, moreover, it was also evident that the tissue mast cell was not the only mediator cell. Two years after describing the mast cell, Ehrlich (1879a) noted the presence of cells with metachromatic granules in blood. Although he termed them “blood mast cells,” he proposed that unlike the tissue mast cells the blood cells were derived from bone marrow and were essentially equivalent to the neutrophil and eosinophil, cells he had also described. Later workers renamed the blood mast cell, the basophil. Eosinophils were discovered by Paul Ehrlich in 1879 and so called because they stained with negatively charged dyes including eosin (Ehrlich 1879b). He also suggested that the bone marrow was their site of origin. Some time earlier (1846) an anatomist at Charing Cross Hospital, London (Thomas Wharton-Jones) described granulated blood cells from several species using a simple compound microscope and no staining methods. His drawings indicate that these were almost certainly eosinophils (Wharton-Jones 1846). Histamine was the first substance to be considered an anaphylactic mediator. Sir Henry Dale (Fig. 1.12) demonstrated the presence of histamine in various tissues (Best et al. 1927). It was not until 1932 that others (Gebauer Fuelnegg in Dragstedt’s laboratory, Bartosch working with Feldberg and Spinelli) were finally successful in demonstrating the release of histamine during in vitro and in vivo anaphylaxis (Bartosch et al. 1932; Gebauer-Fuelnegg et al. 1932; Spinelli 1932). Histamine could explain some but not all the features of anaphylaxis. Schild (1936), for example, pointed out that a hundred times more histamine had to be administered to the guinea-pig lung than was released from shocked lungs to have the same effect in contracting the bronchi. This

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Fig. 1.11 (a) James F. Riley (1912–85) and (b) Geoffrey B. West (1916 –). Riley and West discovered that the mast cell granule was the major source of histamine in tissues. (From Cohen & Samter 1992, with permission.)

(a)

Fig. 1.12 Sir Henry H. Dale (1875–1968). Established the role of histamine in anaphylaxis and demonstrated chemical transmission of nerve impulses. (From Cohen & Samter 1992, with permission.)

and many other observations led to the discovery of slowreacting substance of anaphylaxis. Charles Kellaway and Everton Trethewie (Fig. 1.13) reported that the lungs or jejunum of sensitized guinea pigs perfused with antigen released a substance which gave a slow sustained contraction of guinea-pig ileum (Kellaway & Trethewie 1940). This was unlike the sharp short contraction given by histamine and, accordingly, they named the substance slow-reacting substance (SRS). It was not until

Allergy and Hypersensitivity: History and Concepts

(b)

1953 that Walter Brocklehurst confirmed earlier work showing that perfusates of sensitized guinea-pig lungs challenged with antigen gave a slow contraction of guinea-pig ileum even in the presence of an antihistamine in the organ bath (Brocklehurst 1953, 1962). He renamed the agent SRS-A, the slow-reacting substance of anaphylaxis. SRS-A was eventually chemically characterized by Robert Murphy and Bengt Samuelsson (Fig. 1.14) as leukotriene D and E (later reclassified as LTC4, LTD4, and LTE4) (Borgeat & Samuelsson 1979; Murphy et al. 1979). Leukotrienes and many analogs were totally synthesized by E.J. Corey and with K. Frank Austen (Fig. 1.15) the range of biological activities in humans and experimental animals was established (Weiss et al. 1982). (See Clinical and Experimental Allergy Reviews, volume 1(3), November 2001 for the history of leukotrienes.) The story of bradykinin dates back to the experiments of Rocha e Silva, Beraldo, and Rosenfield who added trypsin or snake venom to serum globulin and obtained a peptide which was hypotensive, stimulated smooth muscle, and was also a vasodilator (Rocha e Silva et al. 1949). They termed the peptide “bradykinin” because it gave a contraction of smooth muscle that was somewhat slower than histamine. Beraldo (1950) demonstrated the liberation of bradykinin into the blood of dogs undergoing anaphylaxis. These results over the succeeding 10 years were confirmed and extended to other species.

Asthma and hay fever Asthma (meaning “panting”) has been recognized since ancient times. Moses Maimonides (1135–1204) (Fig. 1.16) wrote a Treatise on Asthma which described the disease and recommended certain lifestyle changes, especially diet, as

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(b)

Fig. 1.14 Bengt I. Samuelsson (1934–). Identification and chemical characterization of the SRS-A leukotrienes. (From Cohen & Samter 1992, with permission.)

beneficial. The first description of occupational asthma was made by Bernardino Ramazzini (1633–1714) (Fig. 1.17). Thomas Willis (1621– 75) (Fig. 1.18) suggested that asthma may have a nervous or neural component, a concept clearly valid to this day. Throughout the 19th and early 20th century asthma was generally believed to be due to spasm of the bronchial musculature either as result of heightened neural pathways or the result of anaphylaxis due to specific sensitization. Although John Floyer (1649–1734) (Fig. 1.19) recog-

10

Fig. 1.13 (a) Charles H. Kellaway (1889–1952) and (b) Everton R. Trethewie (1913–84). First description of a “slowreacting substance of anaphylaxis” causing smooth muscle contraction. (From Cohen & Samter 1992, with permission.)

Fig. 1.15 K. Frank Austen (1928–). Pioneered the biochemistry of mast cell mediator release and the biological properties of leukotrienes.

nized that asthma had many triggers, as well as a hereditary component, it was Henry Hyde Salter (1823–71) (Fig. 1.20) who made the first attempts to understand asthma mechanisms (McFadden 2004). Salter, himself an asthmatic, noticed that asthma attacks could be triggered by “extrinsic” factors such as exercise, cold air, laughing, coughing, sneezing, chemical and mechanical irritants, and animal and vegetable products. He also realized that other causes were operating and suggested that asthma involvedboth neural and vascular

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Fig. 1.16 Moses Maimonides (1135–1204). A prolific writer and author of a famous Treatise on Asthma. (From Cohen & Samter 1992, with permission.)

Fig. 1.17 Bernardino Ramazzini (1633–1714). First description of occupational diseases, in particular baker’s asthma. (From Cohen & Samter 1992, with permission.)

mechanisms and wrote with amazing accuracy, “The inflammation or congestionof the mucous surface appears to be the stimulus that, throughthe nerves of the air tubes, excites the muscular wall to contract.” On the other hand, Sir William Osler(1849–1919) taught that asthma was a psychoneurosis and because of his prestige this opinion was accepted by many physicians for decades after. It was many years before this view was put in perspective.

Allergy and Hypersensitivity: History and Concepts

Fig. 1.18 Thomas E. Willis (1621–75). Recognized the importance of bronchial innervation in asthma; and asthma as a “nervous disease.” (From Cohen & Samter 1992, with permission.)

Fig. 1.19 Sir John Floyer (1649–1734). Recognition of asthma as a multifactorial disease with many triggers (e.g., tobacco smoke, dust, foods, exercise, emotions, environmental factors). First description of heredity in asthma. (From Cohen & Samter 1992, with permission.)

In studies on the pathology of asthma, Ernst von Leyden (1832–1910) (Fig. 1.21) described colorless, needle-like crystals in the sputum of asthmatics and used the observation to “prove asthma was not a nervous disease.” Much earlier Jean Martin Charcot (1825–93) (Fig. 1.21) had noted similar crystals from a leukemic spleen, hence Charcot–Leyden crystals.

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Fig. 1.20 Henry Hyde Salter (1823–71). Description of the various causes of asthma and of cells (now known as eosinophils) in sputum. (From Cohen & Samter 1992, with permission.)

Fig. 1.22 Francis M. Rackemann (1887–1973). Introduced the term “intrinsic asthma.” (From Cohen & Samter 1992, with permission.)

Many clinicians appreciated that asthma had an allergic component but it was Francis Rackemann (1887–1973) (Fig. 1.22) who introduced the term “intrinsic asthma” to describe patients who gave no history of “allergy” and who were skin test negative to common allergens. There was a well-recognized association between asthma and hay fever but it was John Bostock (Fig. 1.23) who in 1819 was the first to describe hay fever as a disease with distinct symptoms. Much later, in 1873, Charles Blackley (Fig. 1.24), in experiments carried out largely on himself, showed that hay

fever was due to pollen. He was the first to use conjunctival and skin tests and also showed a relationship between the number of pollen grains collected in 24 hours on sticky glass slides and the intensity of symptoms. Dunbar thought that hay fever was caused by a toxin in pollen and he produced an “antitoxin” in horses which he called “Pollatin” which was widely used therapeutically. But it was Leonard Noon (1911) (Fig. 1.25) who successfully introduced specific injection therapy for hay fever. After his premature death from tuberculosis, his colleague John

(a)

12

(b)

Fig. 1.21 (a) Jean Martin Charcot (1825–93) and (b) Ernst V. von Leyden (1832–1910). The needle-like (eosinophil-derived) crystals characteristic of asthmatic sputum are named after Charcot and Leyden. (From Cohen & Samter 1992, with permission.)

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Fig. 1.23 John Bostock (1773–1846). Described “catarrhus aestivus,” later recognized as summer hay fever. (From Cohen & Samter 1992, with permission.)

Fig. 1.24 Charles H. Blackley (1820–1900). Identified pollen as a cause of hay fever and devised methods for pollen counts and clinical challenge tests. (From Cohen & Samter 1992, with permission.)

Freeman (Fig. 1.25) continued the work (Freeman 1914) and by 1920 it was a standard method of treatment among allergists. Cooke (Fig. 1.26) and Vander Veer then recognized a hereditary component to hay fever and other conditions associated with sensitization and, later, Coca and Cooke (1923) introduced the term “atopy” (meaning “out of place”)

which they considered to be a peculiarly human condition in which there was hereditary predisposition to produce reagin but which was quite separate from anaphylaxis. Another antibody beside IgE found in human immediatetype allergic disease is the so-called “blocking antibody.” This was discovered by Cooke et al. (1935) in attempting to find

Fig. 1.25 (a) Leonard Noon (1877–1913) and (b) John Freeman (1877–1962). Noon and Freeman introduced the treatment of hay fever by immunization with pollen extracts. (From Cohen & Samter 1992, with permission.)

(a) (b)

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Fig. 1.26 Robert A. Cooke (1880–1960). Introduced the protein nitrogen unit (PNU) for standardization of allergen extracts, realized the role of hereditary factors in hay fever and described allergic drug reactions. Cooke also discovered “blocking antibody” with Mary Loveless. (From Cohen & Samter 1992, with permission.)

out why the injection treatment for hay fever was successful. The concept that the blocking activity was due to binding of the antibody with the allergen was first explicitly stated by Mary Loveless when she found that blocking activity, unlike the skin-sensitizing activity, was heat stabile, withstanding heating at 56°C (Loveless 1940). Blocking antibody seemed to offer a respectable, “scientific” reason for the efficacy of the injection treatment of hay fever, although doubt continues to be expressed as to whether the development of blocking antibody was responsible for the therapeutic relief claimed for the treatment. Many other “allergy landmarks” are listed in chronologic order in Table 1.1. All were crucial observations even though in many instances their full importance was not recognized at the time.

The Coombs and Gell classification of hypersensitivity reactions Until the 1960s there had been difficulties in relating the various models of hypersensitivity in humans and experimental animals, as well allergic diseases themselves, to some form of systematic classification in order to study disease processes in an ordered fashion. Coombs and Gell (1963) described a

14

“classification of allergic reactions which may be deleterious to the tissues and harmful to the host”. This still remains useful to practicing physicians, scientists, and students today because it relates mechanisms to disease entities. Coombs and Gell predicted correctly that in any one disease it was likely that more than one kind of allergic process was involved. They also emphasized the fact that their classification was primarily one of initiating mechanisms and not of the subsequent events or the diseases themselves. The type I–IV hypersensitivity reactions of Coombs and Gell, with some modification in the light of more recent knowledge, are shown in Fig. 1.27. The type I reaction is initiated by allergen or antigen reacting with tissue cells passively sensitized by antibody produced elsewhere, leading to the release of a wide range of biological agents including pharmacologically active substances, proteases, cytokines, and chemokines. These anaphylactic reactions include general anaphylaxis in humans and other animals as well as local manifestations of anaphylaxis, such as that observed in the skin following diagnostic skin-prick tests, and local responses in the respiratory and gastrointestinal tracts. IgE was discovered shortly after the Coombs and Gell classification was published. The high-affinity IgE receptor was discovered some 15 years later (Lanellopoulis et al. 1980; Perez-Montfort et al. 1983) and was a landmark observation leading to the later elucidation of signal transduction pathways involved in IgE-dependent mediator release. More recently it has been shown that in mice antigenspecific light chains can sensitize mast cells for subsequent antigen-induced release of mediators (Kraneveld et al. 2005). This observation is yet to be confirmed in humans. Type II reactions (cytolytic or cytotoxic) are initiated by antibody reacting either with an antigenic component of a tissue cell or with an antigen or hapten intimately associated with these cells. Complement was usually, but not always, necessary to effect the cellular damage. Examples include drug-induced hemolytic anemia in association with chlorpromazine or phenacetin and thrombocytopenic purpura caused by the now obsolete sedative Sedormid. There are many examples of type II reactions outside the province of the clinical allergist, including incompatible blood transfusion reactions and autoallergic (autoimmune) hemolytic anemia. In some instances antibodies against cell-surface receptors have cell-stimulatory (agonist) effects without necessarily being cytotoxic. An example is Graves’ disease (hyperthyroidism, autoallergic thyroiditis) in which IgG antibodies directed against the thyroid-stimulating hormone (TSH) receptor is produced. These have agonist effects by stimulating thyroid hormone production with subsequent thyrotoxicosis and goitre formation. Similarly, some patients with chronic urticaria have histamine-releasing IgG autoantibodies against the ε subunit of the high-affinity IgE receptor (FcεRIα) (Hide et al. 1993). The antibody is believed to activate normal mast cell function by receptor cross-linking

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Table 1.1 Hypersensitivity reactions: Landmark findings and theories throughout the ages (adapted from De Weck (1997)). 28th BC

Shen Nung

First reference to an anti-asthmatic plant (“ma-huang”), shown later to contain ephedrine, in the first herbal compendium Pen Ts’ao

2698 BC 2641 BC

Huang Ti Menes

First decription of asthma (“noisy breathing”) in the Nei Ching, oldest treatise of internal medicine. Egyptian pharaoh reported to have died from a wasp (“kehb”) sting (first report of an anaphylactic shock?) However, interpretation of hieroglyph controversial (Avenberg & Harper, 1980)

460–365 BC

Hippocrates

Description of asthma, eczema and allergy to goats’ milk and cheese

25 BC–AD 40

Aulus Celsus

Thorough description of dyspnoea, asthma and orthopnoea in treatise “De medica”

AD

c. 40

Marcus Terrentius Varro

Very small animals invisible to the eye, floating in the air, growing in damp places, inhaled and giving rise to serious diseases (mites?)

AD

b.41

Britannicus

Reported to be afflicted by acute allergic reactions to horses

AD

c. 60

Pedanius

Remedies for asthma in classical pharmacology treatise

Aretaeus of Cappadocia

First detailed description and coining of the word asthma

120–AD 180 AD

b.131

Galen

Description of untoward reactions to various milks (goat, cow, ewe, camel, ass): allergy?

AD

b.865

Rhazes

Description of seasonal catarrh due to roses in Persia

1135–1204

Moses Maimonides

Author of famous “Treatise on Asthma”. Physician to Sultan Saladin

b.1306

John of Arderne

Prescription of a “syrup” for asthma

1530

Thomas Moore

Report on acute skin eruption of King Richard III due to ingestion of strawberries (Shakespeare!)

1552

Girolamo Cardano

Cures asthma of Archbishop Hamilton of St Andrew by elimination of bedding feather pillows

1565

Leonardhus Botallus

Description of “rose cold” in Pavia

1570

Pietro Mattioli

First reported challenge of a cat allergic patient by stay in a room containing a concealed cat

c. 1584

Johann Schenk

Coins the term “idiosyncrasy”

b.1603

Kenelm Digby

Blister to rose petal applied on cheek of English court lady hypersensitive to roses (first patch test?)

1603

Felix Platter

Asthma due to obstruction of small pulmonary arteries or to nerve disturbances

c. 1630

Sanctorius

Description of asthma to cat hair

1656

Pierre Borel

Weakness, fainting and asthma upon contact with cats, mice, dogs and horses (particularly in Germans?) Blister upon applying egg on skin of hypersensitive patient (first skin test?)

1662

K.V. Schneider

Nasal catarrh caused by exudation from nasal mucosa, not by secretion from the brain (!)

1665

Philipp Jacob Sachs

Description of a case of urticaria caused by strawberries and of shock upon ingestion of fish

1673

Johannes Binneringus

Description of seasonal rose coryza in Basle

1675

Theophile Bonet

Idiosyncrasies to bread, strawberries and wine

1680

Thomas Willis

Studies of asthma as bronchial disease and role of bronchial innervation; asthma as nervous disease

c. 1680

Nehemiah Green

First microscopic studies of pollen grains

1682

Joan van Helmont

Description of seasonal asthma with itching skin eruption (atopic dermatitis?) and of psychosomatic asthma

1691

Jacob de Rebecque

Coryza due to rose scent but only at the end of spring

1698

John Floyer

Description of asthma causes (tobacco smoke, dust, foods, exercise, emotions, environmental factors) First description of heredity in asthma

1713

Bernardino Ramazzini

First systematic description of occupational diseases, in particular baker’s asthma

1765

Debrest

Description of sudden death by bee sting in Montpellier

1775

William Cullen

Hereditary idiosyncrasy to eggs in “Historia de Materia Medica” Continued p. 16

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Table 1.1 (Cont’d ) 1776

Johann Murray

Ipecac root (emetine), causes asthma attacks in pharmacists

1778

Stolpertus

Description of acute angioneurotic oedema following ingestion of eggs

1783

Friedrich Schademantal

Allergic urticaria due to ingestion of fresh pork meat

1783

Philipp Phoebus

Comprehensive monograph on hayfever. First epidemiological enquiry

1802

William Heberden

Description of summer catarrh and asthma; differentiation from common cold

1816

Henri Laennec

Invents stethoscope. Identifies bronchospasm as important component of asthma

1819

John Bostock

Description of 28 cases of “estival catarrh” or hay-fever, disease restricted to upper classes of society

1839

François Magendie

Description of sudden death of dogs repeatedly injected with egg albumin

1853 1886

Jean Martin Charcot and Ernst van Leyden

Description of Charcot–Leyden crystals in sputum of asthmatics

1868

Henry Hide Salter um

Description of asthma with various causes (animal emanations, foods, hayfever), intrinsic asthma, cells in sputum (later identified as eosinophils)

1872

Heinrich Quincke

First description of angioneurotic oedema

1872

Morrill Wyman

Description of autumnal catarrh in USA and identification of ragweed pollen as cause

1873–80

Charles Blackley

Experimental demonstration of role of grass pollens in hayfever, first pollen counts

1877

Paul Ehrlich

Description and staining of mast cells (1877) and eosinophils (1879)

1894

Samuel Flexner

Experimental “toxic death” whilst injecting dog serum into rabbits

1895

Josef Jadassohn

Establishment of patch tests in contact dermatitis

1895

Josef Jadassohn

Description of various types of drug reactions in the skin

1900

Solomon Solis-Cohen

Role of autonomic imbalance in allergic diseases. Use of adrenal substance in hayfever and asthma

1902

Charles Richet Paul Portier

Discovery of experimental anaphylaxis in dogs

1903

Theobald Smith

Observations of anaphylactic reactions of guinea pigs to horse serum

1903

Maurice Arthus

Experimental localized acute necrotizing vasculitis, first described as local anaphylaxis

1905

Bela Schick

First description of serum sickness disease: skin test for diphtheria susceptibility

1905

Clemens von Pirquet

Studies on serum sickness, coins the term “allergy”: introduces tuberculin skin test in diagnosis

1906

A. Wolff-Eisner

Relationship of human hayfever and urticaria to experimental anaphylaxis

1909

William Schultz

Detection of anaphylaxis by contraction of isolated smooth muscle in vitro

1909

William B. Osler

Asthma associated with neurotic disease

1910

S. Meltzer

Bronchial asthma as a phenomenon of anaphylaxis

1910

William Dunbar

Methodology for pollen extraction; first approaches to pollen immunotherapy

1911

Leonard Noon John Freeman

Wide use of immunotherapy with pollen extracts in hayfever patients

1911

Henry Dale

Role of histamine in anaphylaxis and studies on chemical transmission of nerve impulses

1911

Tomaso Casoni

Skin test in patient infected with Echinococcus

1912

Oscar M. Schloss

Use of scratch test in allergy to foods

1913

William Dunbar

Methodology for pollen extraction, identification of allergenic protein

1914

A.T. Waterhouse

Anaphylactic reactions of beekeepers to stings

16

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Table 1.1 (Cont’d ) 1915

Warfield T. Longcope

Experimental lesions in organs from animals repeatedly injected with foreign proteins

1916

Robert A. Cooke

Standardization of allergen extracts – protein nitrogen unit (PNU), role of hereditary factors in hayfever, description of allergic drug reactions

1918

Francis Rackemann

Description of intrinsic and extrinsic asthma: asthma is not always of allergic origin

1919

M.A. Ramirez

Horse dander asthma following blood transfusion

1921

Carl Prausnitz Heinz Küstner

Passive transfer of immediate skin reactivity of fish allergen by intradermal injection of serum from allergic patient (“reagins”)

1921

Arent de Besche

Passive transfer of serum from horse asthmatics sensitized to horse proteins by injection of diphtheria vaccine

1922

Fernand Widal Pierre Abrami J. Lermoyez

Described triad of asthma, vasomotor rhinitis (with or without nasal polyps) and intolerance to aspirin and aspirin-like medicines (also known as Samter’s syndrome)

1923

Arthur Coca

Reagent for allergen extraction

1923

Arthur Coca

Coined the term “atopy”

1924

F.T. Codham

First description of mould allergy

1924

Ko Kuei Shen Carl F. Schmidt

Systematic investigations of pharmacological actions of ephedrine, the active component of “ma-huang”

1927

Thomas Lewis

Description of similarities between urticaria and skin vascular reactions to histamine (vasodilatation, flare and local oedema as triple response)

1927

Bret Ratner

Experiments on allergic sensitization in utero

1928

Storm van Leeuwen

Inhalation allergy to house dust

1928

Edward Dienes

Induction of cellular delayed hypersensitivity by protein antigens

1934

Mataso Masugi

Experimental glomerulonephritis with anti-kidney antiserum

1935

Ulf von Euler

Discovery of the activity of lipid fraction of seminal fluid on smooth muscle (“prostaglandins”)

1937

Daniel Bovet

First synthesis of antihistaminic drugs

1939

Harry H. Donally

Transmission of food allergens in breast milk

1940

Charles H. Kellaway Everton T. Trethewie

First description of “a slow-reacting substance of anaphylaxis” causing smooth muscle contraction

1940

Mary Loveless

Description of blocking antibodies arising during immunotherapy with pollen extracts. Use of pure venoms in immunotherapy for hymenoptera allergy

1941

Louis B. Jaques

Relationship between mast cells and anaphylaxis in dogs: mast cells as source of released heparin

1941

Joseph Harkavy

Bronchial asthma with recurrent pulmonary eosinophilic infiltration and polyserositis

1942

Merrill W. Chase

Transfer of tuberculin sensitivity by cells from immunized animals

1945

Merrill W. Chase

Transfer of contact dermatitis to simple chemicals by sensitized leukocytes

1945

Robin A. Coombs

Described the antiglobulin (“Coombs”) test

1949

Philip S. Hench Edward C. Kendall

Isolation of cortisone from adrenals for therapy of rheumatoid arthritis

1952

Zoltan Ovary

Development of passive cutaneous anaphylaxis (PCA) for quantification

1953

James F. Riley Geoffrey B. West

Mast cell granules as major source of histamine in tissues

1954

William Frankland Rosa Augustin

First placebo-controlled clinical trial of desensitization (allergen-injection immunotherapy)

Continued p. 18

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Table 1.1 (Cont’d ) 1957

Ernest Witebsky

Experimental autoallergic thyroiditis: pathology and criteria of immune diseases

1958–60

Zoltan Ovary Herman N. Eisen

Elicitation of immediate anaphylactic reactions requires bridging of antibody molecules by bi- or multivalent allergen

1960

Bernard. B. Levine Alain L. de Weck

Identification of major and minor antigenic determinants in penicillin allergy

1962

Alain L. de Weck Charles W. Parker

Diagnostic skin testing for penicillin allergy with synthetic penicilloyl-polylysine polymers

1963

Robin A. Coombs Philip Gell

Classification of the hypersensitivity reactions

1963

K. Frank Austen

Biochemistry of mast cell mediator release

1963

Jack Pepys

Identification of moulds and anti-Thermosopora IgG antibodies as cause of farmer’s lung

1964

Lawrence M. Lichtenstein Abraham G. Osler

Development of allergen-specific histamine release test

1964

T.E. King

Identification of major allergen in ragweed

1966

Barry R. Bloom John R. David

Description of lymphokine-induced cell interaction: macrophage migration inhibitory factor (MIF)

1966

David Marsh

Identification of major grass allergens

1966

J.J. Curry

Asthmatics more sensitive than normals to the action of histamine on the respiratory tract

1967

Kimishige Ishizaka Teruko Ishizaka

Characterization of reagins as IgE immunoglobulins

1967

Hans Bennich Gunnar Johansson

Identification of myeloma ND as IgE immunoglobulin

1967

L. Wide Gunnar Johannsson

Development of a RAdioSorbent Test (RAST) for detection of allergen-specific IgE

1967

Reindert Voorhorst Frederick Spieksma

Identification of Dermatophagoides mites as major allergen source in house dust

1967

Bernard Halpern

Lymphocyte stimulation test in drug allergy

1967

Roger Altounyan

Discovery of sodium cromoglycate as anti-asthmatic drug

1981

K. Frank Austen

Biological properties of leukotrienes

1983

Bengt I. Samuelson

Identification of leukotrienes as slow-reacting substance of anaphylaxis, role in allergic diseases

and in this sense is cytostimulating rather than cytolytic (in which there is destruction of the cells with liberation of preformed histamine). In myasthenia gravis, on the other hand, autoantibodies directed against acetylcholine receptors have been identified. These have antagonist properties leading to a failure to sustain maintained or repeated contraction of striated muscle. Although, in both situations, the initiating event is IgG bound to cell-surface antigen, the outcome is quite different, giving on the one hand cytolytic or cytotoxic reactions, and on the other a cytostimulating hypersensitivity reaction in which there is altered cell function (or cell signaling) with IgG antibody acting either as an agonist or an

18

antagonist. For these reasons, Janeway and Travers (1995) proposed that cytotoxic or cell-stimulatory reaction are subdivided into type IIa (cytotoxic) and type IIb (cell-stimulating) responses (Fig. 1.27). Type III reactions (Arthus reactions and “immune complex” or toxic complex syndrome) occur when antigen and antibody, reacting in antigen excess, form complexes which, possibly with the aid of complement, are toxic to cells. As shown by Jack Pepys (1914–96) (Fig. 1.28), this mechanism operates, at least in part, in farmer’s lung (and other forms of extrinsic allergic alveolitis). Other examples of type III reactions include erythema nodosum leprosum, serum sickness,

Soluble

Antigen

• Certain allergic drug reactions (e.g. penicillin) • Incompatible transfusion reactions • Autoallergic (“autoimmune”) hemolytic anemia

b

Antagonist

Neutrophil-rich inflammatory response

APC

MHC Class II

TCR

Macrophage-rich inflammatory response

Type 1 cytokines

AF

CD4+ type 1

T Lymphocyte

Soluble

Antigen presentation to sensitized CD4+ type 1 T lymphocytes (also called T helper (Th) type 1 cells)

• Tuberculin • Chronic urticaria • Serum sickness reaction (Anti-FceRIa antibody • Extrinsic allergic • Contact – agonist) alveolitis dermatitis • Graves disease • Antigen-antibody • Rheumatoid (Thyroid stimulating complex arthritis antibody – agonist) (“immune complex”) • Myasthenia gravis glomerulonephritis (Anti-acetylcholine receptor antibody – antagonist)

Agonist

IgG

Microvasculature

Soluble

Antigen-antibody complexes, in and around the microvasculature, which activate complement

• • • •

MHC Class II

Chronic asthma Chronic allergic rhinitis Atopic eczema Late-phase allergic reactions (in experimental models of atopic allergic disease)

Eosinophil- and basophil-rich inflammatory response

Type 2 cytokines

APC

CD4+ type 2

T Lymphocyte

Soluble

MHC Class I

• Early-onset, insulin-dependent diabetes • Graft rejection

Cytotoxicity (apoptosis)

Target cell

CD8+ cytotoxic

T Lymphocyte

Cell-associated

Cytotoxic CD8+ T lymphocytes recognize fragments of antigen on the surface of target cells

Cell-mediated eosinophilic hypersensitivity or chronic allergic inflammation Antigen presentation to sensitized CD4+ type 2 T lymphocytes. Sensitized CD8+ type 2 T lymphocytes (also called T cytotoxic (Tc) type 2 cells) may also participate

Tissue injury by cytotoxic T lymphocytes

Th2

Th1

Type IV cytotoxic

Type IV

Type IV

Arthus type (or Classical delayedantigen-antibody type hypersensitivity complex) – often called ‘immune complex’ – hypersensitivity reaction

Type III

Receptor Antigen-antibody complexes + ligand complement

Target cell Receptor

Cell-associated

IgG cell-stimulating antibody interacting with cell surface receptors involved in cell signaling

Cell-stimulating reactions involving altered cell function (or signaling)

Type II

Fig. 1.27 A modification to the Coombs and Gell classification (1963) of hypersensitivity reactions based on more recent knowledge of the initiating events but restricted to human allergic disease. Immediate-type (type I) reactions involve soluble antigen interacting with cell-bound IgE. Type I reaction involves IgE antibodies bound to high-affinity (FceRI) IgE receptors on mast cells or basophils (and possibly macrophages or even eosinophils). Antigen (allergen) induces the release of granule-associated and membrane lipid-derived mediators of hypersensitivity as well as several cytokines including interleukin (IL)-5, IL-3, and granulocyte–macrophage colony-stimulating factor (GM-CSF). Type II reactions are subdivided into type IIa, cytolytic or cytotoxic reactions originally described by Coombs and Gell, in which antibody-sensitized cells are destroyed by complement lysis or removed by the reticuloendothelial (RE) system; and type IIb, those in which antibodies directed against cell-surface receptors cause altered cell function or signaling. In type IIb, antibody is cell-stimulating (cytostimulatory) and acts as either an agonist or antagonist. (From Janeway & Travers 1995.) The type III Arthus-type reaction, or antigen–antibody complex reaction (mostly called immune-complex reaction), is mediated by soluble antigen and involves IgG, complement, and an inflammatory reaction which initially is neutrophilrich. Type IV reactions are subdivided into (i) classical delayed-type hypersensitivity initiated by CD4+ Th1-type lymphocytes (type IV Th1), (ii) cell-mediated eosinophilic hypersensitivity or chronic allergic reactions involving CD4 + (and sometimes CD8 +) Th2-type cells (type IV Th2) and (iii) reactions in which tissue damage is evoked by CD8 + cytotoxic T lymphocytes (type IV cytotoxic).

• Acute symptoms of allergic rhinitis • General and local anaphylaxis • Early-phase allergic reactions (in experimental models of atopic allergic disease)

Complement lysis or removal by the RE system

+/– complement

IgG

Cell surface antigen

Target cell

Cell-associated

IgG antibody interacting with cell surface antigen

Cytolytic, or cytotoxic, reactions

a

CHAPTER 1

Examples in humans

Allergen

Release of granuleassociated mediators (e.g. histamine) and membrane-derived lipid mediators of hypersensitivity

IgE

Mast cell/basophil

Antigen (allergen) interacting with mast cells or basophils passively sensitized by IgE

Initiating event

Simplified scheme of the proposed mechanism

Immediate-type (IgE-dependent, or anaphylactic) hypersensitivity

Descriptive term

Type I

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Fig. 1.28 Jack Pepys (1914–96). Identified thermophilic actinomycetes as a cause of farmer’s lung. Major contributions to our understanding of the etiology and pathogenesis of allergic alveolitis, occupational asthma, and allergic bronchopulmonary aspergillosis. (From Cohen & Samter 1992, with permission.)

antigen–antibody complex glomerulonephritis, and deposition of antigen–antibody complexes at other sites such as the skin as in certain vasculitic skin rashes. Type IV reactions refer to situations where specifically sensitized T cells react with allergen or antigen deposited at the local site, as in delayed- or tuberculin-type hypersensitivity. Classical delayed-type hypersensitivity involves predominantly CD4+ T cells with antigen presented in a major histocompatibility complex (MHC) class II restricted fashion. These reactions are characterized by infiltration of T lymphocytes with a restricted cytokine profile. As described below, and in detail elsewhere (see Chapters 3 and 4), these cells preferentially produce interferon (IFN)-γ and interleukin (IL)-2 and are therefore characteristic of the T helper type 1 (Th1) lymphocyte. Contact dermatitis, an important allergic disease, is another example of a type IV reaction with a prominent Th1-type cytokine response. Th2 cells on the other hand elaborate IL-4, IL-5, IL-9, and IL-13 and are involved in atopic allergic reactions as well as parasitic helminthic disease. Some T lymphocyte-mediated hypersensitivity reactions, of which early-onset (insulin-dependent) diabetes is an example, involves CD8+ cytotoxic T cells. These recognize cell-surface antigen presented to T cells in an MHC class I restricted fashion. After cell–cell contact, programmed cell death (apoptosis) of the target is initiated. Although in health, cytotoxic T cells provide a basic “immune” mechanism for

20

dealing with viruses and other insoluble antigens, in the context of insulin-dependent diabetes and graft rejection they mediate a variant of type IV hypersensitivity, termed type IV cytotoxic (see Fig. 1.27). As stated, the effector cell in classical delayed-type hypersensitivity is the CD4 type 1 (or Th1) lymphocyte whereas allergic tissue damage is mediated by Th2 cells. For this reason it is logical that these two forms of cell-mediated hypersensitivity are referred to as type IV Th1 and type IV Th2 respectively, since the initiating event involves T lymphocytes with distinct characteristics (see Fig. 1.27). The involvement of other classes of T cells or T-cell subsets in allergic reaction is also of current interest and is described in Chapters 3 and 4. Akbari et al. (2006) found that 60% of CD4 + T cells in the airways of asthmatics were invariant natural killer (NK)T cells. This finding remains controversial since others have found low numbers of NKT cells in asthma, chronic obstructive pulmonary disease, and controls (Vijayanand et al. 2007). There is growing interest in the possible role of Th17 cells in allergic disease although their role remains ill-defined in humans. As discussed in Chapter 3, they are distinct from Th1 and Th2 cells are involved in the initiation of a predominantly neutrophil-rich inflammatory response (Romagnani 2006). Control of allergic inflammation by natural and inducible T regulatory cells is discussed in Chapter 4. Some hypersensitivity reactions do not fall neatly into the type 1–IV classification. For example, activation of the plasma cascade via factor XII, prekallikrein, and high-molecularweight kininogen leads to bradykinin formation, the critical mediator of hereditary angioedema (Fields et al. 1983).

Concluding comments The full history of allergy is long and complex and only a relatively superficial account can be given here. The story of direct relevance to atopic allergic disease ranges from the first full description of anaphylaxis in 1903 to the discovery of IgE in the 1960s. Side by side is the unraveling of the structure and biological properties of various biological agents released in the allergic cascade. The coining of the word “allergy” itself, although often misunderstood, laid the foundation for a fundamental rule of immunology, with the concept that humans and animals “alter” their reactivity to antigen when they meet it on second and subsequent occasions.

Acknowledgments I have drawn heavily on the following three excellent and important works in the preparation of this chapter: “Elements of the history of our present concepts of anaphylaxis, hay fever and asthma” by the late Elmer Becker (1999); Excerpts from Classics in Allergy by Sheldon Cohen and Max Samter

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(1992); and “A short history of allergological diseases and concepts” by Alain de Weck (1997).

References Akbari, O., Faul, J.L., Hoyte, E.G. et al. (2006) CD4+ invariant T-cellreceptor + natural killer T cells in bronchial asthma. N Engl J Med 354, 1117–29. Arthus, M. (1903) Injections répétées de serum de cheval chez le lapin. C R Soc Biol (Paris) 50, 20. Avenberg, K.M. & Harper, S.D. (1980) Footnotes on Allergy. Pharmacia, Uppsala, Sweden. Bartosch, R., Feldberg, W. & Nagel, E. (1932) Das Freiwarden eines histaminhnlichen. Stoffes bei der Anaphylaxie des Meerschweinchens. Pflugers Arch ges Physiol 230, 129–53. Becker, E.L. (1999) Elements of the history of our present concepts of anaphylaxis, hay fever and asthma. Clin Exp Allergy 29, 875–95. Bennich, H., Ishizaka, K., Johansson, S.G.O., Rowe, D.S., Stanworth, D.R. & Terry, W.D. (1968) Immunoglobulin E, a new class of human immunoglobulin. Bull WHO 38, 151–2. Beraldo, W.T. (1950) Formation of bradykinin in anaphylactic and peptone shock. Am J Physiol 163, 283– 9. Best, C.H., Dale, H.H., Dudley, H.W. & Thorpe, W.V. (1927) The nature of the vasodilator constituents of certain tissue extracts. J Physiol (Lond) 62, 397– 417. Borgeat, P. & Samuelsson, B. (1979) Transformation of arachidonic acid by rabbit polymorphonuclear leukocytes. Formation of a novel dihydroxy eicosanoic acid. J Biol Chem 254, 2643– 6. Brocklehurst, W.E. (1953) Occurrence of an unidentified substance during anaphylactic shock in cavy lung. J Physiol (Lond) 120, 16P. Brocklehurst, W.E. (1962) Slow reacting substance and related compounds. Prog Allergy 6, 539– 88. Bulloch, W. (1937) The History of Bacteriology. Oxford University Press, London. Coca, A.F. & Cooke, R.A. (1923) On the classification of the phenomena of hypersensitiveness. J Immunol 8, 163– 82. Cohen, S.G. & Samter, M. (1992) Excerpts from Classics in Allergy, 2nd edn. Symposia Foundation (Oceanside Publications), Providence, RI. Cooke, R.A., Barnard, S.H., Hebald, A.T. & Stull, A. (1935) Serological evidence of immunity with co-existing sensitization in a type of human allergy, hay fever. J Exp Med 62, 733–50. Coombs, R.R.A. & Gell, P.G.H. (1963) The classification of allergic reactions responsible for allergic reactions underlying diseases. In: Gell, P.G.H. & Coombs, R.R.A., eds. Clinical Aspects of Immunology. Blackwell Scientific Publications, Oxford, pp. 217–37. De Weck, A. (1997) A short history of allergological diseases and concepts. In: Kay, A.B., ed. Allergy and Allergic Diseases. Blackwell Scientific Publications, Oxford, chapter 1. Doerr, R. (1914) Neuere ergebnisse der anaphylaxieforschung. Ergebnisse Immunittsforsch Hyg Bakteriol Exp Ther 1, 257–76. Ehrlich, P. (1877) Beitrage zur Kenntnis der Anilifarbungen und ihrer Verwedung in der Mikroskopischen Technik. Arch Mikr Anat 13, 263–77. Ehrlich, P. (1879a) Beitrage zür Kenntniss der granulirten Bindegewebszellen und der eosinophilen Leukocythen. Archiv Fur Anatomie und Physiologie: Physiologische Abteilung 166–9.

Allergy and Hypersensitivity: History and Concepts

Ehrlich, P. (1879b) Ueber die specifischen Granulationen des Blutes. Archiv fur Anatomie und Physiologie: Physiologische Abteilung, 571– 9. Fields, T., Ghebrehiwet, B. & Kaplan, A.P. (1983) Kinin formation in hereditary angioedema plasma: evidence against kinin derived from C2 and in support of “spontaneous” generation of bradykinin. J Allergy Clin Immunol 72, 54–60. Freeman, J. (1914) Vaccination against hay fever: a report of results during the last three years. Lancet 183 (4730), 1178–80. Gebauer-Fuelnegg, E., Dragstedt, C.A. & Mullenix, R.B. (1932) Observations on a physiologically active substance appearing during anaphylactic shock. Proc Soc Exp Biol Med 29, 1084–6. Hamburger, F. & Moro, E. (1903) Ueber die biologisch nachweisbaren Veränderungen des menschlich Blutes nach den Seruminjektion. Wien Klin Wochenschr 16, 445–7. Hide, M., Francis, D.M., Grattan, C.E.H., Hakimi, J., Kochan, J.P. & Greaves, M.W. (1993) Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 328, 1599–604. Ishizaka, K. & Ishizaka, T. (1966) Physicochemical properties of human reaginic antibody. I. Association of reaginic antibody with an immunoglobulin other than gA or gG globulin. J Allergy 37, 169– 85. Ishizaka, K. & Ishizaka, T. (1968) Human reaginic antibodies and immunoglobulin E. J Allergy 42, 330–63. Janeway, C. & Travers, P. (1995) Immunobiology, 2nd edn. Garland Press, London, chapter 11. Johansson, S.G.O. & Bennich, H. (1967) Immunological studies of an atypical (myeloma) immunoglobulin. J Immunol 98, 381–94. Karsner, H. & Ecker, E. (1921) Principles of Immunology. Lippincott, Philadelphia, p. 308. Kay, A.B. (1997) Concepts of allergy and hypersensitivity. In: Kay AB, ed. Allergy and Allergic Diseases, Vol. 1. Blackwell Science, Oxford, pp. 23–35. Kay, A.B. (2006) 100 years of “Allergy”: can von Pirquet’s word be rescued? Clin Exp Allergy 36, 555–9. Kellaway, C.H. & Trethewie, E.R. (1940) The liberation of a slowreacting smooth muscle stimulating substance in anaphylaxis. Q J Exp Physiol 30, 121–45. Kraneveld, A.D., Kool, M., van Houwelingen, A.H. et al. (2005) Elicitation of allergic asthma by immunoglobulin free light chains. Proc Natl Acad Sci USA 102, 1578–83. Lanellopoulis, J.M., Liu, T.Y., Poy, G. & Metzger, H. (1980) Composition and subunit structure of the receptor for immunoglobulin E. J Biol Chem 255, 9060. Loveless, M.H. (1940) Immunological studies of pollenosis. I. The presence of two antibodies related to the same pollen-antigen in the serum of treated hay fever patients. J Immunol 38, 25–58. Loveless, M.H. (1964) Reagin production in a healthy male who forms no detectable b2A immunoglobulins. Fed Proc 23, 403. McFadden, E.R. Jr (2004) A century of asthma. Am J Respir Crit Care Med 170, 215–21. Magendie, F. (1839) Lectures on the Blood. Harrington, Barington and Hasswell, Philadelphia. Mahmoud, A.A.F., Austen, K.F. (eds) (1980). The Eosinophil in Health and Disease. Grune & Stratton, p. 5. Murphy, R.C., Hammarstrom, S. & Samuelsson, B. (1979) Leukotriene C. A slow reacting substance from murine mastocytoma cells. Proc Natl Acad Sci USA 76, 4275–9.

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Noon, L. (1911) Prophylactic inoculation against hay fever. Lancet 177 (4580), 1572–3. Perez-Montfort, R., Kinet, J.-P. & Metzger, H. (1983) A previously unrecognized subunit (gamma) of the receptor for immunoglobulin E. Biochemistry 22, 5722. Prausnitz, C. & Kustner, J. (1921) Studien uber die Ueberempfindlichkeit. Zentralbl Bakteriol Mikrobiol Hyg 1 Abt Orig 86, 160–8. Ramirez, M.A. (1919) Horse asthma following blood transfusion. JAMA 73, 984–5. Riley, J.F. (1959) The Mast Cells. E.D. Livingston, Edinburgh. Riley, J.F., West, G.B. (1952) Histamine in tissue mast cells. J Physiol 117, 729–39. Riley, J.F. & West, G.B. (1952) Histamine in tissue mast cells. J Physiol (Lond) 172, 72–3. Riley, J.F., West, G.B. (1953) Mast cells and histamine in normal and pathological tissues. J Physiol 119, 44P. Rocha e Silva, M., Beraldo, W. & Rosenfeld, G. (1949) Bradykinin, a hypotensive and smooth muscle stimulating factor released from plasma globulin by snake venoms and trypsin. Am J Physiol 156, 261–73. Romagnani, S. (2006) Regulation of the T cell response. Clin Exp Allergy 36, 1357–66.

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Rowe, D.S. & Fahey, J.L. (1965) A new class of human immunoglobulins. I. A unique myeloma protein. J Exp Med 121, 171–99. Schild, H.O. (1936) Histamine release and anaphylactic shock in isolated lungs of guinea pigs. Q J Exp Physiol 26, 165–77. Spinelli, A. (1932) Demonstration de la mise en libert de substance type histamine du pumon isole du cobaye en choc anaphylactique. Bull Sez Ital Soc Int Microbiol 14, 257–64. Stuart, E.G. (1952) Mast cell responses to anaphylaxis. Anat Rec 112, 344. Vijayanand, P., Seumois, G., Pickard, C. et al. (2007) Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 356, 1410–22. von Pirquet, C. (1906) Allergie. Munchen Med Wochenschr 53, 1457. von Pirquet, C. (1911) Allergy. Arch Intern Med 7, 259–88, 382–8. von Pirquet, C. & Schick, B. (1905) Die Serum Krankheit. (Serum Sickness, English translation 1951). Williams and Wilkins, Baltimore. Wagner, R. (1968) Clemens von Pirquet. His Life and Work. The Johns Hopkins Press, Baltimore. Weiss, J.W., Drazen, J.M., Coles, N. et al. (1982) Bronchoconstrictor effects of leukotriene C in humans. Science 216, 196–8. Wharton-Jones, T. (1846) The blood-corpuscle considered in the different phases of development in the animal series. Memoir I. Vertebrata. Philos Trans R Soc Lond 136, 63–87.

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Development of Allergy and Atopy Catherine Thornton and Patrick G. Holt

Summary The development and manifestation of IgE-mediated allergic diseases reflects a complex interaction between genetic and environmental factors operational at discrete maturational stages. Central to understanding the evolution of allergic disease in childhood is an appreciation of both immunologic activities and tissue-specific factors that have key roles in disease manifestation. The immune system and tissues affected by allergic disease, especially the airways, continue to mature after birth, so critical features of the host’s genotype and the environment that impact on postnatal maturation and function of these physiologic systems need to elucidated. In particular, factors that regulate the kinetics of postnatal maturation of innate and adaptive immune functions, which are delayed in children at high risk of allergic disease, are poorly characterized and merit more detailed investigation. The epidemiologic observation of an inverse association between family size and risk of developing allergy contains important clues relevant to this issue, and the resultant “hygiene hypothesis” has emerged as a prominent candidate to explain the negative impact of the Western lifestyle on asthma and allergic disease. The current incarnation of the hypothesis relates the innate immune response to immunoregulatory mechanisms and suggests that environmental signals regulate the maturation and pattern of immune responsiveness in early life and that deficiencies in this signaling underlie the increasing prevalence of allergic (and other) diseases. Central to this is the premise that the host response to microbial stimuli has changed as a consequence of alterations in the nature, timing, or dose of microbial signals received postnatally, or possibly even prenatally.

Introduction Numerous studies support the widely held tenet that IgEmediated allergic diseases increased in prevalence during the second half of the 20th century, most dramatically among Allergy and Allergic Diseases, 2nd edition. Edited by A.B. Kay, A.P. Kaplan, J. Bousquet, P.G. Holt. © 2008 Blackwell Publishing. ISBN: 978-1-405-15720-9.

children (Butland et al. 1997; Kosunen et al. 2002; Braback et al. 2004; Burr et al. 2006). While there is now debate about whether a plateau in the prevalence of allergic disease has been reached, these observations are restricted to developed countries that have seen the most dramatic increase in allergic disease prevalence over the last 50 years. The most recent ISAAC survey (Phase III; 66 centers in 37 countries) of worldwide trends in the prevalence of allergic disease symptoms found that increases in prevalence of asthma, allergic rhinoconjunctivitis, and eczema among 6–7 and 13–14 year olds were more common than decreases, especially in the younger age group. However, among 13–14 year olds, asthma had tended to decrease in centers that previously had a high prevalence (Asher et al. 2006). Irrespective of whether a plateau/decline in disease prevalence has occurred in developed countries, allergic diseases still create an enormous social and economic burden and will continue to do so. In the UK treatments for asthma and other allergic disorders account for 10% of primary-care prescribing costs and combined with other direct National Health Service (NHS) costs, such as hospital admissions, the costs of managing allergic problems in the UK are estimated at over £1 billion per annum (Gupta et al. 2004). In the USA the direct medical costs of asthma in 2004 were $US11.5 billion, of which $US5 billion was for prescription drugs and $US3.6 billion related to hospital care (National Heart, Lung, and Blood Institute 2004). Although we are focused on the dramatic increase in allergic disease prevalence over the last 50 years, it is worth noting that other immune-mediated disorders have also increased in prevalence. Notably, there has been a marked increase in type 1 diabetes, with a greater relative increase in children aged under 5 years old compared with all other age groups (EURODIAB ACE Study Group 2000). The dramatic changes in allergic and autoimmune disease prevalence rates among children in particular has prompted much interest in potential shared factors operative in early life that increase the risk of developing these diseases. Interest in the early-life origins of allergic disease has generated a wealth of published data that can be divided broadly into three categories: the immunology of allergy (including tissue-specific aspects of immune development),

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environmental factors that increase/decrease the risk of developing allergic disease, and genetic variation that can predispose to the development of allergy. These are discussed below with a focus on the immunology of allergy and critical environmental factors.

Immunology of allergy Pivotal to the development of allergic disease is sensitization of the host to one or more allergens leading to the production of IgE. Therefore, the early immunologic mechanisms that predispose to the production of IgE on allergen encounter are of great interest. Key effector cells include T lymphocytes, B lymphocytes, dendritic cells, eosinophils, and various populations within affected tissues (e.g., skin keratinocytes and airway epithelial cells). Whereas these populations are relatively well studied in adults, practical and ethical considerations limit the study of these in infants and children. Nevertheless, there is a growing appreciation of the contribution of these same cell populations and the soluble mediators they produce to the initiation and maintenance of atopic disease in early life.

Dendritic cells and Toll-like receptors Dendritic cells are central to the initiation of specific immunologic reactivity to allergens and other antigens. Contiguous networks of dendritic cells are present in the epithelium of the gut, skin, and airways, where they have pivotal roles in surveillance for environmental antigens. In particular, dendritic cells modulate the development of different effector T-cell populations, namely Th1, Th2, or regulatory T cells. Dendritic cells orchestrate antigen-specific activity by T cells

ia ter

ve

iti pos

Gram negative bacteria (including endotoxin) RSV F protein

?

bac

via the provision of major histocompatibility complex (MHC)/ antigenic peptide, costimulatory molecules, and cytokines. Dendritic cell expression of costimulatory molecules, such as the B7 family, and cytokine production are tightly regulated. Expression is particularly controlled by microbial products that interact with receptors on the dendritic cell (Schnare et al. 2001; Barton & Medzhitov 2002). Recent years have seen growing interest in an evolutionarily conserved, germlineencoded family of pattern recognition receptors known as Toll-like receptors (TLRs). There are 10 known functional members of the human TLR family and they recognize a growing list of pathogen-associated molecular patterns (PAMPs) (Fig. 2.1). Interaction between PAMPs and TLRs initiates a signaling cascade on recruitment of an adapter protein (e.g., MyD88), leading to activation of members of the MAP kinase family, NF-κB, and interferon (IFN) regulatory factors among others. There is particular interest in the patterns of cytokines produced by dendritic cells on encounter with microbial stimuli as these cytokines drive the development of effector T-cell populations (Kalinski et al. 1999). Interleukin (IL)-12p70 production by dendritic cells has a pivotal role in induction of Th1 responses and IL-10 is emerging as a key mediator for induction of regulatory T cells; and while prostaglandin (PG)E2 is one of a number of mediators postulated to drive the development of Th2 effector cells, critical mediators of Th2 effector cell development are not well characterized. Different TLR ligands are reported to preferentially favor Th1- or Th2-biased adaptive immune responses. TLR2 ligands generally favor Th2 responses whereas immunostimulatory viral/bacterial DNA (immunostimulatory sequence oligodeoxynucleotides, ISS-ODNs, also called CpG) that signal via

Flagellated bacteria

m Gra gi u F n

TLR10

TLR4

TLR6

TLR5

TLR2

Plasma membrane

TLR1 Viral ssRNA Viral/bacterial DNA Viral dsRNA

TLR7 TLR8 TLR3

24

TLR9

Intracellular vesicle membrane

Fig. 2.1 Toll-like receptors (TLRs) are expressed at the cell surface or on the membranes of intracellular vesicles where they interact with various microbial ligands. Note that TLR10 has been grouped with TLR1, 2 and 6 because of its close phylogenetic relationship to these three TLRs. This diagrammatic representation does not take into account the homodimerization and heterodimerization required to initiate signaling activity. RSV, respiratory syncytial virus. (See CD-ROM for color version.)

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TLR9 inhibit Th2 effector activities and there is growing interest in the use of these in allergy vaccines (Horner 2006). Activation of TLR4 with lipopolysaccharide (LPS; endotoxin) can promote either Th1 (high doses; MyD88-dependent) or Th2 (low doses; MyD88-independent) responses (Horner 2006). Little is known about the Th1/Th2 biasing properties of TLR3, TLR5, TLR7, and TLR8 but as TLR3, TLR7 and TLR8 are activated by viral RNA, the consequences of activating these receptors on immunologic reactivity especially during early childhood is likely of importance. Consequently there is much interest in the capacity of newborns and infants, especially those at low versus high risk of developing allergic disease, to respond to TLR ligands particularly for the production of Th1-trophic cytokines such as IL-12. TLR responsiveness at birth is generally diminished in comparison with the adult, with the exception of TLR8 (Levy et al. 2006) and IFN-γ-primed TLR2- and TLR4stimulated IL-12p70 production both increase from birth to 5–12 years of age even though at 12 years of age adult-like levels have not been attained (Upham et al. 2002). Although the capacity to produce IL-12 matures postnatally, reduced IL-12p70 production in the perinatal period has been associated with stronger neonatal Th2 responses and weaker postnatal allergen-specific Th1 responses, indicating that variation in antigen-presenting cell function in early life might contribute to atopic sensitization in infancy (Prescott et al. 2003). Maternal allergy has also been associated with downregulated expression and responsiveness via TLR2 and TLR4 but the long-term consequences of this remain undetermined (Amoudruz et al. 2005). Importantly, this fetally programmed diminution in the capacity to support Th1 responses postnatally might determine the ability of the host to respond to key environmental factors reputed to alter the risk of developing allergic disease (discussed below).

T lymphocytes: Th1/Th2 and regulatory T cells Th1/Th2 cells The Th1/Th2 paradigm has been an overarching feature of the immunology of allergy for over a decade. A cardinal feature of this paradigm is that Th2 cells produce IL-4 (isotype switching of B cells for IgE synthesis), IL-5 (eosinophil growth and differentiation), IL-9 (mast cell differentiation), and IL-13 (IgE synthesis and airways hyperreactivity) that initiate and amplify the allergic inflammatory response. The ability of Th1 cells to counterregulate Th2 cells bestowed them with a putative beneficial role in allergic disease. Recent years have seen a growing appreciation that the Th1/Th2 paradigm, or at least the way it has been widely interpreted in the context of atopy pathogenesis, is an oversimplification. Key observations that have led to this reappraisal include (i) the biphasic nature of the Th1/Th2 contribution to the initiation and maintenance of eczematous lesions (Th2-skewed in the acute phase and Th1-skewed in the chronic phase); (ii) the observation that the preval-

Development of Allergy and Atopy

ence of Th1-mediated disorders has also increased over recent decades (EURODIAB ACE Study Group 2000; Stene & Nafstad 2001); and (iii) the inverse association between helminth infection (which generates a Th2-biased response involving eosinophils and IgE) and allergic disease. Despite clear evidence that delayed postnatal maturation of Th1 function is strongly associated with risk of developing the Th2-polarized memory responses that underlie allergic sensitization during childhood (Holt et al. 1992; Holt & Macaubas 1997), the observation that both Th1- and Th2mediated diseases have increased in prevalence over recent decades indicates that a general shift in the overall Th1/Th2 polarity of the immune system in the population at large is unlikely to be the primary determinant of changes in disease prevalence. Instead, imbalance between Th1 and Th2 cytokines at crucial stages during the evolution of individual allergen-specific immune responses is more likely to be a downstream component of the sensitization process, driven by whatever the primary mechanism might be. So while there is growing speculation that shared environmental exposures underlie the increases in both Th1- and Th2mediated diseases (Bach 2002), events upstream of the consolidation of T-helper memory are now considered to play key roles in these changing disease patterns. Until recently there was much enthusiasm for the possibility that allergen-specific T-cell memory was initiated during intrauterine development. This was supported by observations made by many groups of proliferative and cytokine responses by umbilical cord blood mononuclear cells to food and inhalant allergens. However, an increasing number of studies have failed to find an association between proliferative response to allergen at birth and maternal (therefore fetal) exposure to the same allergen during pregnancy or various measures of allergic outcome in infancy (Smillie et al. 2001; Marks et al. 2002). These observations raised questions about the significance of cord blood responses to allergens and disease outcomes. More recently, the biological mechanism underlying the ability of cord blood mononuclear cells to respond to allergens has been elucidated. The bulk of this responsiveness has been shown to represent a non-specific response by functionally immature recent thymic emigrants rather than conventional memory T-helper cells (Thornton et al. 2004). This non-specific responsiveness is presumably initiated at around 20–21 weeks of gestation and seems to persist for at least the first 3 months of life, with specific memory responses emerging after 6 months of age (Jones et al. 1996; Szepfalusi et al. 2000; Bottcher et al. 2006). It is the emergence of Th2-biased allergen-specific responses from 6 months of age, rather than reactivity in cord blood, that correlates with sensitization (Rowe et al. 2007). Clarification that the response to allergen at birth is not allergen-specific and therefore not related to maternal allergen exposure during pregnancy questions the scientific basis for existing recommendations for allergen avoidance by high-risk women

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during pregnancy (e.g., peanuts) (Committee on Toxicity of Chemicals in Food 1998). Recognition that the response to allergens measurable at birth is not indicative of the development of T-cell memory does not discount the various studies linking proliferative and cytokine responses at birth with family history of allergic disease or disease outcomes in childhood. Rather than informing us about the development of allergen-specific memory in the perinatal period, they highlight the fact that variation in immune function at birth is linked to subsequent immunologic responsiveness in infancy, which includes the development of allergen-specific IgE and disease outcomes. Numerous studies now support the postulate that the capacity to produce a variety of both Th1 (typically IFN-γ), Th2 (typically IL-13), and regulatory (IL-10) cytokines is diminished at birth in children who are at genetic risk of developing allergic disease or who develop disease during childhood (Holt et al. 1992; Tang et al. 1994; Prescott et al. 1998; Williams et al. 2000). Subsequently, these same children consolidate Th2 responsiveness [phytohaemagglutinin (PHA)-stimulated IL-4, IL-5, IL-13] while failing to adequately upregulate Th1 responsiveness (PHA-stimulated IFN-γ) at 6 months and 1 year of age. This Th2-biased responsiveness during the first year of life is associated with atopic outcomes including sensitization to egg, eosinophilia, and increased IgE by 1 or 2 years of age (Prescott et al. 1999; van der Velden et al. 2001; Neaville et al. 2003). Altered cytokine production patterns at birth might predict susceptibility to particular immunologic sequelae during the first 1–2 years of life. For example, reduced IFN-γ production in early infancy has been associated with increased frequency of viral respiratory infections (Copenhaver et al. 2004) and early-onset wheezing in the first year of life (Guerra et al. 2004a), and reduced IL-13 at birth has likewise been associated with early respiratory syncytial virus (RSV)-induced wheezing (Gern et al. 2006). However, the link between viral infection in early life and the development of asthma remains controversial (as discussed below). Recently, current wheeze/ asthma at 5 years of age has been associated with wheezy and/or febrile lower respiratory tract infection in the subgroup of high-risk children sensitized prior to 2 years of age (Kusel et al. 2007). Thus, accumulating evidence links susceptibility to viral infection and atopy to a common set of transient developmental defects in cellular immune function in early infancy. Lower IFN-γ and IL-13 at birth might therefore be indicators of an overall functionally immature immune system with diminished antiviral capability. Failure to efficiently upregulate IFN-γ might also be the critical step in the development of atopic sensitization in infancy, as a reduced capacity to produce IL-12 at birth has been associated with reduced number of IFN-γ-producing cells at this time, weaker allergen-specific Th1 responses, and the development of skin-prick reactivity and atopic dermatitis during the first 2 years of life (Prescott et al. 2003; Nilsson et al. 2004).

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Of interest now is identification of the genetic and environmental factors that program this pattern of responsiveness. Maternal allergic disease has been associated with reduced IFN-γ and IL-12 at birth but the mechanisms explaining this remain unknown (Prescott et al. 2000; Gabrielsson et al. 2001). The Th2-inhibitory effects of IFN-γ are generally restricted to the early phase of polarization and the capacity to annul commitment of Th1 or Th2 populations is lost progressively with long-term exposure to polarizing stimulation (Murphy et al. 1996). A comparable situation may occur in humans: attenuated IFN-γ production is a hallmark of the immune response at birth in children at increased risk of atopic sensitization whereas (older) children who are sensitized have mixed Th1/Th2 responses (variation in which can be related to different patterns of disease) and even hyperproduction of IFN-γ (Macaubas et al. 1999; Smart & Kemp 2002; Heaton et al. 2005). Thus while there has been a focus on the potential of Th1-biased responsiveness to regulate disease this may only be feasible at the disease induction phase.

Regulatory T cells Recent years have seen a dramatic resurgence in the investigation of T-cell populations that regulate/suppress immunologic reactivity. Initially identified by their ability to suppress autoimmune disease, regulatory T cells have since been shown to modify a broad range of immunologic activities associated with inflammatory and infectious diseases, cancer, and transplantation (Read & Powrie 2001). Moreover, abnormalities in the activity of these cells have been implicated in susceptibility to many conditions with underlying immune etiology, including allergy. Several types of regulatory T cells have been described and these can be broadly subdivided into natural and inducible regulatory T cells. Natural CD4+ regulatory T cells can be identified by the expression of CD25 and low expression of CD127 (IL-7 receptor α chain) (Seddiki et al. 2006). CD4+/CD25+/CD127lo regulatory T cells express FoxP3, which has been described as the master regulator of development and function of this population (Fontenot & Rudensky 2005), and their functional properties have been variously attributed to cytotoxic T-lymphocyte antigen (CTLA)-4, transforming growth factor (TGF)-β, and IL-10 but this remains an area of ongoing investigation and controversy. There are an increasing number of studies investigating the ontogeny of this population from fetal life onwards. A notable contrast with mice, in which many studies of regulatory T-cell populations have been performed, is that T cells with regulatory properties are present in the periphery from very early in human fetal development, whereas in mice these cells do not leave the thymus until after birth. A major difference between human adult and neonatal natural regulatory T cells is the predominance of CD45RA+/CD45RO– “naive” cells among the neonatal population. While activity typical of natural regulatory T cells has been described in umbilical

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cord blood, additional maturation/education of these cells is likely required in the periphery to attain adult comparable functionality (Wing et al. 2002, 2003, 2005; Seddiki et al. 2006; Rowe et al. 2007). The fetal lymph nodes seem to be the site of peripheral education as CD4+CD25+ regulatory T cells within human fetal lymph nodes have acquired a primed/memory phenotype and are highly suppressive of CD4+CD25– T cells (Cupedo et al. 2005). The relative ease of identification of natural regulatory T cells in peripheral and umbilical cord blood has accelerated investigation of the role of these cells in health and disease. There is a burgeoning literature on the contribution of these cells to allergic disease, especially as the phenotype associated with mutations in FoxP3 includes eczema, eosinophilia, elevated serum IgE, and enhanced Th2 responses (Chatila et al. 2000). Notably there has been a shift in the paradigm relating Th2-skewed adaptive immune responses and allergic disease (Fig. 2.2). While there are increasing numbers of publications identifying perturbations in the activity of CD4+CD25+ T cells in allergic adults, a direct causal relationship between these cells and allergic inflammation in humans has not been demonstrated. There have been only a few studies attempting to relate the function of natural regulatory T cells in early life with allergic outcomes in childhood and beyond. In a study examining regulatory T-cell activity both before and after an in vivo milk challenge in children (aged 6–56 months) who had either outgrown or retained their non-IgE mediated cows’ milk allergy, differences in the ability of peripheral blood mononuclear cells to respond to β-lactoglobulin could be explained by enhanced suppressive activity of CD4+CD25+

OLD MODEL Th1

NEW MODEL Th2

Th1

Th2

Treg

Dendritic cell

Dendritic cell

Microbial stimulation

Microbial stimulation

Fig. 2.2 The “old” Th1/Th2 paradigm model to explain the role of the microbial environment in the development of allergen-specific Th2 memory and the “new” model which incorporates the postulated role of regulatory T cells. In the “old” model, microbial exposure of dendritic cells induces a cytokine profile that favors Th1- or Th2-biased activity and further crossregulation by Th1 and Th2 cells prohibits either Th1- or Th2-biased activity depending on the nature of the initial microbial exposure. The “new” model incorporates regulatory T-cell populations and the microbial exposure prevalent at the time of exposure to allergen determines the balance between these effector T-cell populations. (See CD-ROM for color version.)

Development of Allergy and Atopy

T cells in the tolerant children (Karlsson et al. 2004). Also, a greater proportion of CD4+CD25+ T cells in the tolerant children expressed CD45RO. Of even greater interest is the possibility that perturbations in regulatory T-cell activity could be identified and targeted prior to disease onset, i.e., at birth. Elevated IL-10 (protein) and FoxP3 (mRNA) expression after stimulation with a TLR2 ligand has been described in cord blood mononuclear cells of neonates born to nonatopic mothers versus those born to atopic mothers (Schaub et al. 2006). Similarly, it has been suggested that the ability to generate regulatory T cells in response to antigen and LPS is impaired in newborns at risk of developing allergic disease (Haddeland et al. 2005). It is tempting to speculate, therefore, that children born to atopic mothers, who are at increased risk of developing allergy, might have an impaired ability to generate regulatory T-cell activity in early life. However, in the absence of definitive phenotypic and functional data about the cells of interest in each of these studies, this is not possible. However, these studies do highlight the extensive interest in this area and the need for detailed studies relating the phenotype and function of regulatory T-cell subsets to family history and, more importantly, clinical manifestation of allergic disease. Additional regulatory T-cell populations are also of interest but are comparably underinvestigated, and these include CD8+CD25+ regulatory T cells, inducible regulatory T cells, and natural killer (NK)T cells (Akbari et al. 2003). CD8+CD25+ human thymocytes with similar phenotypic and functional characteristics to the CD4+CD25+ population have been described (Cosmi et al. 2003) but there is as yet no information about these in relation to allergy at any age. Similarly, both CD4+ and CD8+ inducible regulatory T-cell subsets have been described and while there is great interest in the therapeutic use of these there are no data concerning the activity of these cells in childhood (Horwitz et al. 2003). Of these additional regulatory T-cell subsets, NKT cells have received the most study in relation to allergy although there are few studies of these in childhood. NKT cells are a T-cell population that have a very narrow T-cell repertoire and express cell surface markers characteristic of NK cells. Unlike conventional T cells, they recognize glycolipid antigen in the context of the monomorphic antigen-presenting molecule CD1d. Interest in their regulatory activity is driven by the capacity of NKT cells to rapidly produce large amounts of Th1 and Th2 cytokines and the postulate that they support Th2 responses in allergy (Akbari et al. 2003; van der Vliet et al. 2004). While adult NKT cells produce both IL-4 and IFN-γ, neonatal NKT cells preferentially produce IL-4 and can produce more IL-4 than adult NKT cells in contrast to conventional neonatal T cells that are comparably poor producers of IL-4 (Kadowaki et al. 2001). Thus a role for them in the initial polarization of antigen-specific Th2 cells is feasible. As discussed below, consideration of the impact of microbial exposures on allergic outcomes relates these to the interplay

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between innate and immunoregulatory mechanisms. The role of TLRs and other relevant receptors on dendritic cells has already been discussed, although regulatory T-cell populations also express TLRs and are therefore responsive to microbial stimuli. CD25-expressing regulatory T cells express TLR2, TLR4, TLR5, and TLR8 and activation via these receptors has variable effects on survival, proliferation, and the suppressive activity of these cells (Sutmuller et al. 2006). There are no data concerning the expression and activity of TLRs on neonatal and pediatric regulatory T-cell populations but this would clearly be of great interest and might potentially have therapeutic implications. The next few years should see some exciting developments in our understanding of regulatory T-cell activity in early childhood and its impact on IgE sensitization and allergic disease outcomes. Other cell types with key roles in the development and manifestation of allergic disease include B cells, as the source of IgE and IgG, and eosinophils.

B lymphocytes, IgE and IgG Potential relationships between IgE and/or IgG and the development of allergic disease have been explored by numerous research groups. As the source of these immunoglobulins, B cells are therefore of interest. B cells can be detected early in fetal life and appear sequentially in the yolk sac (3 weeks), the paraaortic splanchnopleure (5 weeks), the liver (8 weeks), and the bone marrow (12 weeks), with the bone marrow the major site of B-cell generation from mid gestation onwards (Nunez et al. 1996; Holt & Jones 2000). Mature B cells can also be detected in the fetal intestine from around 14 weeks of gestation (Spencer et al. 1986; Golby et al. 2002). Circulating B cells at birth have an immature phenotype, with the majority of cells expressing IgM and CD1c, but postnatal maturation of circulating and tissue B cells and how this might relate to allergic disease outcomes is not extensively studied.

IgE There is much debate about the usefulness of elevated umbilical cord blood IgE as a predictor of the development of atopic disease in childhood and it is now generally well accepted that while it is a strong risk factor for atopic sensitization, it lacks the predictive sensitivity to be useful for identification of those newborns who should be targeted for disease preventive measures (Magnusson 1988; Edenharter et al. 1998). The source of IgE in the fetus/neonate remains unclear, although in the absence of placental transfer of IgE it is presumed that circulating levels in the neonate represent endogenous production by the fetus/newborn (Schreyer et al. 1989; Avrech et al. 1994; Saji et al. 1999). IgE synthesis can be induced from fetal tissues as early as 11 weeks of gestation (Miller et al. 1973) and circulating IgE can be detected as early as 25–27 weeks of gestation (Thornton et al. 2003). VDJCε transcripts can be detected in fetal liver from the second trimester and cord blood from the third trimester but

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become more common in the infant’s blood after 9 months of age (Lima et al. 2000). Sterile Iε transcripts can be detected as early as 8 weeks of gestation, indicating that many fetuses are primed from isotype switching to IgE production by the end of the first trimester of pregnancy. Notably, although numbers were insufficient to achieve statistical significance, the ability to detect early transcription of Iε and VDJCε (and IL-4Rα) was absolutely associated with the presence of a polymorphism in IL-4Rα known to be associated with a high risk of atopy (Lima et al. 2000). Discrepancies between levels of IgE in the circulation and in local tissues are described frequently. During helminth infection IgE is abundant in the gut and circulating levels are only 0.5–1% of total IgE (Negrao-Correa et al. 1996) so local production is not mirrored by circulating levels. Thus IgE levels in the gut might be more useful in very early life but there are few studies on this, although fecal IgE levels at 1 month of age are more often detectable in children with a family history of atopy and are associated with atopic outcome at 18 months of age (Sasai et al. 1994).

IgG Findings from animal models support a key role for maternally derived IgG (either prenatally via the placenta or postnatally via breast milk) in modulation of the infant’s immunologic development. In a mouse model, immunization of the mother against house-dust mite either during pregnancy (Melkild et al. 2002) or prior to conception (Victor et al. 2003) protected the offspring against the development of allergy. Although the mechanism by which this occurs is unknown, maternal IgG has been shown to suppress IgE responses by the offspring (Jarrett & Hall 1983). High IgG anti-IgE levels at birth have been suggested to protect children at increased risk of allergy from the development of disease and/or reduce the severity of symptoms (Vassella et al. 1994). Therefore there has been much interest in how patterns of allergen-specific IgG might relate to the development of allergic disease. IgG in the newborn’s circulation is almost entirely of maternal origin. While IgG transfer from mother to fetus via the placenta begins at around 16 weeks of gestation, much of this IgG is acquired during the last 4 weeks of pregnancy. Maturation of IgG production by the newborn occurs slowly and adult-like levels are not reached until around 3 years of age. Expression of IgG receptors (Fcγ receptor isoforms and the neonatal Fc receptor [FcRn]) by cells of the placenta have a central role in IgG transfer during fetal development (Saji et al. 1999; Thornton & Vance 2002). Expression of FcRn within the gastrointestinal tract also facilities interaction with IgG in breast milk (and amniotic fluid) and this receptor has been implicated in mucosal immune responses to gastrointestinal bacteria via its role in facilitating secretion of IgG into the gut lumen and the delivery of antigen to mucosal dendritic cells (Yoshida et al. 2004, 2006).

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Sensitization to hen’s egg is a recognized risk factor for the later development of inhalant sensitization and asthma (Hattevig et al. 1987, 1993; Nickel et al. 1997) and egg-specific IgG has also been identified as a marker of an underlying allergic process: high levels of egg-specific total IgG, IgG1, and IgG4 are associated with allergic sensitization and disease (Okahata et al. 1990; Eysink et al. 1999). Furthermore, a dichotomous pattern of egg-specific total IgG and subclasses has been observed at 6 months of age in subsequently atopic and nonatopic children, implying that specific IgG responses might predate IgE responses and the clinical manifestation of disease (Jenmalm & Bjorksten 1999). Elevated ovalbumin (OVA)-specific IgG1 at 1 year of age can predict the subsequent development of asthma, with a predictive performance that outranks that of total IgE measurements either at birth or in infancy (Vance et al. 2004). While this might simply mark those children with atopic eczema, which is a wellknown risk factor for the later development of asthma (Kjellman & Hattevig 1994; Bergmann et al. 1998), the measurement of OVA-specific IgG and subclasses in infancy might be a useful serologic adjunct to clinical evaluation and skin-prick testing for the early identification of those children at particular risk of developing later allergic sequelae.

Development of Allergy and Atopy

(Halmerbauer et al. 2000; Gore et al. 2003). Cord blood eosinophilia has been associated with the development of eczema at 1 month of age, the earlier development of atopic dermatitis, and the development of wheezing disease (Matsumoto et al. 2005). Nasal lavage fluid from children at high risk of developing allergy had elevated levels of ECP and EPX at 4 weeks of age, suggesting activation of eosinophils at the respiratory epithelium (Halmerbauer et al. 2000), although the transient or persistent nature of this nasal eosinophilia in very early life remains to be determined. However, peripheral blood but not nasal eosinophilia at 3 months and persisting until 18 months of age was observed in children who developed active atopic disease by 18 months of age, and if coupled with elevated IL-4 was associated with disease persisting until 6 years of age (Borres et al. 1995).

Cytokines and chemokines Cytokines As noted above there is particular interest in Th1/Th2 cytokines (principally the prototypic Th1 cytokine IFN-γ and the Th2 cytokines IL-4, IL-5, IL-9, and IL-13) and, more recently, regulatory cytokines (namely IL-10 and TGF-β). The contribution of Th1, Th2, and regulatory cytokines to allergic disease development has already been discussed.

Eosinophils Blood and tissue eosinophilia are hallmarks of allergy and asthma in adults and children. As umbilical cord blood contains more mature eosinophils than adult blood, neonates have a propensity to high eosinophil counts. Coupled with recognized differences in eosinophil trafficking in neonatal life, this has been postulated to have a physiologic role during colonization of the skin and mucosal surfaces during early extrauterine life (Patel et al. 1994). Additional or alternative roles for eosinophils during early infancy are supported by increased adhesion molecule expression and transmigration activity in neonatal versus adult eosinophils (Moshfegh et al. 2005). Eosinophils are reported to initiate and amplify antigenspecific Th2 cell responses (MacKenzie et al. 2001) so eosinophils present at mucosal surfaces in early life might contribute to the initiation of Th2-biased reactivity to allergens to which the infant is being exposed; in particular, eosinophils within Peyer’s patches cooperate with lymphocytes in the development of mucosal immune responses (Mishra et al. 2000). Although there are no studies of eosinophil phenotype and function in infancy, numerous investigators have sought to determine whether blood eosinophilia at birth or in infancy might be a predictive marker of atopy development. As eosinophilia is supported, among other mediators, by the Th2 cytokine IL-5, postnatal variation in maturation of the Th1 and/or Th2 populations might manifest as increased circulating and/or tissue eosinophils (Neaville et al. 2003). Many studies in children use surrogate markers of eosinophilia such as elevated eosinophil cationic protein (ECP) and eosinophil protein X (EPX) in serum, lavage fluids, or urine

Chemokines Chemokines are small secreted molecules that regulate the trafficking of leukocytes throughout the body by triggering integrin activation, firm arrest to the vascular endothelium, and then localization within tissues. Chemokines therefore have a critical role in the initiation and amplification of inflammation within the gut, skin, and airways. The role of chemokines in the development of allergic disease is best studied in the skin. Keratinocytes (and other cells in the skin) produce a unique profile of chemokines (e.g., TARC/CCL17 and CTACK/ CCL27) recognized to have a role in the development of eczema. These chemokines preferentially attract subsets of cutaneous lymphocyte antigen (CLA)-positive memory T cells via interaction with the chemokine receptors CCR4 and CCR10 (Morales et al. 1999). Serum thymus and activationregulated chemokine (TARC), macrophage-derived chemokine (MDC), cutaneous T-cell attracting chemokine (CTACK) levels are significantly higher in children (aged 4.9 ± 3.3 years, range 2 months to 14 years) with atopic dermatitis and correlate with disease severity in children with either atopic or nonatopic eczema. Levels of TARC and CTACK decline with age, indicating that they are at their highest during the period of greatest likelihood of developing eczema (Song et al. 2006). Understanding the regulation of chemokine/chemokine receptor expression during early life is likely to be crucial in relation to elucidation of mechanisms of allergic disease development in childhood. Chemokine receptor expression by T cells differs dramatically between adults and neonates (Sato et al. 2001) and T-cell trafficking is more promiscuous

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during fetal life as naive T cells can traffic through peripheral tissues and even recirculate through the thymus during this period (Cahill et al. 1999). Presumably this has a critical role in the development of peripheral tolerance but how long these differences persist postnatally remains to be determined. Expression of CCR4 and CCR10 has not been well studied in childhood but the percentage of T cells bearing CLA increases with age from birth, where expression is virtually absent, to adulthood when over 10% of T cells express CLA (Campbell & Kemp 1999). This is likely to reflect the acquisition of memory T cells from birth to adulthood. The role of CLA in childhood atopic dermatitis is unclear, although an increased percentage of T-cell receptor Vβ segments related to Staphylococcus aureus superantigens has been described in CLA-positive cells from children with atopic dermatitis (Torres et al. 1998), and other surface markers might have a more important role.

Tissue-specific aspects of immune development Understanding the maturation of hematopoietic and other cells in the tissues affected by allergic disease is critical to elucidating the underlying mechanisms of disease development.

Skin Atopic eczema is a common, chronic, relapsing, itchy, inflammatory skin condition associated with epidermal barrier dysfunction and cutaneous hyperreactivity to environmental triggers. It is characterized by typically distributed eczematous skin lesions with lichenification, pruritic excoriations, severely dry skin, and susceptibility to cutaneous infection. The clinical presentation of eczema represents complex interactions between susceptibility genes, the environment, defective skin barrier function, and immunologic responses. Around 50% of all atopic eczema develops in the first year of life and 80% develops by 5 years of age. There is a link between food allergy and atopic dermatitis. Food allergens can induce eczematoid skin lesions and nearly 40% of children with moderate to severe atopic eczema have food allergy (skin-prick test positive or circulating IgE to various foods, particularly eggs, milk, wheat, soy, and peanuts) (Eigenmann et al. 1998; Laan et al. 2000). Moreover, food allergen-specific T cells can be cloned from skin lesions of patients with atopic eczema and in mouse models of atopic eczema, oral sensitization with foods (cows’ milk and peanuts) results in the elicitation of eczematous skin lesions on repeat oral food challenges (Li et al. 2001). Children with atopic eczema are more likely than those with nonatopic eczema to have their eczema persist into adulthood and are more likely to develop other atopic disorders, primarily asthma. Indeed, atopic eczema is often the first manifestation of atopic disease in infancy and is generally considered to be the initial cutaneous mani-

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festation of a systemic disorder that leads to other atopic diseases including food allergy, asthma and allergic rhinitis, the so-called “atopic march” (see Chapter 57). Evidence of Th2-biased activity can be found among peripheral blood T cells, and subjects with atopic eczema can also have blood eosinophilia and elevated circulating total IgE. Perturbation of barrier function of the skin is an overriding feature of eczema, whether it is atopic or nonatopic. Skin barrier function is conferred by the stratum corneum, the outermost layer of the epidermis. During fetal development the skin progresses from a single-layered ectoderm to a multilayered keratinized epidermis. Keratinization commences at around 22–25 weeks of gestation (time of initiation varies with anatomic site) and the transitory layer that serves as an interface between the epidermis and amniotic fluid (periderm) is sloughed off into the amniotic fluid at this time (Yosipovitch et al. 2000). Barrier formation thus coincides with the current lower limit of viability of the preterm infant and is completed many weeks before normal term birth. However, the stratum corneum barrier must still adapt to extrauterine life. Epidermal Langerhans cells (the contiguous network of dendritic cells peculiar to the skin) are phenotypically mature in the second trimester, although numbers increase (e.g., density of Langerhans cells up to 23 weeks’ gestation is 10–20% of adult levels) and dendritic processes develop gradually with age (Foster & Holbrook 1989; Fujita et al. 1991). Peptide antibiotics present in the vernix caseosa (the cream-like substance present on the infant’s skin at birth) and skin of the healthy newborn have a role in innate immune protection during fetal and neonatal life (Marchini et al. 2002).

Gastrointestinal tract From birth onwards the gastrointestinal tract is continuously exposed to food antigens and microbial products from the commensal microflora and invading pathogens. In normal healthy humans the gut immune system is in a state of continual high activity, centered on the organized lymphoid tissues in the small intestine (Peyer’s patches), although relevant cell types and even isolated lymphoid follicles are dispersed throughout the lamina propria (MacDonald 2003). Peyer’s patches are the principal site for induction of antigen-specific tolerance to food and commensal flora antigens, including the preferential development of IL-10-secreting T cells with suppressive activity (regulatory T cells) (Fujihashi et al. 2001; Jump & Levine 2002). CD103 expression by dendritic cells within gut-associated lymphoid tissues has a central role in the maintenance of the healthy balance between effector and regulatory T-cell activity within the gut (Annacker et al. 2005). The intestine contains the largest pool of T cells in the body and is a unique immunologic compartment in which hematopoietic (and other) cells come into close contact with the intestinal microflora and food antigens. The neonate is born with a sterile gastrointestinal tract but acquisition of the commensal gut flora, exposure to potential pathogens, and

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introduction of food antigens commences at birth. The gut in particular serves as an interface between the developing immune system and microbial antigens, and the intestinal microbiota has a role in immune maturation (discussed below). The epithelial layer, together with intraepithelial and lamina propria immunocompetent cells, coordinate local innate and adaptive immune responses to the microbial challenge. The gastrointestinal commensal flora shapes both mucosal and systemic immune function throughout life and is implicated in the induction of protective IgA and oral tolerance, including induction of regulatory T cells, and immune deviation. Consequently, the host is highly adapted to its own commensal flora (Macpherson & Harris 2004). Functional heterogeneity and organization of cells within the gastrointestinal tract occurs prior to birth and in the absence of dietary and bacterial antigens (Spencer et al. 1987; Howie et al. 1998). MHC class II-positive cells can be detected in the human fetal gut as early as 11 weeks of gestation: initially these cells are dispersed throughout the lamina propria but aggregates can be found in the forming lymphoid follicles from around 16–19 weeks of gestation. T cells can be detected as early as 12–14 weeks of gestation (Spencer et al. 1986) and the numbers of these cells increase rapidly so that by 19–22 weeks the density is approximately one-third of that in the adult intestine (Howie et al. 1998). B cells can be detected as early as 14 weeks of gestation (Spencer et al. 1986). Once lymphoid follicles and aggregates emerge, clusters of T cells and B cells as well as dendritic cells can be observed within these clusters and costimulatory molecules are expressed by these populations (Spencer et al. 1986; Jones et al. 2001). The gut immune system maintains a balance between remaining relatively unresponsive to dietary and commensal flora antigens yet making a response to pathogens. There is increasing evidence that perturbing the homeostasis between gut antigens and host immunity is a critical determinant in the development of gut inflammation and allergy (MacDonald & Monteleone 2005).

Airways Alterations to lung development during intrauterine and early extrauterine development mediated by genetic or environmental factors might have long-term consequences for airflow limitation and airways disease. The structure and proportions of the infant’s airways and lungs differ to that of the adult and combined with relatively greater chest wall compliance in childhood might accentuate functional differences (Jeffery 1998). The pattern of airway branching is completed by 16 weeks of gestation and the airways continue to increase in size as lung volume increases (Hislop et al. 1972). The diameter of the airways increases linearly from 22 weeks until term and continues to increase after birth, doubling or tripling in diameter and length between birth and adulthood (Hislop & Haworth 1989). During fetal development the fetal airways are relatively

Development of Allergy and Atopy

devoid of hematopoietic cells (Alenghat & Esterly 1984; Grigg et al. 1993) and seeding with resident populations of these cells must occur after birth. Because little change in the leukocyte profile in the lower airways of children is evident after 3 years of age, the first 3 years of life must therefore be the critical period. Notably there is rapid acquisition of an abundant resident population of alveolar macrophages in the first 2 years of life, with a gradual decline to 3 years of age (Grigg et al. 1999). Conversely, lymphocytes are relatively absent from bronchoalveolar lavage fluid collected prior to 2 years of age and increase after this time (Riedler et al. 1995). Thus developmental changes in the lower airway cell profile are relatively restricted to the first few years after birth. The factors that drive the expansion and maturation of these cell populations are unknown but are likely to include microbial stimuli (particularly viruses) and genetic factors are also likely to be involved. There is now much interest in the contribution of the bronchial epithelium to the local immunomodulatory milieu but this has not yet been studied in infancy. Studies of airways dendritic cell distribution and function in early life are generally conducted using animal models. Between birth and weaning dendritic cells are present in very small numbers in the airway wall and express only low levels of surface MHC class II Active immune suppression within the lung microenvironment might be a feature of early life as neonatal airways dendritic cells are hyporesponsive to inflammatory stimuli and activation signals (Nelson et al. 1994; Nelson & Holt 1995). Similarly mature dendritic cells are rare in the airway mucosa of humans prior to the first birthday (Stoltenberg et al. 1993; Tschernig et al. 2001) unless the infant has had a respiratory tract infection (Tschernig et al. 2001). Further evidence that viruses have a critical role in development of this network is the observation of increased dendritic cell numbers in nasal lavage fluid from children aged less than 15 months who have a viral, including RSV, infection. A decrease in these same populations in the blood occurred simultaneously, indicating mobilization of these cells to the mucosa (Gill et al. 2005). Thus, unlike the gut and skin, the respiratory tract dendritic cell network develops almost entirely postnatally.

Environment Studies revealing dramatic differences in allergic disease prevalence in genetically similar populations living in discrete environments (e.g., former East and West Germany, migrant and nonmigrant populations of the same ethnicity; von Mutius et al. 1994; von Hertzen & Haahtela 2004) indicate a central role for environmental factors, especially those related to a Western lifestyle, in the development of allergy and allergic disease. The environmental factors postulated to have a role in modifying the development of allergic disease can be divided broadly into two categories: those that relate to the hygiene hypothesis and those that do not (Table 2.1).

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Table 2.1 Environmental risk factors associated with the development of allergy and allergic disease in childhood. Hygiene hypothesis related Family size, birth order Infectious diseases Vaccinations Antibiotic use Farming Endotoxin Pet ownership Other Breast-feeding Parental smoking Diet and nutrition Obesity Perinatal factors

Hygiene hypothesis Since the inverse association between family size and birth order and the risk of developing allergy was highlighted (Strachan 1989), the hygiene hypothesis has emerged as a prominent candidate to explain this relationship. The current incarnation of the hypothesis relates the innate immune response to immunoregulatory mechanisms and suggests that microbial signals regulate the maturation and pattern of immune responsiveness in early life and that deficiencies in this signaling underlie the increasing prevalence of allergic (and other) diseases (Romagnani 2004; von Hertzen & Haahtela 2004). Central to this is the premise that the host response to microbial stimuli has changed as a consequence of alterations in the nature, timing or dose of microbial signals received postnatally, or even prenatally. A multitude of relevant microbial signals and environmental sources have now been investigated and a variety of epidemiologic, and to a lesser extent experimental, evidence has been provided under the umbrella term “hygiene hypothesis.”

Sibling effect, family size, and birth order Interest in the so-called “sibling effect” was initiated by the observation that the prevalence of hay fever was lower in children from larger families and while both the number of older and younger siblings exerted an effect, this was stronger for the older siblings (Strachan 1989). These observations lead to the (hygiene) hypothesis that the presence of older siblings transmits infections in early life, providing protection against the development of disease. The immunologic mechanism underlying this protective effect was later postulated to be the downregulation/prevention of Th2-skewed reactivity to allergens as a consequence of the ability of infectious organisms to favor Th1 reactivity.

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Numerous investigators have since explored the relationship between family size, birth order, and allergic outcomes. A review of the relevant literature (1965–2000) highlighted that while nearly all studies report an inverse relationship between the number of siblings and eczema, hay fever and atopic sensitization, the relationship is less robust for asthma, with only around 70% of studies reporting an inverse association for asthma/wheezing (Karmaus & Botezan 2002). The contradictory results surrounding the birth-order effect in asthma are likely to reflect the age at which outcome measures are made. For example, an older sibling in the home is associated with more frequent wheezing before the age of 2 years but children of higher birth order are less likely to have frequent wheezing after this age (Ball et al. 2000; McKeever et al. 2001). A major ambiguity in the birth order and allergic outcomes literature lies in the nature of the sibling effect, as authors variably relate their outcome measures to birth order, number of siblings, family size, number of older siblings, number of younger siblings, number of brothers, and even just having an older brother (Karmaus & Botezan 2002). The causal factors underlying the sibling effect remain unknown but the hygiene hypothesis prevails. However, family size is likely to be an indirect measure of some as yet undetermined biologically relevant factor(s) that increases with family size and in other (non-Western) environments with low prevalence of allergic disease (Strachan 2000). Two alternative, but not mutually exclusive, formulations of the birth order/family size effect on allergy and allergic disease have also been considered but to a much lesser extent: (i) the maternal microbial burden changes with each pregnancy that results in a live birth (each successive child increasing this burden) (Hersoug 2006); and (ii) hormonal and other changes in each pregnancy differentially affect the mother’s own allergic disease and the immunologic development of each successive fetus/child (Doull 2001; Rangaraj & Doull 2003). Each of these is postulated to impact on the developing fetal immune system with downstream consequences for the development of allergic disease. In contrast to the prevailing interpretation of the birth order effect (i.e., hygiene hypothesis), there are relatively few studies exploring the impact of changes in maternal immune function in successive pregnancies on the health and atopic status of either the mother or child. The hypothesis that microbial exposures via siblings might account for the protective effect on atopic outcomes as discussed above has now evolved to take into consideration environmental sources that provide or modify patterns of microbial exposure in infancy, such as farming, daycare, vaccinations, and antibiotics. Investigators have also tried to pinpoint the critical exposures that might provide protection against the development of allergic disease and these include infectious diseases of childhood, endotoxin, and the gastrointestinal flora.

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Early life infections While there have been a number of studies addressing the possibility that the dramatic reduction during the 20th century in the incidence of childhood diseases such as measles, mumps, rubella, and chickenpox underlies the increasing prevalence of atopic disease, there are insufficient data to support a critical role for these life-threatening childhood diseases in postnatal maturation of immune, gastrointestinal, skin and/or airways function. Moreover, the microbial burden in general rather than single infections has been suggested to be of greater importance for the regulation of immune responses in early life (Martinez 2001). This has shifted interest to the common respiratory and gastrointestinal bacterial and viral infections that form much of the infectious burden of children growing up in westernized countries. Bacterial, fungal, gastrointestinal, or urinary tract infections in the first year of life were not associated with wheeze between 4 and 7 years of age but repeated viral, other than lower respiratory tract, infection in early life might reduce the risk of developing asthma/wheeze up to 7 years of age and atopy up to at least 5 years of age (Illi et al. 2001). In contrast repeated lower respiratory tract infections (LRTI) with wheezing in the first 3 years of life have a positive association with wheeze up to 7 years of age but this is likely to reflect reverse causation (children predisposed to asthma might be more susceptible to LRTI) (Illi et al. 2001). The observed effects were strongest for infections in the first year of life, with the addition of infections from the second and third year of life having little impact on the results. Thus the nature and timing of infection as well as the host response to infection are critical. Consequently, discussions of the effects of infections on the pathogenesis of allergic disease have become increasingly complex. While a variety of epidemiologic evidence now supports a protective role for infection, viruses trigger around 85% of asthma exacerbations (Openshaw et al. 2004). However, it is the role of viruses in the onset of disease that is of greatest interest and there is a growing appreciation of the complex relationship between viral respiratory tract infections and the development of asthma in particular. RSV infection in infancy has been associated with the later onset of asthma by numerous groups (Openshaw et al. 2004). However, it remains unknown if those infants who suffer RSV-induced bronchiolitis at around 2–6 months of age are the subgroup at risk of developing asthma or if the virus modifies the local environment, both physiologically and immunologically, during this critical period of development. Susceptibility to RSV-associated wheeze is heavily dependent on age of infection and thereby developmental status of the immune system (Culley et al. 2002). Similarly, RSV or influenza/parainfluenza virus favors Th2 responses in the nose (elevated eosinophils and IL-4 in nasal lavage fluids) if infection occurs before 3 months of age (Kristjansson et al. 2005). Thus the nature of the host response, which is likely

Development of Allergy and Atopy

to be developmentally and genetically programmed, is emerging as a key contributor to the impact of microbial exposure on allergic disease development. TLR4 and CD14 have been identified as receptors for RSV (Kurt-Jones et al. 2000) and variation in the expression of these receptors could impact on the response to RSV. Moreover, RSV upregulates TLR4 expression by airways epithelial cells and makes the cells sensitive to endotoxin (Monick et al. 2003). Children who attended daycare, especially daycare centers rather than family daycare homes, have a reduced risk of becoming atopic, with the likelihood of developing atopy decreasing as age of first attendance decreases (Kramer et al. 1999; Haby et al. 2000). However, children who attend daycare centers are more likely to suffer serious respiratory infection, including pneumonia and bronchitis, have a history of repeated respiratory illness, otitis media and the common cold, and suffer from nightly cough and blocked/runny nose without common cold (Celedon et al. 1999; Nafstad et al. 1999; Haby et al. 2000; Slack-Smith et al. 2002; HagerhedEngman et al. 2006). In contrast with atopy, the risk of developing these increases with decreasing age of first attendance at child care. While there are reports of increased risk of current wheezing, doctor-diagnosed asthma, current rhinitis, doctor-diagnosed hay fever, and food allergy among children who attended daycare, this tends to peak prior to 4 years of age (Nafstad et al. 1999; Ball et al. 2000; Hagerhed-Engman et al. 2006) and these children are less likely to suffer these disorders after 4–6 years of age (Ball et al. 2000; HagerhedEngman et al. 2006). So while the burden of common childhood diseases is greatest among children who attend daycare, the long-term outcome appears to be protection against the development of asthma and this protection is presumed to reflect the protective effects of early daycare attendance on the development of atopic sensitization (Ball et al. 2000). While there remains much interest in the impact of respiratory viral infections on postnatal lung development and wheezing/asthma outcomes, there has been another shift in the “hygiene hypothesis” away from the infectious microbial burden to the environmental/commensal microbial burden.

Farm environment The favorable effects of an early childhood spent on a farm have now been demonstrated in many countries and include a reduction in atopic sensitization in children aged 6–15 years (Braun-Fahrlander et al. 1999); reduced prevalence of hay fever, asthma, and skin-prick reactivity among 8–10 year olds (Riedler et al. 2000); lower prevalences of hay fever, asthma, and wheeze in 5–7 year olds (Von Ehrenstein et al. 2000); protection against IgE sensitization in 7–12-year-old children (Downs et al. 2001); lower risk ratio for ever having asthma and/or allergic rhinoconjunctivitis but not skin-test reactivity in children aged 7–8 years (Klintberg et al. 2001); and significantly less current asthma symptoms and current seasonal rhinitis but no difference in eczema (Perkin &

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Strachan 2006). The benefits of farming seem to relate to the presence of livestock, especially barns, stables and unpasteurized milk, and the greatest benefits occur if exposures occur during early life and even prenatally. The critical component of the farming environment postulated to protect against the development of allergy and allergic disease is exposure to microbial antigens in barns, stables, farmhouses, and unpasteurized milk leading to the stimulation of Th1-biased reactivity. Notably elevated levels of bacterial endotoxin, and other microbial products such as mold glucans and fungal extracellular polysaccharides, are a feature of farming households, barns, and stables (Von Mutius et al. 2000; Braun-Fahrlander et al. 2002; Schram et al. 2005; Perkin & Strachan 2006). The timing and duration of exposures are crucial for the protective effect: exposure of children aged less than 1 year to stables and unpasteurized milk was associated with lower frequencies of asthma and atopic sensitization compared with 1–5 year olds, although continual long-term exposure to stables until 5 years was associated with the lowest frequencies of asthma, hay fever, and atopic sensitization (Riedler et al. 2001). The children of farmers have elevated CD14, TLR2, and TLR4 gene expression compared with the children of nonfarmers (Lauener et al. 2002) and the expression of these genes might be fetally programmed in response to maternal exposures in pregnancy as each additional farm species to which the mother was exposed during pregnancy increased the expression of CD14, TLR2, and TLR4 (Ege et al. 2006). Unpasteurized milk consumption, even when infrequent and unrelated to farming status, has been associated with reduced risk of being skinprick test positive, less current eczema, lower total serum IgE, and higher whole blood IFN-γ responses to PHA in childhood (Perkin & Strachan 2006).

Endotoxin The majority of studies report an inverse association between household (farming and nonfarming) levels of endotoxin

and the development of eczema, hay fever, and atopic sensitization in infancy and childhood (Gereda et al. 2000; BraunFahrlander et al. 2002). However, the relationship between endotoxin and asthma/wheezing is far more complex, with reports of no association, an inverse association with atopic but not nonatopic wheeze, and a positive relationship. These studies differ greatly in the times at which endotoxin was measured, the site at which household dust was sampled, the family history of the children, and when disease outcomes were determined. For example, endotoxin levels measured at 3 months of age in the living room but not the mattress were inversely associated with physician-diagnosed asthma during the first 4 years of life (Schram et al. 2005), whereas there was no relationship between living room floor endotoxin levels measured at 5–10 years of age and a diagnosis of asthma at the same age (Gehring et al. 2002). Variation in the effect of/response to endotoxin is likely to reflect the duration, type, and level of exposure and to be determined by inherited predisposition. In particular, exposures immediately after birth might have different effects to exposures that occur once allergen-specific T-cell memory has been established. Animal models support this: exposure to endotoxin early in the sensitization process protects against the development of sensitization, whereas exposure after sensitization exacerbates the inflammatory response in the airways but has no effect on sensitization (Meri et al. 2000) (Fig. 2.3). In humans, household endotoxin levels correlated positively with the percentage of CD4+ T cells producing IFN-γ in infancy (Gereda et al. 2000), whereas among 6–13 year olds LPS-stimulated tumor necrosis factor (TNF)-α, IFN-γ, IL-10, and IL-12 production was inversely related to household endotoxin levels, indicating that by this age endotoxin tolerance had occurred (Braun-Fahrlander et al. 2002). The beneficial effects of early LPS exposure might extend prenatally since maternal exposure to LPS was associated with increased IFN-γ response by neonatal mice and, in OVAsensitized animals, prenatal LPS exposure was accompanied

ENDOTOXIN

Dendritic cell

Th1

Dendritic cell

Allergen

Th2

Th1

Allergen

Th2 Allergic inflammation Tissue remodeling

No allergic disease

Epithelium

ENDOTOXIN Allergic disease exacerbation

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Fig. 2.3 Beneficial and detrimental effects of endotoxin reflect the timing and dose of exposure as well as genetic and other environmental determinants. Early exposure to lipopolysaccharide is postulated to favor Th1 responses and downregulation of Th2-trophic activity prevents the development of allergenspecific IgE. However, once allergen-specific Th2-trophic activity is established and tissue remodeling/inflammation has occurred, exposure to endotoxin exacerbates this inflammation. (See CD-ROM for color version.)

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by reduced OVA-specific IgG1 and IgE and reduced bronchoalveolar lavage fluid eosinophils but had no effect on airway hyperreactivity (Blumer et al. 2005).

Domestic pets Interest in the contribution of cats and dogs to the development of allergy and allergic disease stem from their contribution to both the indoor allergen load and the household endotoxin burden, and even homes without pets contain detectable cat and dog allergens (Nafstad et al. 2001). Controversy continues to surround whether furred pets have a beneficial or detrimental effect on atopic sensitization and the development of allergic disease. As for other environmental exposures, the timing, duration, and level of exposure, as well as family history of allergic disease, are likely to have critical roles in determining allergic outcomes. However, in general cat and/or dog exposure in early life is beneficial whereas current cat (but not dog) ownership or high community cat ownership are significant risks for both sensitization and disease manifestation. The level of exposure in early life might be of critical importance: exposure to cats in the child’s bedroom, which might mark intensive exposure to cats, but not at other sites in the house was associated with reduced prevalence of atopic asthma at 5–7 years of age (Oberle et al. 2003); the highest exposure to cat was associated with decreased prevalence of sensitization to cat and higher prevalence of IgG (including IgG4) to Fel d1, with nonsensitized children exhibiting an IgG (including IgG4) response but not an IgE response (Platts-Mills et al. 2001; Lau et al. 2005). Thus if exposure leads to the production of only specific IgG a child will not develop disease, whereas if IgE and IgG develop the child is at risk of developing wheeze/ asthma (Lau et al. 2005). This relationship might be peculiar to cat allergen (Platts-Mills et al. 2001) and the level of exposure required to achieve this effect is likely to vary between populations.

Vaccinations Routine vaccinations in early life offer essential protection against potentially fatal disease. However, comprehensive vaccine strategies in Western countries have been postulated to contribute to the increase in allergy and allergic disease over recent decades. Vaccinations might have a protective effect on the development of atopy as they could directly stimulate Th1-like immunity or might favor IgE production and allergic disease by reducing the incidence of some infections that indirectly prevent “natural” Th1-like immunity (Gruber et al. 2001). Consequently there are now many studies published that consider the potential relationship between early vaccine exposures (including DTP, MMR, HBV, HIB) and allergic outcomes. While there are reports of an association between some vaccinations and eczema, asthma, and hay fever (Farooqi & Hopkin 1998), most of the available data, including those from large (> 100 000 subjects) multi-

Development of Allergy and Atopy

center studies, suggest that there is no association between any common childhood vaccinations (including individual vaccinations, total doses received, number of different vaccines received, and age at which received) and the development of IgE sensitization or allergic disease up to at least 16 years of age (Anderson et al. 2001; Koppen et al. 2004). Childhood vaccination remains an essential part of “well child” health programs throughout the world and there is no evidence to suggest that this should change, although the immunostimulatory capacity of vaccines could be modified to provide optimal stimulation of the infant’s immune system. (Koppen et al. 2004). However, there is growing interest in the possibility that genetic risk for atopy influences the capacity to respond to vaccinations during infancy (Holt et al. 2003).

Antibiotics Children born between 1980 and 1995 received more antibiotic dispenses and had their first exposure at a younger age than children born in the previous decade (Mullooly et al. 2007). The use of antibiotics in the first year of life has been associated variably with increased risk of developing asthma, hay fever, and eczema and allergic sensitization in childhood, although the association between antibiotic use and wheezing/asthma outcomes is the most robust relationship. Indeed metaanalysis of studies in which antibiotic usage over first year of life was related to physician-diagnosed asthma between 1 and 18 years of age (four retrospective and four prospective) revealed that exposure to at least one course of antibiotics in the first year of life is a risk factor for the development of childhood asthma, although the authors highlighted the need for large-scale prospective studies to confirm this association (Marra et al. 2006). The timing and level of antibiotic exposure might be critical as the adjusted odds ratio for developing asthma was greater for antibiotic use in the first year of life than antibiotic use only after the first year of life or never used and for three or more courses in the first year of life versus zero, one, or two courses (Wickens et al. 1999). However, there is concern that the relationship between antibiotic use and wheezing/asthma outcomes might simply reflect reverse causation. In studies in which antibiotic use for LRTI was excluded, there was no effect of antibiotic use in the first year of life on asthma, recurrent wheezing, allergic rhinitis, or eczema (Illi et al. 2001; Celedon et al. 2002). Moreover while there was a relationship between antibiotic prescriptions prior to 5 years of age and self-reported asthma, especially in those sensitized to aeroallergens, antibiotics in this group were largely prescribed for LRTI (Cullinan et al. 2004) and children with LRTI or environmental tobacco smoke exposure are more likely to have antibiotics prescribed prior to 6 months of age (Droste et al. 2000). Thus early and repeated antibiotic usage might be a surrogate marker for the potential role of infections in the modification of immunologic maturation in early life and identify the

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children most susceptible to the development of LRTI and wheezing/asthma (Mullooly et al. 2007). Any link between antibiotic use and allergy and allergic outcomes might reflect the impact of oral antibiotic use on the gastrointestinal flora. As the composition of the maternal commensal flora late in the third trimester of pregnancy will influence that of the newborn, this could also explain the negative effect of maternal antibiotic use in pregnancy on wheezing/asthma by the child (McKeever et al. 2002a; Jedrychowski et al. 2006; Rusconi et al. 2007). Recent epidemiologic studies and experimental research, as summarized above, have highlighted that the microbial environment and exposure to microbial products in infancy might modify immune responses and enhance tolerance to ubiquitous dietary and environmental allergens. The intestinal microflora are a major external determinant of immune system maturation after birth and are requisite for the normal development of oral tolerance (Bjorksten 2004). Indeed the currently predominant version of the hygiene hypothesis, the “microbial exposure” hypothesis, reflects a critical role for altered patterns of subclinical, commensal, or environmental microbial exposure in early postnatal life (Bjorksten 2004; Noverr & Huffnagle 2005).

Gastrointestinal flora Studies of the fecal microflora in children generally indicate that decreased lactobacilli and bifidobacteria and increased clostridia are particularly associated with an allergic phenotype that typically relates to IgE sensitization, food allergy, and eczema. Differences in microflora composition might even extend to the species level and a more detailed analysis of clostridial species present in feces of allergic versus nonallergic children is warranted (Tonooka et al. 2005). Few studies have attempted to relate the commensal gut flora in childhood to wheezing/asthma outcomes but in keeping with the negative impact of elevated clostridia, increased circulating Clostridium difficile-specific IgG was more common at 1 year of age in atopic children with a history of recurrent wheeze compared with nonatopic children with no wheezing history (Woodcock et al. 2002). However, the prevalence of lactobacilli and bifidobacteria did not differ in stool samples collected from children ≥ 3 years old who were atopic/wheezy or nonatopic/nonwheezy (Murray et al. 2005). Nevertheless, as allergy-associated variations in fecal microflora can exist as early as 3 weeks of age and precede the manifestation of allergic disease, the composition of the gut microflora prior to the first birthday might have a central role in determining disease outcomes. The variations described to date are likely only the tip of the iceberg. The complex ecosystem of the intestinal microflora is estimated to contain approximately 400 microbial species, mostly bacteria. Studies of bacterial colonization in the gut are based almost entirely on conventional culture methods of fecal samples, which can only detect a small frac-

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tion of the commensal gut flora. While feces is the sample of choice, it does not fully represent the complex microflora as species distributions vary throughout the gut and fecal sampling does not give a direct indication of commensal microbiota composition, especially in the upper gastrointestinal tract. Of particular relevance, a molecular analysis of feces obtained during the first week of life showed that microbiotic diversity changes rapidly over the first few days after birth, with the acquisition of unculturable bacteria expanding rapidly after the third day (Park et al. 2005). Can alterations in gastrointestinal flora impact on allergic disease? The gastrointestinal commensal flora shapes both mucosal and systemic immune function throughout life and is implicated in the induction of protective IgA and oral tolerance, including induction of regulatory T cells, and immune deviation (Macpherson & Harris 2004). Germ-free mice develop antigen-specific Th2-biased reactivity. Reconstitution of the intestinal microflora of such mice with Bifidobacterium infantis (a predominant organism of the commensal flora) restores oral tolerance in neonatal but not adult mice (Sudo et al. 1997). Disruption of the normal gastrointestinal commensal microflora has been used as a strategy in mouse models to induce allergic airways disease characterized by increased levels of eosinophils and mast cells, increased Th2 cytokine production, and increased circulating IgE levels (Noverr et al. 2004, 2005). Gastrointestinal infection with helminths has also been shown to prevent the development of allergic airways disease in murine models of asthma, although total and specific IgE levels remain unchanged or increased (Wohlleben et al. 2004; Wilson et al. 2005; Kitagaki et al. 2006). Thus manipulation of the gastrointestinal flora can potentially dramatically affect systemic reactivity to allergens and allergic airways disease.

Other environmental factors Diet and obesity The fall in the consumption of saturated fat while the amount of polyunsaturated fat in the diet has increased parallels changes in allergic disease prevalence. Similarly, the prevalence of obesity in Western populations has increased concurrently with asthma and other allergic diseases. These observations have piqued interest in a link between dietary factors, obesity, and allergic disease.

Diet Of particular interest is maternal intake of various dietary components during pregnancy. Maternal zinc intake during pregnancy has been inversely associated with wheezing to 2 years of age (Litonjua et al. 2006) and asthma ever and current asthma at 5 years of age (Devereux et al. 2006). Low maternal vitamin E intake during pregnancy has been associated with increased proliferative responses by cord blood mononuclear cells (Devereux et al. 2002), increased likelihood of wheezing to 2 years of age (Martindale et al.

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2005; Litonjua et al. 2006), and an increased likelihood of asthma/wheezing symptoms during the first 5 years of life (Devereux et al. 2006). The child’s own nutrient intake was not associated with any of the outcomes measured. Dietary intake of polyunsaturated fatty acids (PUFAs) has also attracted interest as there is the possibility that manipulating the levels of these in the diet might have therapeutic benefits. Conversely to zinc and vitamin E intake, the intake of fatty acids by the child might be particularly relevant. A high dietary intake of PUFAs has been associated with increased risk of recent asthma in 3–5-year-old children (Haby et al. 2001), although the n-3 and n-6 fatty acid profile at birth was not associated with atopic sensitization or eczema and asthma outcomes up to 4 years of age (Newson et al. 2004). Despite this latter observation, maternal dietary supplementation during pregnancy with n-3 PUFAs has been associated with appropriate changes in the n-3/n-6 fatty acid content of umbilical cord blood erythrocytes (Dunstan et al. 2004) and modifications of immune function at birth (Dunstan et al. 2003). The long-term therapeutic benefits of such a strategy remain to be determined. Mechanisms for the impact of dietary factors on allergic status and disease manifestation include the following: 1 Modification of fetal airways development and dietary manipulation studies in rodent models support this hypothesis (Islam et al. 1999). 2 The PUFA linoleic acid, a precursor of arachidonic acid, can be converted to PGE2, which favors Th2 responses and IgE production (Black & Sharpe 1997), although animal models indicate that PUFAs alter the Th1/Th2 balance via inhibition of Th1 cytokine production (Wallace et al. 2001). 3 Methylation and/or chromatin conformation can be affected by environmental factors including diet and these would likely have long-term health effects (Vercelli 2004).

Obesity Obesity precedes asthma and persists after controlling for diet and physical activity (Weiss 2005). The mechanisms whereby obesity influences the asthma phenotype remain unknown but are postulated to include mechanical function of the lungs, changes in immune or inflammatory response, sex-specific effects of hormones, maternal diet, and fetal programming. Obesity likely potentiates and worsens asthma via specific inflammatory mechanisms. There is particular interest in the appetite-regulating peptides leptin and ghrelin that are both recognized to have additional immunomodulatory properties, with ghrelin downregulating the proinflammatory effects of leptin (Fantuzzi & Faggioni 2000; Dixit et al. 2004). Overweight children with asthma have twofold greater serum leptin levels than overweight children without asthma and leptin levels correlated positively with circulating IFN-γ levels (Mai et al. 2004). Obese children had significantly higher IgE levels and serum ghrelin levels inversely correlated with IgE levels (Matsuda et al. 2006).

Development of Allergy and Atopy

These observations highlight the need to ascertain the impact of mediators of neuroendocrine function on relevant immunologic mechanisms.

Perinatal risk factors and anthropometric measurements Mode of delivery The potential negative impact of cesarean section delivery on allergic outcomes has received much interest. However, while two small studies found (i) a slightly increased risk of wheezing with respiratory tract infection and food allergen sensitization up to 2 years of age in children delivered by cesarean section (Negele et al. 2004) and (ii) that delivery by cesarean section was associated with increased cumulative incidence of asthma at 7 years of age and increased risk of being skin-prick test positive (Kero et al. 2002), four very large birth cohort studies in the UK, Italy and the USA indicate that mode of delivery is not a risk factor for the development of allergic disease including allergic sensitization and wheeze/asthma (McKeever et al. 2002b; Maitra et al. 2004; Juhn et al. 2005; Rusconi et al. 2007).

Maternal atopy Maternal atopy has been revealed to be a greater risk than paternal atopy for the development of allergic disease in the offspring by many investigators and is particularly associated with an increased likelihood of the child developing eczema in infancy and an earlier age of onset of eczema. As this is deemed the first step on the atopic march, understanding this relationship is critical and maternal and/or placental factors have been postulated to impact on the development of the fetal immune system and thereby allergy and allergic disease. In a canine model, the offspring of allergic parents developed elevated total and specific IgE and IgG and increased pulmonary resistance to histamine and allergen as well as increased eosinophils in bronchoalveolar lavage fluid (Barrett et al. 2003). The authors argued that the maternal component was the primary parental contributor via maternal factors that influence the development of the fetal/infant immune system. Thus some component of the maternal/ placental immune response, presumably related to the mother’s own elevated total IgE/allergen-specific IgE regulates the development of Th2-biased reactivity to allergen by the offspring and the clinical manifestation of atopic disease in the first year of life. To this end, detectable concentrations of IFN-γ, IL-4, and TNF-α in the neonatal circulation at birth have been associated with a lower risk of physiciandiagnosed asthma, current asthma, current wheeze and/or atopy at 6 years of age (Macaubas et al. 2003). Maternal smoking in particular was associated with reduced levels of IFN-γ and IL-4 and increased risk of wheeze at 6 years of age. Although the cellular sources of circulating cytokines at birth were not determined, the trophoblast and other cell populations of the placenta are probable sources. Thus the same

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attenuated cytokine response extends beyond the neonatal T-cell compartment to the placenta (a fetally derived tissue).

Fetal growth/anthropometric measurements A possible relationship between fetal growth and measures of atopy/atopic disease was first suggested by the observation that raised serum total IgE levels at 50 years of age were associated with increased head circumference at birth. This relationship was independent of adult physique, maternal pelvis size, and maternal parity. This study sparked numerous investigations exploring the relationship between anthropometric measurements at birth and various atopic outcomes. However, rather than considering the relationship between individual anthropometric measures and atopic outcomes, it is probably best to consider what these measures mean and how they relate to the outcome of interest. Thus markers of overnutrition, including increased birth weight, increased gestational age, and increased ponderal index (a measure of the relationship between birth weight and birth length), tend to be associated with atopic sensitization, eczema, hay fever, and asthma. Fetal undernutrition has also been linked to current wheezing (Bolte et al. 2004) but this is likely to reflect the relationship between reduced lung function in infancy to low birth weight (Dezateux et al. 2004; Hoo et al. 2004). Notably, early postnatal growth fails to compensate for this and higher rates of weight gain in early infancy might actually have a negative impact (Lucas et al. 2004). Fetal growth is determined by a variety of factors including maternal health and nutrition, placental function, and fetal growth potential. The fetal origins of child/adult health and disease hypothesis suggests that fetal growth and maturation characteristics influence the likelihood of several diseases later in life and early adverse events operating at a critical period of fetal development result in an increased risk of disease (fetal programming; Barker 2004). Thus intrauterine programming of the developing immune and other organ systems pivotal to the development of allergic disease might occur secondary to fetal overnutrition or other events that impact on fetal health and well-being.

Breast-feeding Human milk contains an array of nutrients, hormones, growth factors, and immunoactive molecules that influence the growth, development, and immune status of the newborn. Immunoactive mediators orchestrate the development of the mucosal immune system, especially at the gastrointestinal tract, and probably serve to compensate for developmentally programmed downregulation of many immune functions during infancy (Jones & Warner 2000). Breast-fed versus bottle-fed babies have been noted to have a lower incidence of gastrointestinal infections and inflammatory conditions as well as allergic diseases. However, the protective effect of breast-feeding on the development of allergic diseases remains divisive. Metaanalyses of prospective studies found that exclus-

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ive breast-feeding for the first 3 months after birth protects against the development of allergic rhinitis in childhood from both allergic and nonallergic families (Mimouni et al. 2002) and the development of atopic dermatitis and asthma particularly in children from at-risk families (Gdalevich et al. 2001a,b). Still, studies that find a positive effect, no effect, or even a negative effect of breast-feeding on atopic sensitization, eczema, allergic rhinoconjunctivitis and/or asthma continue to be published. Ambiguity surrounding what comprises breast-feeding, including duration, exclusivity, weaning age, weaning food, and family history, might account for some of these discrepancies. Moreover, the well-known potential benefit of breast milk might contribute to the controversy as women who have a child at risk of developing allergy or who have a child that develops allergy very early in life are likely to keep breast-feeding for longer, thereby masking the protective effect of breast-feeding (Lowe et al. 2006). Protection via breast-feeding has been variously ascribed to a number of mechanisms, in addition to those related to hygiene and to milk components such as maternal immunocompetent cells, immunoglobulins, antimicrobial peptides, oligosaccharides, growth factors, cytokines, lysozyme, lactoferrin, complement, and nutrients. The relationship between allergic disease and breast-feeding has prompted investigations of the biological mediators in breast milk that might explain this. Thus investigators have sought to identify how levels of critical mediators might differ in breast milk fed to children who do and do not develop disease. These critical mediators include dietary fatty acids, IgA, TGF-β, soluble (s)CD14, and IL-10 among others. Instead of providing an overview of findings relating to each of these, sCD14 has been chosen as an example. Breast milk sCD14, as well as other yet unidentified constituents of human milk (LeBouder et al. 2006), have been postulated to have a critical role during bacterial colonization of the gut immediately after birth and to modulate gastrointestinal innate and adaptive immunologic responsiveness during this time (Labeta et al. 2000). sCD14 is also a lipid carrier so could influence production of fatty acid-derived eicosanoids and link microbial and dietary exposures (Yu et al. 1997). sCD14 is produced by mammary epithelial cells and is abundant in human milk but not infant formulas (Labeta et al. 2000). Maternal milk and circulating sCD14 levels do not correlate and levels appear to be regulated differentially by the same single nucleotide polymorphism: CD14/–550T is associated with high breast milk sCD14 but low plasma sCD14 levels (Guerra et al. 2004b). A number of studies have associated reduced breast milk sCD14 with eczema in the first year of life (Jones et al. 2002) and atopic symptoms and sensitization by age 4 (Savilahti et al. 2005), but elucidating the role of a single candidate molecule in a complex disease process is fraught with difficulties (Laitinen et al. 2006). The link between maternal atopy and increased disease risk of the offspring and the potential detrimental effect of

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prolonged feeding by atopic women (Wright et al. 1999) has prompted interest in the possibility that variation in the composition of breast milk from allergic versus nonallergic mothers might explain some of the controversy surrounding the beneficial effects of breast-feeding. However, with exception of TGF-β1 (Rigotti et al. 2006), no significant effect of maternal allergy on breast milk composition that could be related to allergic disease outcomes by the child have been described. The many benefits of breast-feeding warrant its continued recommendation. Elucidating the interaction between specific defense factors in milk, the duration of breast-feeding, and genetic predisposition and how these might modulate the development of allergic disease should be the focus of investigation.

Genetics The interplay between genes and the environment has emerged as a key area of interest in understanding the development of allergy and allergic disease. However, few studies take into account the additional interaction with the developmental stage of the host, i.e., age as a confounder. Additionally, it has become apparent that the effect of an environmental factor or an intervention strategy on allergic outcomes must take into account the host’s genotype. The genetics of allergy and allergic disease are discussed in detail

Development of Allergy and Atopy

elsewhere (see Chapter 55), although we briefly discuss some of those so far revealed of relevance to the early life origins of allergic disease.

IgE production Elucidating the underlying genetic variation that accounts for elevated IgE production has generated many studies of IL-4 and IL-13 and their common signaling pathway. However, most of these studies are of single genes and it is only recently that investigators have attempted to study combined extended haplotypes to better gauge the impact of genetic variation in this critical pathway. Combinations of genetic alterations in IL-4, IL-13, IL-4Rα (the shared receptor chain) and the intracellular signal transducer and activator of transcription (STAT6, the shared signaling molecule) significantly influence total serum IgE levels and the development of asthma at 9–11 years of age (Kabesch et al. 2006).

Innate immune response Interest in the interaction between innate immune function and the development of effector T cells with Th1, Th2 or regulatory activity has driven studies investigating the relationship between polymorphisms in relevant genes, disease outcomes and, on occasion, appropriate immunologic activity. The first of these was CD14. Membrane and soluble CD14 support cellular responses to various bacterial components including LPS (Fig. 2.4). The role of CD14 in promoting IL-12

mCD14+ cells

Membrane CD14-negative cells

Fig. 2.4 Postulated role of soluble and membrane CD14 in modification of innate immune responsiveness in early childhood. Soluble CD14 facilitates the delivery of lipopolysaccharide (LPS) to TLR4 on membrane CD14-positive cells (e.g., monocytes/macrophages) and CD14negative cells (e.g., dendritic and epithelial cells). Soluble/membrane CD14 delivers LPS to TLR4/MD2 to enable intracellular signaling and thereby changes in cytokine production and costimulatory molecule expression. (See CD-ROM for color version.)

Signal

LPS

LBP

CD14

TLR4

MD2

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production and thereby Th1 activity prompted investigation of the relationship between genetic variation in CD14, circulating levels of CD14, and disease phenotypes. The first study to explore this revealed a single nucleotide polymorphism, a C→T transition at –159 from the major transcription start site (CD14/–159), that was associated with serum sCD14 and total IgE levels in 11-year-old non-Hispanic white children (Baldini et al. 1999). TT homozygotes had significantly higher serum sCD14 levels than children with CC or CT genotypes and, among skin-prick test-positive children, lower total IgE levels and fewer positive skin-prick tests. An inverse relationship between serum sCD14 levels and concanavalin-A stimulated IL-4 production by peripheral blood mononuclear cells was also noted. While a similar relationship between this genetic variation and allergic disease severity has also been reported in adults (Koppelman et al. 2001), there have been contradictory findings (Kabesch et al. 2004). However, serum sCD14 levels increase dramatically after birth so that they exceed adult levels by 6 months of age, presumably reflecting changes in the prevailing microbial burden of the host (Jones et al. 2002). So it is unsurprising that CD14/–159 might have different effects on serum total and specific IgE in different environments such as a farming environment with high endotoxin levels and exposure to various animals (Eder et al. 2005) and have a role in childhood rather than adult onset of atopy and allergic symptoms (O’Donnell et al. 2004). A natural progression from these studies of CD14 has been to consider the contribution of polymorphisms in other receptors and signaling molecules involved in innate immunity to the development of allergic disease. There is particular interest in how relevant genotypes might interact with environmental stimuli to determine disease outcomes. As discussed above, growing up on a farm is now recognized as protective against the development of allergy and allergic diseases. Farmers’ children, but not children from the same rural community who did not live on a farm, carrying one or two T alleles of a polymorphism in TLR2 (TLR2/–16934) were less likely to have a diagnosis of asthma, current asthma or hay fever, and atopy. Also a polymorphism in TLR4 (TLR4/+4334) while not differentially expressed in farming versus nonfarming children or associated with symptoms was associated with a reduced likelihood of being atopic among children exposed to high endotoxin levels (Eder et al. 2004). Within the same population a strong protective effect of a farming environment on allergies was only found in children homozygous for the T allele (CARD4/–21596) in CARD4 (caspase recruitment domain protein 4), an intracellular pattern recognition receptor (Eder et al. 2006). The functional significance of genetic polymorphisms are even less well studied but a TLR4 polymorphism (Asp299Gly) has been related to decreased LPS-stimulated IL-12p70 by peripheral blood mononuclear cells of 8- and 14-year-old children and to an increased prevalence of asthma but not allergic rhinoconjunctivitis (Fageras Bottcher et al. 2004).

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ALLERGIC DISEASE IgE sensitization

Environment

Tissue-specific factors

Development

Genetics

Fig. 2.5 The “allergy pyramid” summarizes the interaction of the environment, genetics, and developmental stage on IgE sensitization and tissue-specific factors in the skin, gut and airways and, ultimately, on the manifestation of allergic disease. (See CD-ROM for color version.)

Tissue-specific genes There is increasing evidence that variation in genes operational at a tissue-specific level also contribute to variations in allergic disease phenotypes. These genes typically have been identified using family linkage studies followed by positional cloning, an approach which has revealed genes that would not have been considered as candidate genes and which are of wide-ranging function (Ober 2005). However, few studies have examined the interplay between environmental risk factors operational during early life and genetic risk for asthma and allergic disease. The importance of such studies is highlighted by the observation that polymorphisms in one of these identified “asthma genes” (ADAM33) predicts impaired lung function at 3 and 5 years of age but not allergic sensitization or physician-diagnosed asthma (Simpson et al. 2005).

Conclusion The key immunologic, environmental, and genetic factors that contribute to the development of allergy and allergic disease have been discussed to highlight that the development of allergy during early childhood is a complex multifactorial process (Fig. 2.5). A pivotal factor determining the longterm consequences of the relevant gene-by-environment interactions driving disease pathogenesis is the maturational status of a variety of cellular functions both within and exterior to the immune system, at the time these interactions occur. As an increasing number of investigators attempt to resolve these complex interactions, our understanding of the development of allergy and allergic diseases will improve and additional therapeutic strategies should be devised.

References Akbari, O., Stock, P., DeKruyff, R.H. & Umetsu, D.T. (2003) Role of regulatory T cells in allergy and asthma. Curr Opin Immunol 15, 627–33. Alenghat, E. & Esterly, J.R. (1984) Alveolar macrophages in perinatal infants. Pediatrics 74, 221–3.

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CHAPTER 2

Amoudruz, P., Holmlund, U., Malmstrom, V. et al. (2005) Neonatal immune responses to microbial stimuli: is there an influence of maternal allergy? J Allergy Clin Immunol 115, 1304–10. Anderson, H.R., Poloniecki, J.D., Strachan, D.P., Beasley, R., Bjorksten, B. & Asher, M.I. (2001) Immunization and symptoms of atopic disease in children: results from the International Study of Asthma and Allergies in Childhood. Am J Public Health 91, 1126– 9. Annacker, O., Coombes, J.L., Malmstrom, V. et al. (2005) Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J Exp Med 202, 1051– 61. Asher, M.I., Montefort, S., Bjorksten, B. et al. (2006) Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 368, 733–43. Avrech, O.M., Samra, Z., Lazarovich, Z., Caspi, E., Jacobovich, A. & Sompolinsky, D. (1994) Efficacy of the placental barrier for immunoglobulins: correlations between maternal, paternal and fetal immunoglobulin levels. Int Arch Allergy Immunol 103, 160–5. Bach, J.F. (2002) The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 347, 911–20. Baldini, M., Carla Lohman, I., Halonen, M., Erickson, R.P., Holt, P.G. & Martinez, F.D. (1999) A polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 20, 976– 83. Ball, T.M., Castro-Rodriguez, J.A., Griffith, K.A., Holberg, C.J., Martinez, F.D. & Wright, A.L. (2000) Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. N Engl J Med 343, 538–43. Barker, D.J.P. (2004) The developmental origins of adult disease. J Am Coll Nutr 23, 588S–595S. Barrett, E.G., Rudolph, K., Bowen, L.E. & Bice, D.E. (2003) Parental allergic status influences the risk of developing allergic sensitization and an asthmatic-like phenotype in canine offspring. Immunology 110, 493–500. Barton, G.M. & Medzhitov, R. (2002) Control of adaptive immune responses by Toll-like receptors. Curr Opin Immunol 14, 380–3. Bergmann, R.L., Edenharter, G., Bergmann, K.E. et al. (1998) Atopic dermatitis in early infancy predicts allergic airway disease at 5 years. Clin Exp Allergy 28, 965– 70. Bjorksten, B. (2004) Effects of intestinal microflora and the environment on the development of asthma and allergy. Springer Semin Immunopathol 25, 257–70. Black, P.N. & Sharpe, S. (1997) Dietary fat and asthma: is there a connection? Eur Respir J 10, 6–12. Blumer, N., Herz, U., Wegmann, M. & Renz, H. (2005) Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma. Clin Exp Allergy 35, 397–402. Bolte, G., Schmidt, M., Maziak, W. et al. (2004) The relation of markers of fetal growth with asthma, allergies and serum immunoglobulin E levels in children at age 5–7 years. Clin Exp Allergy 34, 381–8. Borres, M.P., Odelram, H., Irander, K., Kjellman, N.I.M. & Bjorksten, B. (1995) Peripheral blood eosinophilia in infants at 3 months of age is associated with subsequent development of atopic disease in early childhood. J Allergy Clin Immunol 95, 694–8. Bottcher, M.F., Jenmalm, M.C., Voor, T., Julge, K., Holt, P.G. & Bjorksten, B. (2006) Cytokine responses to allergens during the

Development of Allergy and Atopy

first 2 years of life in Estonian and Swedish children. Clin Exp Allergy 36, 619–28. Braback, L., Hjern, A. & Rasmussen, F. (2004) Trends in asthma, allergic rhinitis and eczema among Swedish conscripts from farming and non-farming environments. A nationwide study over three decades. Clin Exp Allergy 34, 38–43. Braun-Fahrlander, C., Gassner, M., Grize, L. et al. (1999) Prevalence of hay fever and allergic sensitization in farmer’s children and their peers living in the same rural community. Clin Exp Allergy 29, 28–34. Braun-Fahrlander, C., Riedler, J., Herz, U. et al. (2002) Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med 347, 869–77. Burr, M.L., Wat, D., Evans, C., Dunstan, F.D.J., Doull, I.J.M. on behalf of the British Thoracic Society Research Committee (2006) Asthma prevalence in 1973, 1988 and 2003. Thorax 61, 296–9. Butland, B.K., Strachan, D.P., Lewis, S., Bynner, J., Butler, N. & Britton, J. (1997) Investigation into the increase in hay fever and eczema at age 16 observed between the 1958 and 1970 British birth cohorts. BMJ 315, 717–21. Cahill, R.N., Kimpton, W.G., Washington, E.A., Holder, J.E. & Cunningham, C.P. (1999) The ontogeny of T cell recirculation during foetal life. Semin Immunol 11, 105–14. Campbell, D.E. & Kemp, A.S. (1999) Cutaneous lymphocyteassociated antigen expression in children with atopic dermatitis and non-atopic healthy children. Pediatr Allergy Immunol 10, 253–7. Celedon, J.C., Litonjua, A.A., Weiss, S.T. & Gold, D.R. (1999) Day care attendance in the first year of life and illnesses of the upper and lower respiratory tract in children with a familial history of atopy. Pediatrics 104, 495–500. Celedon, J.C., Litonjua, A.A., Ryan, L., Weiss, S.T. & Gold, D.R. (2002) Lack of association between antibiotic use in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years. Am J Respir Crit Care Med 166, 72–5. Chatila, T.A., Blaeser, F., Ho, N. et al. (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106, R75–R81. Committee on Toxicity of Chemicals in Food (1998) Peanut Allergy. Department of Health, London. Copenhaver, C.C., Gern, J.E., Li, Z. et al. (2004) Cytokine response patterns, exposure to viruses, and respiratory infections in the first year of life. Am J Respir Crit Care Med 170, 175–80. Cosmi, L., Liotta, F., Lazzeri, E. et al. (2003) Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 102, 4107–14. Culley, F.J., Pollott, J. & Openshaw, P.J.M. (2002) Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood. J Exp Med 196, 1381–6. Cullinan, P., Harris, J., Mills, P. et al. (2004) Early prescriptions of antibiotics and the risk of allergic disease in adults: a cohort study. Thorax 59, 11–15. Cupedo, T., Nagasawa, M., Weijer, K., Blom, B. & Spits, H. (2005) Development and activation of regulatory T cells in the human fetus. Eur J Immunol 35, 383–90. Devereux, G., Barker, R.N. & Seaton, A. (2002) Antenatal determinants of neonatal immune responses to allergens. Clin Exp Allergy 32, 43–50. Devereux, G., Turner, S.W., Craig, L.C. et al. (2006) Low maternal vitamin E intake during pregnancy is associated with asthma in 5-year-old children. Am J Respir Crit Care Med 174, 499–507.

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Dezateux, C., Lum, S., Hoo, A.F., Hawdon, J., Costeloe, K. & Stocks, J. (2004) Low birth weight for gestation and airway function in infancy: exploring the fetal origins hypothesis. Thorax 59, 60–6. Dixit, V.D., Schaffer, E.M., Pyle, R.S. et al. (2004) Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114, 57–66. Doull, I.J.M. (2001) Does pregnancy prevent atopy? Clin Exp Allergy 31, 1335–7. Downs, S.H., Marks, G.B., Mitakakis, T.Z., Leuppi, J.D., Car, N.G. & Peat, J.K. (2001) Having lived on a farm and protection against allergic diseases in Australia. Clin Exp Allergy 31, 570–5. Droste, J.H.J., Wieringa, M.H., Weyler, J.J., Nelen, V.J., Vermeire, P.A. & Van Bever, H.P. (2000) Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease? Clin Exp Allergy 30, 1548–53. Dunstan, J.A., Mori, T.A., Barden, A. et al. (2003) Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial. J Allergy Clin Immunol 112, 1178–84. Dunstan, J.A., Mori, T.A., Barden, A. et al. (2004) Effects of n-3 polyunsaturated fatty acid supplementation in pregnancy on maternal and fetal erythrocyte fatty acid composition. Eur J Clin Nutr 58, 429–37. Edenharter, G., Bergmann, R.L., Bergmann, K.E. et al. (1998) Cord blood-IgE as risk factor and predictor for atopic diseases. Clin Exp Allergy 28, 671– 8. Eder, W., Klimecki, W., Yu, L. et al. (2004) Toll-like receptor 2 as a major gene for asthma in children of European farmers. J Allergy Clin Immunol 113, 482– 8. Eder, W., Klimecki, W., Yu, L. et al. (2005) Opposite effects of CD14/–260 on serum IgE levels in children raised in different environments. Allergy and Endotoxin (ALEX) Study Team. J Allergy Clin Immunol 116, 601–7. Eder, W., Klimecki, W., Yu, L. et al. (2006) Association between exposure to farming, allergies and genetic variation in CARD4/ NOD1. Allergy 61, 1117–24. Ege, M.J., Bieli, C., Frei, R. et al. (2006) Prenatal farm exposure is related to the expression of receptors of the innate immunity and to atopic sensitization in school-age children. J Allergy Clin Immunol 117, 817–23. Eigenmann, P.A., Sicherer, S.H., Borkowski, T.A., Cohen, B.A. & Sampson, H.A. (1998) Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics 101, E8. EURODIAB ACE Study Group (2000) Variation and trends in incidence of childhood diabetes in Europe. Lancet 355, 873–6. Eysink, P.E., De Jong, M.H., Bindels, P.J. et al. (1999) Relation between IgG antibodies to foods and IgE antibodies to milk, egg, cat, dog and/or mite in a cross-sectional study. Clin Exp Allergy 29, 604–10. Fageras Bottcher, M., Hmani-Aifa, M., Lindstrom, A. et al. (2004) A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children. J Allergy Clin Immunol 114, 561–7. Fantuzzi, G. & Faggioni, R. (2000) Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68, 437–46. Farooqi, I.S. & Hopkin, J.M. (1998) Early childhood infection and atopic disorder. Thorax 53, 927–32. Fontenot, J.D. & Rudensky, A.Y. (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6, 331–7.

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Foster, C.A. & Holbrook, K.A. (1989) Ontogeny of Langerhans cells in human embryonic and fetal skin: cell densities and phenotypic expression relative to epidermal growth. Am J Anat 184, 157–64. Fujihashi, K., Dohi, T., Rennert, P.D. et al. (2001) Peyer’s patches are required for oral tolerance to proteins. Proc Natl Acad Sci USA 98, 3310–15. Fujita, M., Furukawa, F., Horiguchi, Y., Ueda, M., KashiharaSawami, M. & Imamura, S. (1991) Regional development of Langerhans cells and formation of Birbeck granules in human embryonic and fetal skin. J Invest Dermatol 97, 65–72. Gabrielsson, S., Soderlund, A., Nilsson, C., Lilja, G., Nordlund, M. & Troye-Blomberg, M. (2001) Influence of atopic heredity on IL-4-, IL-12- and IFN-gamma-producing cells in in vitro activated cord blood mononuclear cells. Clin Exp Immunol 126, 390–6. Gdalevich, M., Mimouni, D., David, M. & Mimouni, M. (2001a) Breast-feeding and the onset of atopic dermatitis in childhood: a systematic review and meta-analysis of prospective studies. J Am Acad Dermatol 45, 520–7. Gdalevich, M., Mimouni, D. & Mimouni, M. (2001b) Breast-feeding and the risk of bronchial asthma in childhood: a systematic review with meta-analysis of prospective studies. J Pediatr 139, 261–6. Gehring, U., Bischof, W., Fahlbusch, B., Wichmann, H.E. & Heinrich, J. (2002) House dust endotoxin and allergic sensitization in children. Am J Respir Crit Care Med 166, 939–44. Gereda, J.E., Leung, D.Y.M., Thatayatikom, A. et al. (2000) Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 355, 1680–3. Gern, J.E., Brooks, G.D., Meyer, P. et al. (2006) Bidirectional interactions between viral respiratory illnesses and cytokine responses in the first year of life. J Allergy Clin Immunol 117, 72–8. Gill, M.A., Palucka, A.K., Barton, T. et al. (2005) Mobilization of plasmacytoid and myeloid dendritic cells to mucosal sites in children with respiratory syncytial virus and other viral respiratory infections. J Infect Dis 191, 1105–15. Golby, S., Hackett, M., Boursier, L., Dunn-Walters, D., Thiagamoorthy, S. & Spencer, J. (2002) B cell development and proliferation of mature B cells in human fetal intestine. J Leukoc Biol 72, 279–84. Gore, C., Peterson, C.G.B., Kissen, P. et al. (2003) Urinary eosinophilic protein X, atopy, and symptoms suggestive of allergic disease at 3 years of age. J Allergy Clin Immunol 112, 702–8. Grigg, J., Arnon, S., Chase, A. & Silverman, M. (1993) Inflammatory cells in the lungs of premature infants on the first day of life: perinatal risk factors and origin of cells. Arch Dis Child 69, 40–3. Grigg, J., Riedler, J., Robertson, C.F., Boyle, W. & Uren, S. (1999) Alveolar macrophage immaturity in infants and young children. Eur Respir J 14, 1198–205. Gruber, C., Nilsson, L. & Bjorksten, B. (2001) Do early childhood immunizations influence the development of atopy and do they cause allergic reactions? Pediatr Allergy Immunol 12, 296–311. Guerra, S., Lohman, I.C., Halonen, M., Martinez, F.D. & Wright, A.L. (2004a) Reduced interferon γ production and soluble CD14 levels in early life predict recurrent wheezing by 1 year of age. Am J Respir Crit Care Med 169, 70–6. Guerra, S., Carla, L.I., LeVan, T.D., Wright, A.L., Martinez, F.D. & Halonen, M. (2004b) The differential effect of genetic variation on soluble CD14 levels in human plasma and milk. Am J Reprod Immunol 52, 204–11.

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Gupta, R., Sheikh, A., Strachan, D.P. & Anderson, H.R. (2004) Burden of allergic disease in the UK: secondary analyses of national databases. Clin Exp Allergy 34, 520– 6. Haby, M.M., Marks, G.B., Peat, J.K. & Leeder, S.R. (2000) Daycare attendance before the age of two protects against atopy in preschool age children. Pediatr Pulmonol 30, 377–84. Haby, M.M., Peat, J.K., Marks, G.B., Woolcock, A.J. & Leeder, S.R. (2001) Asthma in preschool children: prevalence and risk factors. Thorax 56, 589–95. Haddeland, U., Karstensen, A.B., Farkas, L. et al. (2005) Putative regulatory T cells are impaired in cord blood from neonates with hereditary allergy risk. Pediatr Allergy Immunol 16, 104–12. Hagerhed-Engman, L., Bornehag, C.G., Sundell, J. & Aberg, N. (2006) Day-care attendance and increased risk for respiratory and allergic symptoms in preschool age. Allergy 61, 447–53. Halmerbauer, G., Gartner, C., Koller, D. et al. (2000) Eosinophil cationic protein and eosinophil protein X in the nasal lavage of children during the first 4 weeks of life. Allergy 55, 1121–6. Hattevig, G., Kjellman, B. & Bjorksten, B. (1987) Clinical symptoms and IgE responses to common food proteins and inhalants in the first 7 years of life. Clin Allergy 17, 571– 8. Hattevig, G., Kjellman, B. & Bjorksten, B. (1993) Appearance of IgE antibodies to ingested and inhaled allergens during the first 12 years of life in atopic and non-atopic children. Pediatr Allergy Immunol 4, 182– 6. Heaton, T., Rowe, J., Turner, S. et al. (2005) An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet 365, 142– 9. Hersoug, L.G. (2006) A reformulation of the hygiene hypothesis: maternal infectious diseases confer protection against asthma in the infant. Med Hypotheses 67, 717–20. Hislop, A.A. & Haworth, S.G. (1989) Airway size and structure in the normal fetal and infant lung and the effect of premature delivery and artificial ventilation. Am Rev Respir Dis 140, 1717– 26. Hislop, A., Muir, D.C., Jacobsen, M., Simon, G. & Reid, L. (1972) Postnatal growth and function of the pre-acinar airways. Thorax 27, 265– 74. Holt, P.G. & Jones, C.A. (2000) The development of the immune system during pregnancy and early life. Allergy 55, 688–97. Holt, P.G. & Macaubas, C. (1997) Development of long-term tolerance versus sensitisation to environmental allergens during the perinatal period. Curr Opin Immunol 9, 782–7. Holt, P.G., Clough, J.B., Holt, B.J. et al. (1992) Genetic “risk” for atopy is associated with delayed postnatal maturation of T-cell competence. Clin Exp Allergy 22, 1093– 9. Holt, P.G., Rowe, J., Loh, R. & Sly, P.D. (2003) Developmental factors associated with risk for atopic disease: implications for vaccine strategies in early childhood. Vaccine 21, 3432–5. Hoo, A.F., Stocks, J., Lum, S. et al. (2004) Development of lung function in early life: influence of birth weight in infants of nonsmokers. Am J Respir Crit Care Med 170, 527–33. Horner, A.A. (2006) Toll-like receptor ligands and atopy: a coin with at least two sides. J Allergy Clin Immunol 117, 1133–40. Horwitz, D.A., Zheng, S.G. & Gray, J.D. (2003) The role of the combination of IL-2 and TGF-β or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J Leukoc Biol 74, 471–8.

Development of Allergy and Atopy

Howie, D., Spencer, J., DeLord, D. et al. (1998) Extrathymic T cell differentiation in the human intestine early in life. J Immunol 161, 5862–72. Illi, S., von Mutius, E., Lau, S. et al. (2001) Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ 322, 390–5. Islam, S., Narra, V., Cote, G.M., Manganaro, T.F., Donahoe, P.K. & Schnitzer, J.J. (1999) Prenatal vitamin E treatment improves lung growth in fetal rats with congenital diaphragmatic hernia. J Pediatr Surg 34, 172–7. Jarrett, E.E. & Hall, E. (1983) IgE suppression by maternal IgG. Immunology 48, 49–58. Jedrychowski, W., Galas, A., Whyatt, R. & Perera, F. (2006) The prenatal use of antibiotics and the development of allergic disease in one year old infants. A preliminary study. Int J Occup Med Environ Health 19, 70–6. Jeffery P. (1998) The development of large and small airways. Am J Respir Crit Care Med 157, 174S–180S. Jenmalm, M.C. & Bjorksten, B. (1999) Development of immunoglobulin G subclass antibodies to ovalbumin, birch and cat during the first eight years of life in atopic and non-atopic children. Pediatr Allergy Immunol 10, 112–21. Jones, A.C., Miles, E.A., Warner, J.O., Colwell, B.M., Bryant, T.N. & Warner, J.A. (1996) Fetal peripheral blood mononuclear cell proliferative responses to mitogenic and allergenic stimuli during gestation. Pediatr Allergy Immunol 7, 109–16. Jones, C.A., Vance, G.H.S., Power, L.L., Pender, S.L.F., MacDonald, T.T. & Warner, J.O. (2001) Costimulatory molecules in the developing human gastrointestinal tract: a pathway for fetal allergen priming. J Allergy Clin Immunol 108, 235–41. Jones, C.A., Holloway, J.A., Popplewell, E.J. et al. (2002) Reduced soluble CD14 levels in amniotic fluid and breast milk are associated with the subsequent development of atopy, eczema, or both. J Allergy Clin Immunol 109, 858–66. Jones, C.A. & Warner, C.O. (2000) Breast milk as an alternative source of cytokines for offspring. Clin Exp Allergy 30, 599–601. Juhn, Y.J., Weaver, A., Katusic, S. & Yunginger, J. (2005) Mode of delivery at birth and development of asthma: a population-based cohort study. J Allergy Clin Immunol 116, 510–16. Jump, R.L. & Levine, A.D. (2002) Murine Peyer’s patches favor development of an IL-10-secreting, regulatory T cell population. J Immunol 168, 6113–19. Kabesch, M., Hasemann, K., Schickinger, V. et al. (2004) A promoter polymorphism in the CD14 gene is associated with elevated levels of soluble CD14 but not with IgE or atopic diseases. Allergy 59, 520–5. Kabesch, M., Schedel, M., Carr, D. et al. (2006) IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma. J Allergy Clin Immunol 117, 269–74. Kadowaki, N., Antonenko, S., Ho, S. et al. (2001) Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells. J Exp Med 193, 1221–6. Kalinski, P., Hilkens, C.M., Wierenga, E.A. & Kapsenberg, M.L. (1999) T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today 20, 561–7. Karlsson, M.R., Rugtveit, J. & Brandtzaeg, P. (2004) Allergenresponsive CD4+CD25+ regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med 199, 1679–88. Karmaus, W. & Botezan, C. (2002) Does a higher number of siblings protect against the development of allergy and asthma? A review. J Epidemiol Community Health 56, 209–17.

43

9781405157209_4_002.qxd 4/1/08 14:25 Page 44

PART 1

Immunology of the Allergic Response

Kero, J., Gissler, M., Gronlund, M.M. et al. (2002) Mode of delivery and asthma: is there a connection? Pediatr Res 52, 6–11. Kitagaki, K., Businga, T.R., Racila, D., Elliott, D.E., Weinstock, J.V. & Kline, J.N. (2006) Intestinal helminths protect in a murine model of asthma. J Immunol 177, 1628– 35. Kjellman, B. & Hattevig, G. (1994) Allergy in early and late onset of atopic dermatitis. Acta Paediatr 83, 229– 31. Klintberg, B., Berglund, N., Lilja, G., Wickman, M. & Hage-Hamsten, M. (2001) Fewer allergic respiratory disorders among farmers’ children in a closed birth cohort from Sweden. Eur Respir J 17, 1151–7. Koppelman, G.H., Reijmerink, N.E., Colin Stine, O. et al. (2001) Association of a promoter polymorphism of the CD14 gene and atopy. Am J Respir Crit Care Med 163, 965– 9. Koppen, S., de Groot, R., Neijens, H.J., Nagelkerke, N., van Eden, W. & Rumke, H.C. (2004) No epidemiological evidence for infant vaccinations to cause allergic disease. Vaccine 22, 3375–85. Kosunen, T.U., Hook-Nikanne, J., Salomaa, A., Sarna, S., Aromaa, A. & Haahtela, T. (2002) Increase of allergen-specific immunoglobulin E antibodies from 1973 to 1994 in a Finnish population and a possible relationship to Helicobacter pylori infections1. Clin Exp Allergy 32, 373– 8. Kramer, U., Heinrich, J., Wjst, M. & Wichmann, H.E. (1999) Age of entry to day nursery and allergy in later childhood. Lancet 353, 450–4. Kristjansson, S., Bjarnarson, S.P., Wennergren, G. et al. (2005) Respiratory syncytial virus and other respiratory viruses during the first 3 months of life promote a local Th2-like response. J Allergy Clin Immunol 116, 805–11. Kurt-Jones, E.A., Popova, L., Kwinn, L. et al. (2000) Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol 1, 398– 401. Kusel, M., de Klerk, N., Kebadze, T. et al. (2007) Early life respiratory viral infections, atopic sensitization and risk of subsequent development of persistent asthma. J Allergy Clin Immunol 119, 1105–10. Laan, M.P., Baert, M.R., Bijl, A.M. et al. (2000) Markers for early sensitization and inflammation in relation to clinical manifestations of atopic disease up to 2 years of age in 133 high-risk children. Clin Exp Allergy 30, 944– 53. Labeta, M.O., Vidal, K., Nores, J.E.R. et al. (2000) Innate recognition of bacteria in human milk is mediated by a milk-derived highly expressed pattern recognition receptor, soluble CD14. J Exp Med 191, 1807–12. Laitinen, K., Hoppu, U., Hamalainen, M., Linderborg, K., Moilanen, E. & Isolauri, E. (2006) Breast milk fatty acids may link innate and adaptive immune regulation: analysis of soluble CD14, prostaglandin E2, and fatty acids. Pediatr Res 59, 723–7. Lau, S., Illi, S., Platts-Mills, T.A.E. et al. (2005) Longitudinal study on the relationship between cat allergen and endotoxin exposure, sensitization, cat-specific IgG and development of asthma in childhood. Report of the German Multicentre Allergy Study (MAS 90). Allergy 60, 766–73. Lauener, R.P., Birchler, T., Adamski, J. et al. (2002) Expression of CD14 and Toll-like receptor 2 in farmers’ and nonfarmers’ children. Lancet 360, 465– 6. LeBouder, E., Rey-Nores, J.E., Raby, A.C. et al. (2006) Modulation of neonatal microbial recognition: TLR-mediated innate immune responses are specifically and differentially modulated by human milk. J Immunol 176, 3742–52.

44

Levy, O., Suter, E.E., Miller, R.L. & Wessels, M.R. (2006) Unique efficacy of Toll-like receptor 8 agonists in activating human neonatal antigen-presenting cells. Blood 108, 1284–90. Li, X.M., Kleiner, G., Huang, C.K. et al. (2001) Murine model of atopic dermatitis associated with food hypersensitivity. J Allergy Clin Immunol 107, 693–702. Lima, J.O., Zhang, L., Atkinson, T.P., Philips, J., Dasanayake, A.P. & Schroeder, J. (2000) Early expression of Iε, CD23 (FcεRII), IL-4Rα, and IgE in the human fetus. J Allergy Clin Immunol 106, 911–17. Litonjua, A.A., Rifas-Shiman, S.L., Ly, N.P. et al. (2006) Maternal antioxidant intake in pregnancy and wheezing illnesses in children at 2 y of age. Am J Clin Nutr 84, 903–11. Lowe, A.J., Carlin, J.B., Bennett, C.M. et al. (2006) Atopic disease and breast-feeding: cause or consequence? J Allergy Clin Immunol 117, 682–7. Lucas, J.S., Inskip, H.M., Godfrey, K.M. et al. (2004) Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function. Am J Respir Crit Care Med 170, 534–40. Macaubas, C., Sly, P.D., Burton, P. et al. (1999) Regulation of Thelper cell responses to inhalant allergen during early childhood. Clin Exp Allergy 29, 1223–31. Macaubas, C., de Klerk, N.H., Holt, B.J. et al. (2003) Association between antenatal cytokine production and the development of atopy and asthma at age 6 years. Lancet 362, 1192–7. MacDonald, T.T. (2003) The mucosal immune system. Parasite Immunol 25, 235–46. MacDonald, T.T. & Monteleone, G. (2005) Immunity, inflammation, and allergy in the gut. Science 307, 1920–5. McKeever, T.M., Lewis, S.A., Smith, C. et al. (2001) Siblings, multiple births, and the incidence of allergic disease: a birth cohort study using the West Midlands general practice research database. Thorax 56, 758–62. McKeever, T.M., Lewis, S.A., Smith, C. & Hubbard, R. (2002a) The importance of prenatal exposures on the development of allergic disease: a birth cohort study using the West Midlands general practice database. Am J Respir Crit Care Med 166, 827–32. McKeever, T.M., Lewis, S.A., Smith, C. & Hubbard, R. (2002b) Mode of delivery and risk of developing allergic disease. J Allergy Clin Immunol 109, 800–2. MacKenzie, J.R., Mattes, J., Dent, L.A. & Foster, P.S. (2001) Eosinophils promote allergic disease of the lung by regulating CD4+ Th2 lymphocyte function. J Immunol 167, 3146–55. Macpherson, A.J. & Harris, N.L. (2004) Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 4, 478– 85. Magnusson, C.G. (1988) Cord serum IgE in relation to family history and as predictor of atopic disease in early infancy. Allergy 43, 241–51. Mai, X.M., Bottcher, M.F. & Leijon, I. (2004) Leptin and asthma in overweight children at 12 years of age. Pediatr Allergy Immunol 15, 523–30. Maitra, A., Sherriff, A., Strachan, D. & Henderson, J. (2004) Mode of delivery is not associated with asthma or atopy in childhood. Clin Exp Allergy 34, 1349–55. Marchini, G., Lindow, S., Brismar, H. et al. (2002) The newborn infant is protected by an innate antimicrobial barrier: peptide antibiotics are present in the skin and vernix caseosa. Br J Dermatol 147, 1127–34.

9781405157209_4_002.qxd 4/1/08 14:25 Page 45

CHAPTER 2

Marks, G.B., Zhou, J., Yang, H.S., Joshi, P.A., Bishop, G.A. & Britton, W.J. (2002) Cord blood mononuclear cell cytokine responses in relation to maternal house dust mite allergen exposure. Clin Exp Allergy 32, 355– 60. Marra, F., Lynd, L., Coombes, M. et al. (2006) Does antibiotic exposure during infancy lead to development of asthma? A systematic review and metaanalysis. Chest 129, 610–18. Martindale, S., McNeill, G., Devereux, G., Campbell, D., Russell, G. & Seaton, A. (2005) Antioxidant intake in pregnancy in relation to wheeze and eczema in the first two years of life. Am J Respir Crit Care Med 171, 121– 8. Martinez, F.D. (2001) The coming-of-age of the hygiene hypothesis. Respir Res 2, 129–32. Matsuda, K., Nishi, Y., Okamatsu, Y., Kojima, M. & Matsuishi, T. (2006) Ghrelin and leptin: a link between obesity and allergy? J Allergy Clin Immunol 117, 705– 6. Matsumoto, K., Shimanouchi, Y., Kawakubo, K. et al. (2005) Infantile eczema at one month of age is associated with cord blood eosinophilia and subsequent development of atopic dermatitis and wheezing illness until two years of age. Int Arch Allergy Immunol 137 (suppl. 1), 69– 76. Melkild, I., Groeng, E.C., Leikvold, R.B., Granum, B. & Lovik, M. (2002) Maternal allergen immunization during pregnancy in a mouse model reduces adult allergy-related antibody responses in the offspring. Clin Exp Allergy 32, 1370– 6. Meri, K.T., Wale, J.L., Holt, P.G. & Sly, P.D. (2000) Modification of the inflammatory response to allergen challenge after exposure to bacterial lipopolysaccharide. Am J Respir Cell Mol Biol 22, 604–12. Miller, D.L., Hiravonen, T. & Gitlin, D. (1973) Synthesis of IgE by the human conceptus. J Allergy Clin Immunol 52, 182–8. Mimouni, B.A., Mimouni, D., Mimouni, M. & Gdalevich, M. (2002) Does breastfeeding protect against allergic rhinitis during childhood? A meta-analysis of prospective studies. Acta Paediatr 91, 275– 9. Mishra, A., Hogan, S.P., Brandt, E.B. & Rothenberg, M.E. (2000) Peyer’s patch eosinophils: identification, characterization, and regulation by mucosal allergen exposure, interleukin-5, and eotaxin. Blood 96, 1538– 44. Monick, M.M., Yarovinsky, T.O., Powers, L.S. et al. (2003) Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. J Biol Chem 278, 53035–44. Morales, J., Homey, B., Vicari, A.P. et al. (1999) CTACK, a skinassociated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci USA 96, 14470–5. Moshfegh, A., Lothian, C., Hallden, G., Marchini, G., Lagercrantz, H. & Lundahl, J. (2005) Neonatal eosinophils possess efficient eotaxin/ IL-5- and N-formyl-methionyl-leucyl-phenylalanine-induced transmigration in vitro. Pediatr Res 58, 138– 42. Mullooly, J.P., Schuler, R., Barrett, M. & Maher, J.E. (2007) Vaccines, antibiotics, and atopy. Pharmacoepidemiol Drug Saf 16, 275– 88. Murphy, E., Shibuya, K., Hosken, N. et al. (1996) Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J Exp Med 183, 901–13. Murray, C.S., Tannock, G.W., Simon, M.A. et al. (2005) Fecal microbiota in sensitized wheezy and non-sensitized non-wheezy children: a nested case-control study. Clin Exp Allergy 35, 741–5. Nafstad, P., Hagen, J.A., Oie, L., Magnus, P. & Jaakkola, J.J. (1999) Day care centers and respiratory health. Pediatrics 103, 753–8.

Development of Allergy and Atopy

Nafstad, P., Magnus, P., Gaarder, P.I. & Jaakkola, J.J.K. (2001) Exposure to pets and atopy-related diseases in the first 4 years of life. Allergy 56, 307–12. National Heart, Lung, and Blood Institute (2004) Morbidity and Mortality: 2004 Chartbook on Cardiovascular, Lung, and Blood Diseases. US Department of Health and Human Services, Bethesda, MD. Neaville, W.A., Tisler, C., Bhattacharya, A. et al. (2003) Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life. J Allergy Clin Immunol 112, 740–6. Negele, K., Heinrich, J., Borte, M. et al. (2004) Mode of delivery and development of atopic disease during the first 2 years of life. Pediatr Allergy Immunol 15, 48–54. Negrao-Correa, D., Adams, L.S. & Bell, R.G. (1996) Intestinal transport and catabolism of IgE: a major blood-independent pathway of IgE dissemination during a Trichinella spiralis infection of rats. J Immunol 157, 4037–44. Nelson, D.J. & Holt, P.G. (1995) Defective regional immunity in the respiratory tract of neonates is attributable to hyporesponsiveness of local dendritic cells to activation signals. J Immunol 155, 3517–24. Nelson, D.J., McMenamin, C., McWilliam, A.S., Brenan, M. & Holt, P.G. (1994) Development of the airway intraepithelial dendritic cell network in the rat from class II major histocompatibility (Ia)negative precursors: differential regulation of Ia expression at different levels of the respiratory tract. J Exp Med 179, 203–12. Newson, R.B., Shaheen, S.O., Henderson, A.J., Emmett, P.M., Sherriff, A. & Calder, P.C. (2004) Umbilical cord and maternal blood red cell fatty acids and early childhood wheezing and eczema. J Allergy Clin Immunol 114, 531–7. Nickel, R., Kulig, M., Forster, J. et al. (1997) Sensitization to hen’s egg at the age of twelve months is predictive for allergic sensitization to common indoor and outdoor allergens at the age of three years. J Allergy Clin Immunol 99, 613–17. Nilsson, C., Larsson, A.K., Hoglind, A., Gabrielsson, S., Blomberg, M.T. & Lilja, G. (2004) Low numbers of interleukin-12-producing cord blood mononuclear cells and immunoglobulin E sensitization in early childhood. Clin Exp Allergy 34, 373–80. Noverr, M.C. & Huffnagle, G.B. (2005) The “microflora hypothesis” of allergic diseases. Clin Exp Allergy 35, 1511–20. Noverr, M.C., Noggle, R.M., Toews, G.B. & Huffnagle, G.B. (2004) Role of antibiotics and fungal microbiota in driving pulmonary allergic responses. Infect Immun 72, 4996–5003. Noverr, M.C., Falkowski, N.R., McDonald, R.A., McKenzie, A.N. & Huffnagle, G.B. (2005) Development of allergic airway disease in mice following antibiotic therapy and fungal microbiota increase: role of host genetics, antigen, and interleukin-13. Infect Immun 73, 30–8. Nunez, C., Nishimoto, N., Gartland, G.L. et al. (1996) B cells are generated throughout life in humans. J Immunol 156, 866–72. Ober, C. (2005) Perspectives on the past decade of asthma genetics. J Allergy Clin Immunol 116, 274–8. Oberle, D., Mutius, E. & Kries, R. (2003) Childhood asthma and continuous exposure to cats since the first year of life with cats allowed in the child’s bedroom. Allergy 58, 1033–6. O’Donnell, A.R., Toelle, B.G., Marks, G.B. et al. (2004) Age-specific relationship between CD14 and atopy in a cohort assessed from age 8 to 25 years. Am J Respir Crit Care Med 169, 615–22. Okahata, H., Nishi, Y., Mizoguchi, N., Yumiba, C., Fujii, H. & Ueda, K. (1990) Development of serum Dermatophagoides farinae-,

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PART 1

Immunology of the Allergic Response

ovalbumin- and lactalbumin-specific IgG, IgG1, IgG4, IgA and IgM in children with bronchial asthma/allergic rhinitis or atopic dermatitis. Clin Exp Allergy 20, 39– 44. Openshaw, P.J.M., Yamaguchi, Y. & Tregoning, J.S. (2004) Childhood infections, the developing immune system, and the origins of asthma. J Allergy Clin Immunol 114, 1275–7. Park, H.K., Shim, S.S., Kim, S.Y. et al. (2005) Molecular analysis of colonized bacteria in a human newborn infant gut. J Microbiol 43, 345–53. Patel, L., Garvey, B., Arnon, S. & Roberts, I.A. (1994) Eosinophilia in newborn infants. Acta Paediatr 83, 797– 801. Perkin, M.R. & Strachan, D.P. (2006) Which aspects of the farming lifestyle explain the inverse association with childhood allergy? J Allergy Clin Immunol 117, 1374– 81. Platts-Mills, T., Vaughan, J., Squillace, S., Woodfolk, J. & Sporik, R. (2001) Sensitisation, asthma, and a modified Th2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet 357, 752– 6. Prescott, S.L., Macaubas, C., Holt, B.J. et al. (1998) Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile. J Immunol 160, 4730–7. Prescott, S.L., Macaubas, C., Smallacombe, T., Holt, B.J., Sly, P.D. & Holt, P.G. (1999) Development of allergen-specific T-cell memory in atopic and normal children. Lancet 353, 196– 200. Prescott, S.L., Holt, P.G., Jenmalm, M. & Bjorksten, B. (2000) Effects of maternal allergen-specific IgG in cord blood on early postnatal development of allergen-specific T-cell immunity. Allergy 55, 470–5. Prescott, S.L., Taylor, A., King, B. et al. (2003) Neonatal interleukin12 capacity is associated with variations in allergen-specific immune responses in the neonatal and postnatal periods. Clin Exp Allergy 33, 566–72. Rangaraj, S. & Doull, I. (2003) Hormones not hygiene? Birth order and atopy. Clin Exp Allergy 33, 277– 8. Read, S. & Powrie F. (2001) CD4+ regulatory T cells. Curr Opin Immunol 13, 644–9. Riedler, J., Grigg, J., Stone, C., Tauro, G. & Robertson, C.F. (1995) Bronchoalveolar lavage cellularity in healthy children. Am J Respir Crit Care Med 152, 163– 8. Riedler, J., Eder, W., Oberfeld, G. & Schreuer, M. (2000) Austrian children living on a farm have less hay fever, asthma and allergic sensitization. Clin Exp Allergy 30, 194– 200. Riedler, J., Braun-Fahrlander, C., Eder, W. et al. (2001) Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey. Lancet 358, 1129– 33. Rigotti, E., Piacentini, G.L., Ress, M., Pigozzi, R., Boner, A.L. & Peroni, D.G. (2006) Transforming growth factor-beta and interleukin-10 in breast milk and development of atopic diseases in infants. Clin Exp Allergy 36, 614–18. Romagnani, S. (2004) The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology 112, 352– 63. Rowe, J., Kusel, M., Holt, B.J. et al. (2007) Prenatal versus postnatal sensitization to environmental allergens in a high-risk birth cohort. J Allergy Clin Immunol 119, 1164–73. Rusconi, F., Galassi, C., Forastiere, F. et al. (2007) Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children. Am J Respir Crit Care Med 175, 16–21.

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Saji, F., Samejima, Y., Kamiura, S. & Koyama, M. (1999) Dynamics of immunoglobulins at the feto-maternal interface. Rev Reprod 4, 81–9. Sasai, K., Furukawa, S., Kaneko, K., Yabuta, K. & Baba, M. (1994) Fecal IgE levels in infants at 1 month of age as indicator of atopic disease. Allergy 49, 791–4. Sato, K., Kawasaki, H., Nagayama, H. et al. (2001) Chemokine receptor expressions and responsiveness of cord blood T cells. J Immunol 166, 1659–66. Savilahti, E., Siltanen, M., Kajosaari, M., Vaarala, O. & Saarinen, K.M. (2005) IgA antibodies, TGF-β1 and -β2, and soluble CD14 in the colostrum and development of atopy by age 4. Pediatr Res 58, 1300– 5. Schaub, B., Campo, M., He, H. et al. (2006) Neonatal immune responses to TLR2 stimulation: influence of maternal atopy on Foxp3 and IL-10 expression. Respir Res 7, 40. Schnare, M., Barton, G.M., Holt, A.C., Takeda, K., Akira, S. & Medzhitov, R. (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2, 947–50. Schram, D., Doekes, G., Boeve, M. et al. (2005) Bacterial and fungal components in house dust of farm children, Rudolf Steiner school children and reference children: the PARSIFAL Study. Allergy 60, 611–18. Schreyer, P., Avrech, O., Caspi, E., Samra, Z. & Sompolinsky, D. (1989) The source of immunoglobulin E in the fetus at term. Gynecol Obstet Invest 27, 129–32. Seddiki, N., Santner-Nanan, B., Martinson, J. et al. (2006) Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 203, 1693–700. Simpson, A., Maniatis, N., Jury, F. et al. (2005) Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function. Am J Respir Crit Care Med 172, 55–60. Slack-Smith, L.M., Read, A.W. & Stanley, F.J. (2002) Experience of respiratory and allergic illness in children attending childcare. Child: Care Health Dev 28, 171–7. Smart, J.M. & Kemp, A.S. (2002) Increased Th1 and Th2 allergeninduced cytokine responses in children with atopic disease. Clin Exp Allergy 32, 796–802. Smillie, F.I., Elderfield, A.J., Patel, F. et al. (2001) Lymphoproliferative responses in cord blood and at one year: no evidence for the effect of in utero exposure to dust mite allergens. Clin Exp Allergy 31, 1194–204. Song, T.W., Sohn, M.H., Kim, E.S., Kim, K.W. & Kim, K.E. (2006) Increased serum thymus and activation-regulated chemokine and cutaneous T cell-attracting chemokine levels in children with atopic dermatitis. Clin Exp Allergy 36, 346–51. Spencer, J., MacDonald, T.T., Finn, T. & Isaacson, P.G. (1986) The development of gut associated lymphoid tissue in the terminal ileum of fetal human intestine. Clin Exp Immunol 64, 536–43. Spencer, J., MacDonald, T.T. & Isaacson, P.G. (1987) Heterogeneity of non-lymphoid cells expressing HLA-D region antigens in human fetal gut. Clin Exp Immunol 67, 415–24. Stene, L.C. & Nafstad, P. (2001) Relation between occurrence of type 1 diabetes and asthma. Lancet 357, 607–8. Stoltenberg, L., Thrane, P.S. & Rognum, T.O. (1993) Development of immune response markers in the trachea in the fetal period and the first year of life. Pediatr Allergy Immunol 4, 13–19. Strachan, D.P. (1989) Hay fever, hygiene, and household size. BMJ 299, 1259–60.

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Strachan, D.P. (2000) Family size, infection and atopy: the first decade of the “hygiene hypothesis”. Thorax 55, 2S–10S. Sudo, N., Sawamura, S., Tanaka, K., Aiba, Y., Kubo, C. & Koga, Y. (1997) The requirement of intestinal bacterial flora for the development of an IgE production system fully susceptible to oral tolerance induction. J Immunol 159, 1739– 45. Sutmuller, R.P.M., Morgan, M.E., Netea, M.G., Grauer, O. & Adema, G.J. (2006) Toll-like receptors on regulatory T cells: expanding immune regulation. Trends Immunol 27, 387–93. Szepfalusi, Z., Pichler, J., Elsasser, S. et al. (2000) Transplacental priming of the human immune system with environmental allergens can occur early in gestation. J Allergy Clin Immunol 106, 530–6. Tang, M.L., Kemp, A.S., Thorburn, J. & Hill, D.J. (1994) Reduced interferon-gamma secretion in neonates and subsequent atopy. Lancet 344, 983–5. Thornton, C.A. & Vance, G.H.S. (2002) The placenta: a portal of fetal allergen exposure. Clin Exp Allergy 32, 1537–9. Thornton, C.A., Holloway, J.A., Popplewell, E.J., Shute, J.K., Boughton, J. & Warner, J.O. (2003) Fetal exposure to intact immunoglobulin E occurs via the gastrointestinal tract. Clin Exp Allergy 33, 306–11. Thornton, C.A., Upham, J.W., Wikstrom, M.E. et al. (2004) Functional maturation of CD4+ CD25+ CTLA4+ CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens. J Immunol 173, 3084– 92. Tonooka, T., Sakata, S., Kitahara, M. et al. (2005) Detection and quantification of four species of the genus Clostridium in infant feces. Microbiol Immunol 49, 987– 92. Torres, M.J., Gonzalez, F.J., Corzo, J.L. et al. (1998) Circulating CLA+ lymphocytes from children with atopic dermatitis contain an increased percentage of cells bearing staphylococcal-related T-cell receptor variable segments. Clin Exp Allergy 28, 1264–72. Tschernig, T., Debertin, A.S., Paulsen, F., Kleemann, W.J. & Pabst, R. (2001) Dendritic cells in the mucosa of the human trachea are not regularly found in the first year of life. Thorax 56, 427–31. Upham, J.W., Lee, P.T., Holt, B.J. et al. (2002) Development of interleukin-12-producing capacity throughout childhood. Infect Immun 70, 6583– 8. Vance, G.H.S., Thornton, C.A., Bryant, T.N., Warner, J.A. & Warner, J.O. (2004) Ovalbumin-specific immunoglobulin G and subclass responses through the first 5 years of life in relation to duration of egg sensitization and the development of asthma. Clin Exp Allergy 34, 1542–9. van der Velden, V.H., Laan, M.P., Baert, M.R., de Waal Malefyt, R., Neijens, H.J. & Savelkoul, H.F. (2001) Selective development of a strong Th2 cytokine profile in high-risk children who develop atopy: risk factors and regulatory role of IFN-gamma, IL-4 and IL-10. Clin Exp Allergy 31, 997–1006. van der Vliet, H.J.J., Molling, J.W., von Blomberg, B.M. et al. (2004) The immunoregulatory role of CD1d-restricted natural killer T cells in disease. Clin Immunol 112, 8–23. Vassella, C.C., Odelram, H., Kjellman, N.I., Borres, M.P., Vanto, T. & Bjorksten, B. (1994) High anti-IgE levels at birth are associated with a reduced allergy prevalence in infants at risk: a prospective study. Clin Exp Allergy 24, 771–7. Vercelli, D. (2004) Genetics, epigenetics, and the environment: switching, buffering, releasing. J Allergy Clin Immunol 113, 381–6. Victor JR Jr, Fusaro, A.E., Duarte, A.J. & Sato, M.N. (2003) Preconception maternal immunization to dust mite inhibits the type I

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hypersensitivity response of offspring. J Allergy Clin Immunol 111, 269– 77. von Ehrenstein, O.S., von Mutius, E., Illi, S., Baumann, L., Bohm, O. & von Kries, R. (2000) Reduced risk of hay fever and asthma among children of farmers. Clin Exp Allergy 30, 187–93. von Hertzen, L.C. & Haahtela, T. (2004) Asthma and atopy: the price of affluence? Allergy 59, 124–37. von Mutius, E., Martinez, F.D., Fritzsch, C., Nicolai, T., Roell, G. & Thiemann, H.H. (1994) Prevalence of asthma and atopy in two areas of West and East Germany. Am J Respir Crit Care Med 149, 358–64. von Mutius, E., Braun-Fahrlander, C., Schierl, R. et al. (2000) Exposure to endotoxin or other bacterial components might protect against the development of atopy. Clin Exp Allergy 30, 1230–4. Wallace, F.A., Miles, E.A., Evans, C., Stock, T.E., Yaqoob, P. & Calder, P.C. (2001) Dietary fatty acids influence the production of Th1- but not Th2-type cytokines. J Leukoc Biol 69, 449–57. Weiss, S.T. (2005) Obesity: insight into the origins of asthma. Nat Immunol 6, 537– 9. Wickens, K., Pearce, N., Crane, J. & Beasley, R. (1999) Antibiotic use in early childhood and the development of asthma. Clin Exp Allergy 29, 766–71. Williams, T.J., Jones, C.A., Miles, E.A., Warner, J.O. & Warner, J.A. (2000) Fetal and neonatal IL-13 production during pregnancy and at birth and subsequent development of atopic symptoms. J Allergy Clin Immunol 105, 951–9. Wilson, M.S., Taylor, M.D., Balic, A., Finney, C.A.M., Lamb, J.R. & Maizels, R.M. (2005) Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 202, 1199–212. Wing, K., Ekmark, A., Karlsson, H., Rudin, A. & Suri-Payer, E. (2002) Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 106, 190–9. Wing, K., Lindgren, S., Kollberg, G. et al. (2003) CD4 T cell activation by myelin oligodendrocyte glycoprotein is suppressed by adult but not cord blood CD25+ T cells. Eur J Immunol 33, 579–87. Wing, K., Larsson, P., Sandstrom, K., Lundin, S.B., Suri-Payer, E. & Rudin, A. (2005) CD4+ CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology 115, 516–25. Wohlleben, G., Trujillo, C., Muller, J. et al. (2004) Helminth infection modulates the development of allergen-induced airway inflammation. Int Immunol 16, 585–96. Woodcock, A., Moradi, M., Smillie, F.I., Murray, C.S., Burnie, J.P. & Custovic, A. (2002) Clostridium difficile, atopy and wheeze during the first year of life. Pediatr Allergy Immunol 13, 357–60. Wright, A.L., Sherrill, D., Holberg, C.J., Halonen, M. & Martinez, F.D. (1999) Breast-feeding, maternal IgE, and total serum IgE in childhood. J Allergy Clin Immunol 104, 589–94. Yoshida, M., Claypool, S.M., Wagner, J.S. et al. (2004) Human neonatal Fc receptor mediates transport of IgG into luminal secretions for delivery of antigens to mucosal dendritic cells. Immunity 20, 769–83. Yoshida, M., Kobayashi, K., Kuo, T.T. et al. (2006) Neonatal Fc receptor for IgG regulates mucosal immune responses to luminal bacteria. J Clin Invest 116, 2142–51. Yosipovitch, G., Maayan-Metzger, A., Merlob, P. & Sirota, L. (2000) Skin barrier properties in different body areas in neonates. Pediatrics 106, 105–8. Yu, B., Hailman, E. & Wright, S.D. (1997) Lipopolysaccharide binding protein and soluble CD14 catalyze exchange of phospholipids. J Clin Invest 99, 315–24.

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T Cells and Cytokines in Asthma and Allergic Inflammation Chris Corrigan

Summary The past 20 years have seen considerable advances in T-cell biology. There is increased understanding of the shaping of the T-cell antigenic repertoire, and the recognition that this might be susceptible to manipulation early in life. The concept of active, antigen-specific suppression of immune responses by T cells has also turned full circle from skepticism to acceptance, although what were named “suppressor” T cells have now been renamed “regulatory” T cells. The recognition that such cells may limit immune responses to both self and external antigens provides considerable promise for future therapeutic maneuvers. In this same time-frame, the Th1/Th2 concept has ignited, exploded, and now somewhat simmered down. New triggers for Th2 T-cell differentiation, such as the costimulatory molecule OX40, and new cytokines like thymic stromal lymphopoietin are being uncovered. Concurrently, attention has switched from attempts to “skew” polarized Th2 T-cell responses in allergic disease to recognition that induction of long-lived, allergen-specific T regulatory cells may be a better strategy. In this regard, the cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β have received increasing attention as mediators of this regulation, while tumor necrosis factor (TNF)-α is being increasingly singled out as a key proinflammatory cytokine in both Th1- and Th2-mediated inflammatory responses. The T-cell hypothesis of asthma has blossomed in these 20 years, and few investigators would now seriously contest that T cells and some of their cytokine products play some sort of role in asthma. There is still, however, a great deal of uncertainty about the mechanisms of this process. The concept that the effects of cytokines are mediated through “effector” cells such as eosinophils in the bronchial mucosa has been seriously challenged (but not killed outright) by therapeutic experiments with agents such as humanized monoclonal antibodies. At the same time, there has been increasing recognition that cytokines can bring about many of the bronchial mucosal changes associated with asthma, collectively termed “remodeling,” without the necessity for intervention of inflammatory granulocytes. Above all, what has remained stubbornly elusive is any glint of light in the chasm of uncertainty as to how the observable immunologic and structural changes in the airways caused by these cytokines actually cause the clinical symptoms of asthma. This chapter contains a

Allergy and Allergic Diseases, 2nd edition. Edited by A.B. Kay, A.P. Kaplan, J. Bousquet, P.G. Holt. © 2008 Blackwell Publishing. ISBN: 978-1-405-15720-9.

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summary of new advances in T-cell biology, particularly as applied to asthma and allergy, an up-to-date account of the known or suspected role of cytokines in the asthma process, and some speculations on new approaches to therapy in the future.

Development and properties of T lymphocytes T lymphocytes (T cells) play a fundamental role in the orchestration of immune responses, against both external invading allergens and self allergens in autoimmune diseases. Through their antigen receptor complexes they are able to recognize peptides derived from the sequence of antigenic proteins when these are presented on the surface of class I or II major histocompatibility (MHC) antigens (Rudolph et al. 2006). Following activation by peptides, T cells produce a range of protein mediators called cytokines which, through their actions on other immune cells, shape the development of the subsequent immune response. T-cell-derived cytokines play a major role in determining whether an immune response will be largely cell-mediated or humoral (mediated by antibodies). With the exception of certain antigens, which can bind to conserved structural regions of the T-cell antigen receptor directly and thereby activate T cells polyclonally, antigen recognition depends on the presentation to T cells of processed peptides. While all cells express class I MHC molecules, class II MHC molecules, which present to CD4+ T cells, are restricted in their expression. Antigen presentation to CD4+ T cells is brought about generally by professional antigen-presenting cells, particularly dendritic cells, which express MHC class II antigens and other essential costimulatory molecules (see below) following activation. However, other cells may express MHC class II, particularly in conditions of inflammation, and act as antigen-presenting cells. The process of uptake and degradation of antigen into peptides, and association of the peptides with MHC class I or II molecules is a highly ordered process depending on lysosomal degradation and ordered assembly of the MHC–peptide complexes within the endoplasmic reticulum, and subsequently the outer cell membrane. While immature B cells express antibodies with low affinity for antigens, they also require

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cognate interaction with T cells in order to proliferate. During this process, B cells expressing antibody with high affinity for the stimulating antigen are selected. This process is known as affinity maturation, and depends on somatic hypermutation of the genes encoding the variable regions of antibody heavy and light chains, which together bind to the antigens. Consequently, it can be said that all immune reactions are initiated by T cells. A fundamental distinction between T-cell and B-cell antigen recognition is that, unlike antibodies produced by B cells, which recognize antigens by their three-dimensional shape, T cells do not recognize the shape of antigens but particular amino acid peptide sequences derived from proteolytic processing of the antigens. Such sequences typically comprise approximately 10–13 amino acids and are known as T-cell “epitopes.” Each antigenic peptide has variable numbers of T-cell epitopes. Since epitopes are presented on the surface of MHC molecules, different epitopes from a single antigen activate T cells variably well in different individuals because of their differing MHC haplotypes. The epitope–MHC complex specificity of T cells is determined by random association of the V, D, and J gene segments encoding the α and β chains of the T-cell antigen receptor. There are many families of these genes and their random association results in T-cell receptors with a potential epitope repertoire that is more than enough to cover epitopes from external antigens, as well as self antigens. Thus, unlike B cell-derived antibodies, the structures of which “mature” during B-cell proliferation by somatic hypermutation, the epitope specificity of any T cell is determined from the moment of the expression of its antigenic peptide receptor, and is immutable. T cells are divided into two principal functional phenotypes signaled by the expression of the surface marker complexes

T Cells and Cytokines in Asthma and Allergic Inflammation

CD4 and CD8. CD4+ T cells recognize antigenic peptides in the context of MHC class II, and are producers of cytokines that govern the nature of inflammatory responses. CD8+ T cells, which recognize antigens in the context of MHC class I, function principally as cytotoxic cells that kill target cells invaded with foreign intracellular organisms such as viruses, or tumor cells. Since most of the studies of the involvement of T cells in asthma concern CD4+ T cells (the few exceptions are mentioned later), most of this chapter is concerned with CD4+ T-cell biology and regulation.

Early T-cell development Early developing T cells in the thymus express both CD4 and CD8, and their epitope specificity, as mentioned, is determined at random. During thymic development, those T cells whose receptors happen by chance to recognize peptides derived from “self” antigens must be silenced or eliminated, otherwise they would attack the host (Fig. 3.1). The fact that autoimmune diseases do exist demonstrates that this silencing system, while ingenious and very efficient, is not perfect. Developing T cells in the thymic epithelium that happen to bind self-peptide–MHC class I or II complexes presented by thymic cortical epithelial cells proliferate: this process is called primary positive selection (Starr et al. 2003). The remainder of the cells, which have no affinity for self antigens whatsoever, die by neglect. Surviving T cells migrate on to the thymic medulla. T cells with a very high affinity for self antigen begin to proliferate but, in the absence of costimulatory signals provided by dendritic cells, undergo activationinduced apoptotic cell death. This is reflected by surface expression of Fas (CD95) and its ligand (CD95L) which interact and activate caspase enzymes that direct cell death. Mutations in Fas, its ligand, and caspase genes result in autoimmune CD4+ CD8+

Fig. 3.1 Model of central thymic tolerance. In primary positive selection, nonself-reactive T cells in the thymic cortex die by neglect. In the thymic medulla, cells with low self affinity may escape selection and become conventional naive T cells. Very high self-affinity cells undergo apoptosis when binding antigen expressed by thymic medullary epithelial cells and presented by immature dendritic cells (DC) (the AIRE factor facilitates expression of promiscuous self antigens). Intermediate affinity cells undergo secondary positive selection to become T regulatory cells (Treg). This is facilitated by ingress of dendritic cells bearing peripheral self antigenic peptides from the periphery and primed by thymic stromal lymphopoietin (TSLP) made in Hassall’s corpuscles (HC) of the thymic medulla. (Adapted from Liu et al. 2006.)

Immature T cell

Thymic cortical epithelium Primary positive selection

CD4+

CD4+

Intermediate anti-self affinity

High anti-self affinity

HC

TSLPactivated DC

TSLP

Secondary positive selection

AIRE

Non-self reactive T cells eliminated

CD4+

Immature DC

Thymic medullary epithelium CD4+

CD4+ CD25+ FoxP3+

Low-affinity anti-self T cells

Negative selection

Naive T cells in the periphery

Death

Treg cell in the periphery

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lymphoproliferative syndrome in humans (Worth et al. 2006). Although this process, called negative selection, is a major one for establishment of self-tolerance, many T cells with medium/high affinity for self antigens do not die but undergo a process called nondeletional central tolerance, or secondary positive selection, in which they give rise to immunosuppressive CD4+ T cells, now known as naturally occurring T regulatory cells (Sakaguchi 2004). These cells are characterized by expression of CD25 and FoxP3, one of the forkhead family of DNA-binding transcription factors. This factor likely plays a critical role in the development of naturally occurring T regulatory cells, since congenital mutations of the FoxP3 gene result in major disruption of immune regulation, in particular the IDEX (immune dysregulation, polyendocrinopathy, enteropathy X-linked) syndrome in humans (Bennett et al. 2001). T cells with low-affinity receptors for self antigens escape all these processes completely and enter the periphery as conventional naive T cells (Fig. 3.1). Only about 3% of all T-cell precursors entering the thymus survive selection and migrate to the periphery and colonize secondary lymphoid organs such as the spleen and lymph nodes. They bind self antigenic peptides with low avidity, yet constitute the population of T cells that will deal with foreign peptides presented by dendritic cells in the binding grooves of MHC molecules. The removal by these mechanisms of T cells with high affinity for self antigenic peptides, occurring as it does solely in the thymus gland, is a remarkable feat. Several mechanisms have been proposed to explain how this phenomenon occurs. There is evidence, for example, for promiscuous expression of a huge variety of self antigens from outside the thymus in thymic medullary epithelial cells, so that T cells can be exposed to the entire repertoire of self antigenic peptides. This is partly regulated by a gene called “autoimmune regulator” or AIRE (Su & Anderson 2004). Mutations in AIRE result in immune polyendocrinopathy syndrome type 1 (Peterson & Peltonen 2005). This mechanism may be principally involved in removal of self-reactive T cells by negative selection (again by antigen presentation by dendritic cells in the absence of costimulation), since in mice AIRE deficiency results in compromised negative selection of T cells recognizing self antigenic peptides but does not compromise the development of CD4+CD25+FoxP3+ T regulatory cells (Anderson et al. 2002). Another process that may be important in self tolerance involves the IL-7-like cytokine thymic stromal lymphopoietin (TSLP) which, as its name suggests, is produced by stromal cells such as epithelial and endothelial cells as well as inflammatory leukocytes. Recent studies show that TSLP is selectively expressed in Hassall’s corpuscles in the thymic medulla in association with an activated subpopulation of myeloid dendritic cells (Watanabe et al. 2005). These dendritic cells, on activation by TSLP, have the capacity to induce the production of T regulatory cells in the thymus, since they have the ability to express the T-cell costimulatory molecules CD80 and CD86, ligands for CD28 on the T-cell surface. Develop-

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ment of T regulatory cells in the thymus depends on CD28 signaling (Watanabe et al. 2005). There is evidence that these dendritic cells migrate into the thymus from the periphery (Donskoy & Goldschneider 2003), and could sample peripheral self antigens and present them to developing T cells within the thymus, resulting in self tolerance. Thus, while many T cells recognizing self antigenic peptides are eliminated in the thymus, others acquire a T regulatory phenotype and actively suppress anti-self responses. Reversal of this phenotype in particular circumstances may give rise to autoimmune disease, while there is some evidence that gaps in the repertoire of naturally occurring T regulatory cells may also cause exaggerated responses to external antigens, including allergens (see below). T cells in human neonates developing in utero and soon after birth are almost certainly exposed to external antigens, including allergens, at the time that the natural T regulatory cell repertoire evolves, providing a mechanistic rationale for the influence of early life exposure to allergens in regulating subsequent immune effector responses. The mechanisms of action of these cells are not well characterized. Some studies suggest that cell–cell interaction is important, and they exert their suppressive functions on potential effector T cells by membrane-bound TGF-β and its receptor CD152 (Nakamura et al. 2001). Alternatively, other studies suggest that these cells can interfere with the direct contact of naive T cells with dendritic cells, thus preventing their activation (Bluestone & Tang 2005; Tadokoro et al. 2006).

T-cell differentiation While CD8+ T cells recognize and kill cells expressing antigenderived peptides on MHC class I molecules derived from intracellular invading organisms such as viruses, and new proteins expressed by tumor cells, CD4+ T cells play a major role in directing other inflammatory responses. Immune responses have been broadly divided into “cell-mediated” and “humoral” immune responses, depending on whether invading foreign antigens are attacked principally by other immune leukocytes such as macrophages, neutrophils or eosinophils, or whether the response is mediated principally by antibodies, resulting in neutralization of foreign antigens, activation of complement, and clearance by the reticuloendothelial system. This broad division of immunologic responses into cellmediated and humoral is reflected in a somewhat similar functional division of CD4+ T cells and is reflected in the cytokines they produce. Over 20 years ago, it was observed that activated CD4+ T cells could be classified into two polarized groups, called Th1 and Th2, according to the “signature” cytokines they produce (Fig. 3.2). Th1 cells are characterized most constantly by the production of and interferon (IFN)γ, a cytokine with particular functions in activating cellmediated immunity. They also favor the production of IgG1 and IgG3 opsonizing and complement-fixing antibodies, thus being very useful for protection against intracellular parasites

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Th2

Th1

Signature cytokines

IFN-g

IL-4, IL-5, IL-13

IL-12 receptor b2-chain

+++

+/−

Chemokine receptors

CXCR3 CCR5

CCR3 CCR4 CXCR4 CCR8

Chandra protein

+

−

Costimulatory molecule ICOS

−

+

CRTH2

−

+

TIM (mice)

TIM-3

TIM-2

Signaling

STAT4 T-bet

STAT6 GATA3 c-Maf

Fig. 3.2 Phenotypic differences between Th1 and Th2 T cells. See text for further discussion and definition of abbreviations. For further information on Chandra protein, see Venkataraman et al. (2000).

(Abbas et al. 1996). On the other hand, Th2 T cells produce IL-4, IL-5, IL-9, and IL-13. These cytokines are also concerned with the activation of B cells and with the class of antibodies produced in immune responses. Thus, broadly, Th2 cells favor humoral immune responses, and are generally poorly protective against the majority of infectious agents, except perhaps some nematodes (Abbas et al. 1996). Th2type cytokines are also implicated in allergic and asthmatic inflammation, since these cytokines also influence the functions of effector leukocytes such as eosinophils and mast cells implicated in these diseases. Furthermore, IL-4 and IL-13 are the only two cytokines that can induce B-cell class switching to the production of IgE antibody, which is the basis of the atopic phenotype. The process of differentiation of naive CD4+ T cells into Th1 and Th2 cells is influenced by a number of factors, but the most important determinant is probably that of interaction with antigen-presenting cells, particularly dendritic cells. Further, the outcome of an encounter between a T cell and a dendritic cell appears to depend on maturation signals received by the dendritic cells at a relatively immature stage. Th1 differentiation appears to be activated as a result of production of IL-12 by dendritic cells during the process of presentation of antigenic peptides to naive T cells. IL-12 production is in turn stimulated by direct interaction of immature dendritic cells with microbial products. Dendritic cells and other immune leukocytes, including mast cells, T cells, and monocytes, express a series of pattern-recognition receptors,

T Cells and Cytokines in Asthma and Allergic Inflammation

of which the Toll-like receptors (TLRs) are best characterized in humans (Duez et al. 2006). These receptors recognize pathogen-associated molecular patterns (PAMPs) derived from microorganisms. So far, 10 TLRs have been described in humans. TLR1, TLR2, TLR4, TLR5, and TLR6 recognize constituents of extracellular bacterial pathogens. For example, TLR2, associated with TLR1 or TLR6, recognizes lipoproteins from the cell wall of Gram-negative bacteria, whereas TLR4 recognizes lipopolysaccharide from the same origin. TLR5 recognizes flagellin from flagellated bacteria. TLR3, TLR7, TLR8, and TLR9 are expressed intracellularly and recognize viral and bacterial nucleic acid fragments. TLRs signal through mitogen-activated protein kinase (MAPK), STAT1, and NF-κB. Once IL-12 production is established in dendritic cells as a result of exposure to PAMPs, it promotes Th1 differentiation of T cells by sustaining expression of the β2 chain of the IL-12 receptor (Smits et al. 2001). This receptor is therefore a “signature” cytokine receptor of Th1 cells (see Fig. 3.2). Molecules that recognize fragments of invading intracellular microorganisms should, through their actions on dendritic cells, promote Th1 T-cell differentiation, which in turn promotes cell-mediated immunity. It is less clear what initiates Th2 T-cell differentiation. While Th2-type cytokines such as IL-4 encourage propagation of established Th2 cells, there is no clear counterpart of IL-12 produced by dendritic cells that performs this function during Th2 cell differentiation. Some studies suggest that other receptors on dendritic cells may drive Th2 differentiation. For example, interaction of the Notch receptor with the Jagged ligand on dendritic cells has been suggested as a possible trigger for Th2 differentiation since it induces production of IL-4 by T cells (Amsen et al. 2004). In some parasitic infections, IL-4 may be produced by a still undefined cell type (non-T, non-B, c-kit+, FcεRI −) in response to IL-25 produced by macrophages or mast cells (Fallon et al. 2006), but the generality of this phenomenon is in doubt. TSLP is also a possible prototype candidate. While activation of dendritic cells by both TLRs and TSLP results in increased expression of MHC class II molecules, as well as the T-cell costimulatory molecules CD80, CD83 and CD86, TSLP in contrast to TLRs does not induce dendritic cells to produce IL-12 or any members of the IL-12 family of cytokines such as IL-23 or IL-27 (Soumelis et al. 2002). However, TSLP does induce expression of the TNF superfamily protein OX40 ligand (OX40L) on dendritic cells. A recent study has shown that OX40L signaling through its receptor OX40 on T cells directly induces Th2 lineage commitment by inducing the transcriptional regulatory factor NF-ATc1, which triggers IL-4 production and then IL-4-dependent transcription of GATA-3 (So et al. 2006). This process is overridden in the presence of IL-12, which may provide a mechanism for inhibition of Th2 cell differentiation in the presence of IL-12-inducing PAMPs, which is a possible mechanistic explanation for the hygiene hypothesis. This scenario suggests that OX40L represents the

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original critical polarizing signal for Th2 development and that IL-4, conventionally considered the trigger factor for Th2 development, plays a secondary, autocrine Th2-stabilizing function (Ito et al. 2005). TSLP expression has been documented within epidermal keratinocytes in lesional skin of patients with atopic dermatitis (Soumelis et al. 2002), while we have demonstrated its expression in the bronchial mucosa in human asthma (Ying et al. 2005). Triggers for its production in these compartments remain to be defined, although mast cells activated through engagement of the FcεRI receptor, for example through cross-linking by allergen, expressed TSLP (Soumelis et al. 2002), which could form a link between IgE-mediated allergic inflammation and the setting up of Th2 polarized inflammatory responses locally within target organs of allergic disease. Th1 and Th2 cells are characterized by differential expression of transcriptional regulators, reflecting the distinct pattern of cytokines they express. Th1-type cytokine expression is initiated by engagement of the T-cell receptor (TCR) with antigen by dendritic cells along with production of a STAT1 stimulatory signal, which is provided principally by IL-12 as mentioned above, but also by other members of the IL-12 cytokine family such as IL-27 and the interferons, receptors for which are expressed on T cells. STAT1 signaling induces production of the transcriptional regulator T-bet, which can be regarded as a “master regulator” of Th1-cell cytokine expression (Szabo et al. 2000; Lametschwandtner et al. 2004). In turn, T-bet upregulates expression of IFN-γ and the β2 receptor chain of IL-12 and the α chain of the receptor for IL-18, expression of which enables IL-12 signaling through STAT4 and responsiveness to IL-18. Th2 differentiation is induced by engagement of the TCR in concert with signaling through IL-4 or OX40, as described above. This in turn activates the STAT6 signaling pathway, causing low-level expression of the transcriptional regulatory factor GATA-3, which can be regarded as the “master regulator” of Th2 cell differentiation (Zheng & Flavell 1997). GATA-3 induces expres-

sion of the IL-4, IL-5, and IL-13 genes while suppressing factors critical to Th1 differentiation including STAT4 and the IL-12 receptor β chain (Zhu et al. 2004). A consequence of these mutually antagonistic signaling systems in Th1 and Th2 cells is that T-cell differentiation is somewhat plastic, and that Th1 cytokines inhibit the development of Th2 cells and vice versa. For example, Th2 responses can be shifted, at least in vitro, to a Th1 profile by antigen stimulation in the presence of IL-12, which seems to reflect persistent expression of the β2 chain of the IL-12 receptor even in polarized Th2 cells (Smits et al. 2001). Conversely, IL-4 inhibits the development of Th1 cells and shifts them to a less polarized phenotype (Skapenko et al. 2004). Chemokines, the receptors for which are differentially expressed on Th1 and Th2 cells (see below), can also affect T-cell polarization. For example, IP-10/CXCL10 promotes the production of Th1-type cytokines and inhibits that of Th2-type cytokines, while PF-4/CXCL4 does the reverse (Romagnani et al. 2005).

Th17 T cells The IL-17 family comprises six homologous cytokines (Table 3.1). The cytokines IL-17A, B, C, D, and F were identified through database searches and degenerative polymerase chain reaction (PCR) strategies (Aggarwal & Gurney 2003; Kawaguchi et al. 2004; Kolls & Linden 2004). IL-17E was independently identified and named IL-25 (Fort et al. 2001). IL-25 is least well related to the other members of the IL-17 family, showing only 16% identity with IL-17A at the primary amino acid sequence in humans. IL-17A and IL-17F are syntenic, with tightly linked expression in all species examined to date. The remaining family members each map to different chromosomes. The family as a group shows no sequence homology with other known human proteins. The IL-17 family is a cysteine knot family of homodimeric proteins, so named for their unusual pattern of inter- and intra-chain disulfide bonds. The receptors for these cytokines also form a

Table 3.1 The IL-17 cytokine family. Name

Alternative names

Cellular sources

Receptor

IL-17A

IL-17, CTLA-8

IL-17RA (IL-17R)

IL-17B IL-17C IL-17D IL-17E

CXI, NERF CX2 IL-27 IL-25

Th17 cells, CD8 T cells, NK cells, gd T cells, neutrophils ? ? ? CD4 T cells, B cells ? Th2 cells, eosinophils, mast cells

IL-17F

ML-1

Th17 cells, T cells, NK cells, gd T cells, neutrophils, mast cells, basophils

?, cellular sources/receptor(s) not yet clear.

52

? ? ? IL-17RB (IL-17RH1) (IL-25R) IL-17RA, IL-17RC (IL-17RL)

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unique family of proteins (see Table 3.1). IL-17R (or IL-17RA) is the founding member, along with IL-17RB (or IL-17RH1 or IL-25R), IL-17RD (or SEF or IL-17RLM), IL-17RC (or IL17RL), and IL-17RE. They are predicted to be single-pass transmembrane structures with extracellular amino-termini and large intracellular tails (Moseley et al. 2003). Only IL-17RA and IL-17RH1 have been shown to bind to the IL-17 family of cytokines. The cytokines IL-17A and IL-17F are produced by a recently described functional subset of T cells distinct from Th1 and Th2 cells called Th17 cells (Kolls & Linden 2004; Weaver et al. 2006). They are also produced by CD8 T cells, γδ T cells, natural killer (NK) cells, and neutrophils. The IL-17A and IL-17F genes are expressed coordinately as mentioned, and may thus represent “signature cytokines” for Th17 cells. The receptor for these cytokines, IL-17RA, is very widely expressed and they have been described as acting on epithelial and endothelial cells, fibroblasts, osteoblasts, and macrophages. Depending on the cellular target, these cytokines induce the production of colony-stimulating factors, CXC chemokines, metalloproteinases, and IL-6. They thus have important activities in the recruitment and activation of neutrophils (Oda et al. 2005). In contrast, IL-25 (IL-17E) induces the production of CC chemokines, such as CCL5 (RANTES) and CCL11 (eotaxin-1), as well as Th2 cytokines in appropriate target cells (Fort et al. 2001). It also acts on airway smooth muscle cells (Letuve et al. 2006). It is thus more implicated in allergic inflammation and the recruitment and mobilization of eosinophils. IL-17A has been implicated in limiting allergic inflammation in a mouse model of asthma by inhibiting the production of Th2-attracting chemokines such as eotaxin (CCL11) and TARC (CCL17) by dendritic cells. Its production in this model is in turn limited by the Th2 cytokine IL-4 (Schnyder-Candrian et al. 2006). Th17 cells were first discovered as a subset of T cells induced by Borrelia burgdorferi infection in mice (Infante-Duarte et al. 2000) producing IL-17A, granulocyte–macrophage colonystimulating factor (GM-CSF), TNF-α, and IL-6 but not IFN-γ or IL-4. It was later discovered that the subset is stimulated by IL-23, a member of the IL-12 family comprising the p40 chain of IL-12 and a unique p19 chain (Aggarwal et al. 2003). Th17 cells appear to play a particular role in certain models of autoimmune disease in mice (e.g., collagen-induced arthritis). They probably represent a distinct Th1- and Th2independent lineage of development from naive CD4 T-cell precursors, since Th17 development in mice is unimpaired in the presence of IFN-γ or T-bet deficiency (Park et al. 2005); indeed interferons, which activate STAT1-induced expression of T-bet and Th1 development, as well as IL-4, strongly inhibit Th17 development. Although IL-23 amplifies Th17 cell development, it is not absolutely required for Th17 commitment, and does act directly on naive CD4 T cells (Iwakura & Ishigame 2006). Instead, it appears that the cytokines TGFβ and IL-6 act cooperatively and nonredundantly to achieve

T Cells and Cytokines in Asthma and Allergic Inflammation

Th17 commitment. TGF-β appears to be a critical factor for Th17 commitment, while IL-6 acts to deviate TGF-β-driven development of FoxP3-expressing T regulatory cells toward Th17 (Bettelli et al. 2006). Thus, antagonistic effects of TGF-β/ IL-6 versus IFN-γ signaling early in activation of naive T cells deviates lineage development toward Th17 or Th1 respectively, with concomitant upregulation of IL-23 or IL-12 receptor components, respectively. This requirement for TGF-β in Th17 development is shared with adaptive T regulatory cells, which default to FoxP3 induction in the absence of IL-6, induced by pathogen-induced activation of innate immune cells by TLRs. The orphan nuclear receptor retinoic orphan receptor (ROR)γT may be a “master regulator” of Th17 development (Ivanov et al. 2006), although its putative ligand remains unidentified. The cytokine IL-27, another member of the IL-12 family that is a heterodimer with chains homologous to the IL-12 p40 and p35 chains and which is produced by cells similar to those producing IL-12 and IL-23 (dendritic cells, macrophages), seems to play an important role in curbing Th17 responses by limiting development of Th17 effectors. Its receptor, a heterodimer composed of a unique IL-27R α chain and gp130, shared by several members of the IL-6 receptor family, is expressed on naive T cells (Stumhofer et al. 2006). It acts directly on naive T cells to suppress the development of Th17 effectors through a STAT1-dependent, T-bet-independent mechanism. IL-25 (IL-17E) is produced by memory Th2 cells and amplifies Th2 responses. It is not detected in naive T cells, Th1 cells, B cells, dendritic cells, mast cells, or endothelial cells. In vivo its expression appears most abundant in mucosal tissues (Fort et al. 2001). Administration of IL-25 to mice recapitulates many of the features of Th2-type immunity, at least partly by induction of Th2-type cytokines such as IL-4, IL-5 and IL-13, along with elevated serum IgE, IgG1 and IgA, epithelial hyperplasia, goblet cell hypertrophy, and eosinophilia. Reports suggest that these effects occur independently of lymphocytes (Fort et al. 2001; Hurst et al. 2002) and may reflect the actions of IL-25 on an as-yet unidentified innate immune cell of hematopoietic origin (Hurst et al. 2002). Thus, IL-25 may amplify Th2-type inflammation by acting on both adaptive (memory Th2) and innate immune cells.

T-cell costimulatory molecules When CD4 T cells interact with antigenic epitopes presented on MHC class II molecules by antigen-presenting cells such as dendritic cells, their function is critically regulated not only by production of cytokines by the dendritic cells but also by two-way communication between the dendritic cells and the T cells involving surface receptors called costimulatory molecules. T-cell costimulatory molecules may modify T-cell function in a positive or negative fashion. Recently a series of these molecules has been identified (reviewed by Kroczek et al. 2004). Many of these molecules are constitutively expressed (Table 3.2), but others are expressed de novo

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Table 3.2 T-cell costimulatory molecules and their receptors.

CD28 CD27 HVEM BTLA† ICOS‡ OX40 (CD134)‡ CD30‡ 4-1BB (CD137) SLAM† CTLA-4 (CD152) PD-1

Naive T cells

Activated Th2 cells

Memory T cells

Other cells*

+++ ++ +++ +++ − − − − + − −

+++ +++ ++ +++ +++ +++ ++ +++ +++ +++ ++

+++ +++ +++ ++ + − − − − − −

Yes Yes Yes Yes No No Yes Yes No No No

Counterreceptor(s)

Action

CD80, CD86 ? BTLA HVEM ICOS-L OX40L ? 4-1BB-L

+ + +? − + + + + + − −?

CD80, CD86 PD-L1, PD-L2

* Cells other than T cells. † More expressed on Th1 cells. ‡ More expressed on Th2 cells. HVEM, herpesvirus entry mediator; BTLA, B- and T-lymphocyte attenuator; CTLA-4, cytotoxic T-lymphocyte antigen-4; PD-1, programmed death-1; PD-L1/2, PD-1 ligand 1/2; SLAM, signaling lymphocyte activation molecule; ICOS, inducible costimulator; +, stimulatory; −, inhibitory.

on T-cell activation. Several costimulatory molecules that are constitutively expressed (e.g., CD40L interacting with CD40 on B cells and dendritic cells, and CD28 interacting with CD80 and CD86 on dendritic cells) appear to play some role in interactions of all T cells with antigen-presenting cells, and only CD40L is relatively abundant on Th2-type effector T cells. This made it an attractive target for the inhibition of Th2 cell responses until it was discovered that CD40L is also expressed on platelets and that administration of anti-CD40L monoclonal antibodies causes thromboembolic episodes (Kawai et al. 2000). There is now great interest in the roles of induced costimulatory molecules in T-cell activation. These latter comprise the positive costimulators ICOS, OX40, CD30, 4-1BB, and SLAM and the negative costimulators CTLA-4 and PD-1. While positive costimulatory molecules are possible therapeutic targets in strategies to inhibit inflammation, negative costimulators are less attractive because studies in animals suggest that blockade of these molecules may result in unbridled T-cell proliferation. Of the positive costimulators, ICOS, CD30, OX40, and possibly 4-1BB are particularly involved in the activation of Th2 effector cells. In addition to driving Th2-type T-cell responses (Gonzalo et al. 2001), ICOS substantially contributes to the induction of antibodies, including IgE, by B cells and is absolutely required for the generation of memory B cells (Grimbacher et al. 2003). OX40 is particularly involved in regulating longterm T-cell survival and the generation of T-cell immunologic memory (Croft 2003) (see also discussion above). The roles of CD30 and 4-1BB are less well defined but can result in Th2 cell differentiation (Croft 2003; Tarkowski 2003). The

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relative contribution of the interactions of these molecules with their respective ligands to ongoing Th2 cytokine production is not well understood. Their precise contribution to T-cell activation in human allergy and asthma remains to be defined. Furthermore, the contributions of particular molecules may vary according to the nature of the antigenpresenting cell and its environment. For example, costimulation through CD86 appears to be important in the function of alveolar macrophages in presenting allergens to T cells in atopic asthmatics (Larche et al. 1998), whereas with respiratory tract dendritic cells and whole bronchial biopsy cultures, both CD80 and CD86 appear to be implicated (Jaffar et al. 1999; Faith et al. 2005). There may in some circumstances be redundancy in signaling, requiring simultaneous blockade of several molecules. Blockade of ICOS and OX40 interactions with their ligands are particularly attractive therapeutic strategies, at least in theory, in asthmatic and allergic inflammation, since the expression of these ligands is limited to activated T cells with a bias to Th2 differentiation (Lane 2000). It is conceivable that short-term, accurately targeted blockade of these molecules could not only abolish Th2 effector T-cell activation, with concomitant reduction of help for allergen-specific IgE antibody synthesis by B cells, but also substantially ablate memory cells, creating a sustained effect. These are exciting prospects for the future. A caveat is that T regulatory responses may also depend on costimulatory molecule signaling (Lohning et al. 2003). Animal models of asthma and allergy have shed some further light on the possible roles of costimulatory molecules in allergic inflammation. Mice lacking ICOS show marked

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defects in humoral (especially IgG1 and IgE) responses and Th2 cytokine expression (Dong et al. 2001). ICOS blockade reduced lung inflammation and airway hyperresponsiveness following adoptive transfer of highly polarized Th2 cells into naive mice and was effective up to 21 days following allergen priming of naive animals (Coyle et al. 2000), suggesting that ICOS is important for maintaining Th2 effector function but not differentiation. In contrast, blockade of CD28–CD80/86 interactions after priming had no effect on the Th2 effector response. As suggested in humans, however, ICOS may also be important in the development of allergen-specific, IL-10producing adaptive T regulatory cells (Akbari et al. 2002). In summary, there is still much to be learnt about the influences of costimulatory molecules on T-cell activation. It seems likely that a balance between stimulatory and inhibitory signals is required for effective T-cell responses and for maintaining T-cell tolerance. It is not clear whether these possible interactions provide redundant positive and negative regulatory signals or whether there is some hierarchy in the organization of the signals. CD28 and ICOS synergize to promote T-cell activation, with CD28 having a predominant role in initial T-cell activation and ICOS regulating differentiated T cells. Of the multiple negative inhibitory signals provided through these interactions, CTLA-4 is the predominant one, but it has synergistic nonredundant interactions with those of PD-1 (Oflazoglu et al. 2004; Radhakrishnan et al. 2005).

gd T cells As discussed above, early T-cell differentiation in the thymus gives rise to CD8+ and CD4+ T cells which recognize peptides presented with MHC class I and II molecules respectively. In addition, a subset of T cells arising in the thymus recognizes a limited range of antigens in a non-MHC-restricted fashion. These cells have antigen receptors composed of distinct polypeptide chains called γ and δ, in contrast to the α and β chains used by the majority of MHC-restricted T cells. In humans, γδ T cells comprise 1–5% of circulating T cells. They have been implicated (mostly from animal experiments) in specific primary immune responses, immunoregulation, and tumor surveillance (Hayday & Tigelaar 2003). They are particularly abundant at mucosal surfaces, especially of the skin and gut, and their tissue localization appears to be dependent on the particular γ and δ TCR genes they express (Pennington et al. 2005). γδ T cells do not pass through a “double-positive” CD4/CD8 stage during maturation, but appear to develop from double-negative cells in the thymus. Since physiologic ligands for their receptors have so far been poorly characterized, it is not clear if and how they are positively and negatively selected. Mature γδ T cells are activated in the presence of products of some microorganisms such as Mycoplasma and cell wall components of Mycobacterium, as well as self glycosphingolipids induced in antigen-presenting cells in association with a variety of bacterial, and possibly also viral,

T Cells and Cytokines in Asthma and Allergic Inflammation

infections (De Libero et al. 2005). They also recognize self molecules produced by cellular “stress,” such as CD1 and F1ATP synthase (Scotet et al. 2005). In addition to antigen receptors composed of γ and δ chains, these cells also express innate cell-surface receptors such as TLRs, and under certain conditions can act as antigen-presenting cells, expressing the lymph node homing receptor CCR7, MHC class II, and costimulatory molecules such as CD40, CD80 and CD86 (Brandes et al. 2005). They also induce dendritic cell maturation (Conti et al. 2005). A recent study (Jin et al. 2005) suggests that a subset of γδ cells expressing the Vγ4 TCR gene can suppress airway hyperresponsiveness in an ovalbuminchallenge murine model of asthma. Since these γδ cells are not antigen-specific, they are perhaps activated by antigenpresenting cells such as dendritic cells.

Natural killer T cells NKT cells are a specialized subset of thymus-derived cells that express conventional αβ TCR chains as well as NK-specific markers such as NK1.1. In humans, a large majority of these cells (termed type I, or iNKT, or classical NKT cells) express an invariant TCR comprising the Vα24/Jα18 TCR α chain paired with a Vβ8 or Vβ2 β chain, hence their name “invariant” NK T cells. These cells are restricted by the nonpolymorphic MHC class I-like protein CD1d. CD1d is widely expressed in the body by mucosal epithelial cells, hepatocytes, T cells, B cells, macrophages, and dendritic cells. Like iNKT cells, type II NKT cells (or noninvariant NKT cells) are CD1d restricted, but have a more diverse TCR repertoire. These cells have been implicated in the pathogenesis of some human diseases such as ulcerative colitis (Fuss 2004). Type III NKT cells express a diverse repertoire of T-cell antigen receptors restricted by conventional MHC class I and II molecules. Evidence suggests that NKT cells develop from committed, double CD4+CD8+ T-cell precursors by a mechanism that is not yet clear. Many inherited diseases that affect T-cell development also affect NKT cells, such as X-linked severe combined immunodeficiency (mutation of CD132, the common γ-chain receptor of IL-2, IL-4, IL-7, and IL-15) (Jordan et al. 2004). Following expression of the TCR, CD1d-restricted cells can be identified before the appearance of NKT cell-specific markers. The most immature cells lack the surface markers DX5 and NK1.1. Mature NKT cells are divided almost equally into DX5+/NK1.1+ and DX5–/NK1.1+ cells (Gadue & Stein 2002). In humans, most iNKT cells also express CD4, while a small proportion expresses CD8 and a more substantial proportion expresses neither CD4 nor CD8. NKT cells are distributed in the same way as conventional T cells. Their most striking effector function is to produce large quantities of the cytokines IL-2, IL-4, IFN-γ, and TNF-α following activation. They are able to do this because they accumulate cytokine-specific mRNA in the resting state (Stetson et al. 2003). The invariant receptor of NKT cells is unique in its interaction with the nonclassical MHC molecule CD1d. This

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molecule has a deep, hydrophobic, antigen-binding pocket that allows it to present lipid and glycolipid antigens rather than conventional peptide antigens. Natural ligands for NKT cell receptors are poorly characterized, although some have been described (Brigl & Brenner 2004; Zhou et al. 2004). A synthetic glycolipid, α-galactosylceramide (α-GalCer), derived from marine sponges has been identified as a surrogate NKT cell ligand in humans and mice and has been useful not only for functional studies but for identifying these cells by their binding to α-GalCer complexes with CD1d tetramers. Stimulation of NKT cells with α-GalCer induces a proliferative response, expression of activation molecules, elevated cytotoxic activity, and production of large amounts of cytokines. As with T cells, NKT cell cytokine production can be skewed by external influences. For example, stimulation through the NK1.1 receptor results in high production of IFN-γ but not IL-4. Exogenous cytokines also exert an influence. For example, exogenous IL-7 encourages IL-4 production, whereas exogenous IL-12 favors IFN-γ (Godfrey et al. 2000). NKT cells can also exhibit cytotoxic activities similar to those of CD8+ T cells. Studies in humans suggest that this may be a particular property of subsets of NKT cells. In vitro, activation of NKT cells by α-GalCer leads to multiple secondary effects on other cells such as NK cells, dendritic cells, and subsets of conventional T and B cells, probably through their production of cytokines. The rapid response of NKT cells to nonpeptide ligands suggests that they play a role in innate rather than adaptive immunity. They do however regulate adaptive immune responses: in mouse models they have been implicated in regulating adaptive immune responses against a number of viral infections, tumor immunity and autoimmune diseases (Mercer et al. 2005). Of particular interest here is a possible role in asthma. CD1d knockout mice, which lack NKT cells, showed markedly attenuated airway hyperresponsiveness and inflammation in a model of allergen sensitization and challenge (Bilenki et al. 2004). Furthermore, activation of NKT cells using α-GalCer exacerbated airways inflammation and bronchial hyperreactivity in this model, an effect that was not seen in mice lacking CD1d. Adoptive transfer of NKT cells from mice deficient in both IL-4 and IL-13 to Jα18-deleted (and therefore iNKT deficient) mice failed to restore the induction of airway hyperresponsiveness following allergen challenge (Akbari et al. 2003), suggesting that production of IL-4 and/or IL-13 by NKT cells is required for the development of airway hyperresponsiveness in this situation. This observation is remarkable since allergen-specific Th2 cells as well as IgE responses develop normally in CD1d or Jα18 knockout mice, but at least in these experiments such normal T-cell responses appear to be insufficient for the development of airway hyperreactivity. Consideration of an additional role for NKT cells in the development of organ-specific disease despite normal Th2 and IgE responses to allergens might throw some light on the

56

age-old question of why only some subjects sensitized to allergens develop allergic diseases such as asthma and rhinitis in the target organs. Using CD1d tetramers loaded with α-GalCer and PCR analysis of the expression of the invariant TCR of NKT cells, it has recently been suggested that, in human asthma, approximately 60% of airway CD4+ cells are not conventional MHC class II restricted T cells, as has hitherto been assumed, but NKT cells expressing the invariant Vα24/Jα18 receptor (Akbari et al. 2006). These cells exhibited a cytokine expression profile similar to that of conventional Th2 cells. This finding was striking considering that NKT cells comprise <1% of the CD4+ population in the peripheral blood of humans. These studies suggest that CD4+ NKT cells are selectively recruited to the asthmatic airways, possibly through CCR9 expression (Sen et al. 2005). At present these studies are contentious (Mutalithas et al. 2007; Vijayanand et al. 2007) but if verified by scientific consensus may force a shift in our current understanding of the relative contributions of conventional CD4+ Th2 cells and NKT cells to the production of IL-4 and IL-13 in asthma and of the contribution of these cells to asthma pathogenesis in general. It is unclear what could be activating NKT cells in this situation, but glycolipids indigenous to the mucosal environment are obvious theoretical candidates. In addition, human NKT cells have been shown to be activated by exogenous lipids such as those found in certain tree pollens (Agea et al. 2005). Finally, it is of interest that NKT cells are relatively resistant to glucocorticoid inhibition (Tamada et al. 1998), which could, at least in theory, form one explanation for clinical glucocorticoid refractoriness in asthma (assuming that NKT cells are involved).

T-cell memory The adaptive immune system is characterized by the presence of immunologic memory, which augments or at least maintains subsequent immune responses to encounters with particular antigens, including allergens, following initial exposure. Expression of the CD45RO isotype on memory T cells distinguishes them from their naive counterparts that express CD45RA. Memory CD4+ T cells have been further classified into two distinct types based on the presence or absence of expression of the chemokine receptor CCR7. Central memory T cells (TCM) expressing CCR7 preferentially migrate to secondary lymphoid tissues, and proliferate on antigen encounter, giving rise to a progeny of effector T cells. In contrast, effector memory T cells (TEM), which lack CCR7, traffic directly to inflamed tissue and respond rapidly on activation, thereby exerting their effector functions in the tissues. Thus, memory cells have been defined as CD45RO+CCR7+CD62L+ (TCM) and CD45RO+CCR7−CD62L− (TEM) (Fig. 3.3) (Sallusto et al. 2004). TCM cells are maintained long term in the immune system by the cytokines IL-7 and IL-15, which induce “homeostatic proliferation” of these cells to prevent them from disappearing (Geginat et al. 2001). On

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Pre-Th1 TCM

CXCR3

Pre-Th2 TCM

CCR4

Th2 TCM

CRTH2

Th1 TEM

CXCR3

Th2 TEM

CCR4

Th2 TEM

CRTH2

CCR7

TCM CD62L +

Fig. 3.3 Phenotypes of human CD4 memory T-cell subsets. Th2 TEM cells have not been formally demonstrated (hence the question mark) but such cells have been identified at sites of ongoing Th2 inflammation and would be predicted to exhibit a TEM phenotype. The question mark by the large arrow indicates that it is controversial whether effector memory cells develop from central memory cells or de novo from naive T cells. TM, memory T cell; TCM, central memory T cell; TEM, effector memory T cell. See Rivino et al. (2004), Sallusto et al. (2004) and Wang et al. (2006).

?

Antigen reexposure

TM CD45RO

reencounter with antigen, they can differentiate into effectors (TEM). Distinct patterns of chemokine receptor expression are also said to distinguish pre-Th1 and pre-Th2 TCM cells. CXCR3-bearing cells differentiate into Th1 effectors, whereas CCR4-expressing cells differentiate into Th2 effectors (Rivino et al. 2004), although this distinction is not absolute since reports suggest that CCR4 can be expressed by both pre-Th1 and pre-Th2 TCM cells, as well as T regulatory cells (Andrew et al. 2001; Iellem et al. 2001). In addition, selective expression of a novel seven-transmembrane G protein-coupled receptor called CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) has been described on a subpopulation of memory cells committed to the production of IL-4, IL-5 and IL-13 but not IFN-γ following TCR triggering (Nagata et al. 1999; Hirai et al. 2001), suggesting that these cells are committed memory Th2 cells. Very recent studies (Wang et al. 2006) show that CRTH2+CD4+ cells from the blood of normal human donors exhibit a central memory phenotype and respond to allergens in vitro. In this particular study, priming of dendritic cells with the IL-7-like cytokine TSLP appeared to be necessary for generating allergen-specific recall responses in CRTH2+CD4+ T cells, although it is not clear whether this is an obligatory activation pathway for all Th2 committed memory T cells since, in vitro, T-cell recall responses are regularly generated in response to allergen in the absence of exogenous TSLP. TSLP-activated dendritic cells can maintain CRTH2+CD4+ T cells in vitro, without altering their central memory phenotype or Th2 commitment (Watanabe et al. 2004). This is one possible mechanism whereby allergenspecific Th2 memory cells may persist in vivo for many years. TSLP is emerging as an important mediator of T-cell

TEM

?

responses to allergens, since it not only maintains Th2 committed memory T cells but also strongly activates dendritic cells which then prime naive T cells to differentiate into Th2 cells (Fig. 3.4). Furthermore, TSLP expression has been described, as mentioned above, in lesional skin keratinocytes of patients with atopic dermatitis as well as the bronchial mucosa of asthmatics (Soumelis et al. 2002; Ying et al. 2005). The presence of TSLP at the critical interface between the mucosal surface and the environment raises important questions for the future concerning how TSLP expression is regulated by environmental influences such as allergen exposure and infections. Despite this augmentation of knowledge about the physiology of T-cell memory in recent years, many fundamental questions regarding the maintenance of T-cell memory remain. Whether memory T cells arise from effector T cells, or naive cells, or both has long been debated and is currently uncertain. How long it takes allergen-specific memory Th2 cells to develop is also unclear. Furthermore, it is not clear whether maintenance of the memory T-cell repertoire against a particular antigen depends on, or is shaped by, chronic exposure. It is clear that antigen-specific T cells persist for at least many years in the peripheral blood of humans (Bohle et al. 1998). The mechanisms discussed above for the maintenance of TCM cells are likely important in maintaining immunologic memory, and it may well be the case that continued exposure to antigen is not necessary to maintain it. It is conceivable, for example, that environmental influences maintaining TSLP expression at mucosal surfaces may preserve antigen-specific TCM cells without the necessity for the persistence of the antigen. The studies described above

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Immunology of the Allergic Response Allergen Mucosal surface DC

TSLP

Other sources?

TSLP DC

MHC/peptide/TCR DC

OX40/OX40L

Effector Th2

Lymph node

Th2 CRTH2

Th2 TEM CRTH2

Effector memory Th2

Naïve T cell

Trafficking to target organ

Th

Central memory Th2

Th2 TCM CRTH2

Inflammatory Th2 Th2 CRTH2

suggest that interaction between the costimulatory molecule OX40 expressed on memory T cells and its ligand OX40L expressed on dendritic cells is important not only for the persistence of TCM cells but also recall responses to allergens (Soumelis et al. 2002; Wang et al. 2006). Therapeutic strategies directed against the formation or persistence of TCM cells may constitute an important (and largely neglected) strategy in atopic diseases involving long-term sensitization to allergens (Epstein 2005). Equally important is the prospect of directing memory T-cell responses in early life, which is a corollary of the hygiene hypothesis, but much more work must be done to clarify the cellular targets of environmental factors such as endotoxin, whether the timing of exposure to such factors is critical, and whether redirection of allergen-specific Th2 type immunologic memory by agents such as endotoxin requires continued allergen exposure. The effects of T regulatory cells on immunologic memory have not yet begun to be explored.

T regulatory cells Although Th1 and Th2 cells are mutually inhibitory, it has long been apparent that simple, mutually antagonistic interactions between these cells cannot explain the regulation of Th2 activity in humans. For example, in animal models of asthma, allergen-specific Th1 cells have in some cases been reported to augment allergic inflammation (Hansen et al. 1999). Helminthic infections, which promote Th2 responses, do not appear to be associated with increased risk of allergy and asthma and on the contrary in some studies appear to be protective (Yazdanbakhsh et al. 2002). Finally, epidemiologic data in the last 40 years have shown a parallel rise in the prevalence of “Th1-type” diseases such as diabetes and “Th2type” diseases such as asthma (Sheikh et al. 2003), an observation that, while not necessarily reflecting direct mutual Th1/Th2 antagonism, certainly does not support it. It is in this setting that T regulatory cells have come to the fore as being capable of suppressing Th1 and Th2 cells independently. Environmental influences altering the function of T

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Fig. 3.4 Dendritic cells (DC) activated by thymic stromal lymphopoietin (TSLP) produced at mucosal surfaces migrate to lymph nodes and induce Th2 inflammatory cells while maintaining Th2 central memory cells. At the mucosal surface, DC activate allergen-specific effector/memory T cells in situ. OX40/OX40L interaction is necessary for both these processes. TCR, T-cell receptor.

regulatory cells seem a more likely candidate to explain the aforementioned data, rather than mutual antagonism of Th1 and Th2 responses within individuals. T regulatory cells may be “natural” (arising in the course of normal development of the immune system) or “adaptive” (arising because of immune encounters). As described previously, natural T regulatory cells arise largely to promote tolerance to self antigens. They constitute 5–10% of circulating CD4+ T cells (Fehervari & Sakaguchi 2004), and there is some evidence that they recognize self antigens but with broad specificity (Hsieh et al. 2004). They are characterized by high expression of CD25 (which confounds their identification since this is also an activation marker of effector T cells). They proliferate poorly in vitro in response to conventional T-cell activation stimuli and appear to inhibit adaptive T-cell responses through contact with T cells when they synapse with dendritic cells during activation. The precise mechanisms are unclear, but signaling through surface molecules such as CTLA-4, Notch 3, and LAG-3 has been implicated. Ligation of CTLA-4 on dendritic cells induces the enzyme indoleamine 2,3-dioxygenase (IDO), which starves T cells of tryptophan (Mellor & Munn 2004). In addition to CD25, natural T regulatory cells express CTLA-4, CD45RO, CD38, CD62L, the glucocorticoid-induced TNF receptor gene GITR, and neuropilin-1, although none of these markers is specific. As mentioned above, the transcriptional regulator FoxP3 is overexpressed in natural T regulatory cells as compared with resting and conventionally activated T cells, although again this is troublesome as an identification marker for these cells since FoxP3 is not a surface marker, and again FoxP3 expression is not entirely limited to T regulatory cells. The precise actions of FoxP3 are not clear, but retroviral transfer of FoxP3 is sufficient to confer regulatory T-cell function (Yagi et al. 2004). Humans carrying loss-of-function mutations in FoxP3 develop the IDEX syndrome (see above). They also have an increased incidence of eczema and food allergy, suggesting that underlying defects in T regulatory cells cause these symptoms, and more importantly that efficient natural

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T regulatory cell function is important for maintaining normal immune homeostasis in health. Adaptive T regulatory cells arise generally in the periphery from naive T cells on encounter with antigens presented by tolerogenic dendritic cells. Tolerogenic dendritic cells are generally semimature cells with increased expression of MHC class II molecules and CD86, but low expression of CD40 and secretion of proinflammatory cytokines such as IL-6 and TNF-α (Lutz & Schuler 2002). Repetitive stimulation of T cells with such dendritic cells generates IL-10-producing Tr1 adaptive T regulatory cells (Jonuleit et al. 2001). Similarly, inhibition of dendritic cell maturation by inhibiting NF-κB activation with 1,25-dihydroxyvitamin D3, glucocorticoids, or mycophenolate mofetil induces development of Tr1 T regulatory cells; this may also occur directly in the presence of such drugs by activating naive CD4+ T cells in the absence of dendritic cells (Barrat et al. 2002). Again the mechanism is not completely understood, but appears to depend on secretion of IL-10 (Tr1) or TGF-β (Tr3) by immature dendritic cells. Tolerance induced to mucosally applied antigens also appears to induce tolerogenic dendritic cells producing IL-10 or TGF-β (Weiner 2001). As has been discussed, the role of T regulatory cells in controlling the development and expression of allergic diseases in asthma is only beginning to be explored (reviewed by Akdis et al. 2005). Whether these cells play an important role in sensitization to allergens in intrauterine or early life is not yet clear. In patients with established allergy, evidence of deficiency of allergen-specific natural T regulatory cells has been reported in some (Ling et al. 2004) but not all (Bellinghausen et al. 2003) studies. The former study suggested that allergen-specific T regulatory cell activity was reduced compared with nondiseased controls in subjects with allergic rhinitis during the pollen season when they have symptoms, rather an outside it, suggesting that deficient T regulatory cell activity may somehow be involved with the clinical expression of allergic disease, although these experiments do not make it clear if clinical disease is caused by reduced natural T regulatory cell activity or is a consequence of it. What these studies do show for certain is that external allergens seem to be included in the antigenic repertoire of natural T regulatory cells. A further study (Karlsson et al. 2004) showed increased numbers of CD4+CD25+ βlactoglobulin-specific T cells in the blood of children who had outgrown cows’ milk allergy compared with others who had not. The inhibitory effect of these cells appeared to depend on cell contact, implying a role for natural T regulatory cells. There are similar data suggesting deficiency of allergen-specific IL-10-producing Tr1 adaptive T regulatory cells in patients who develop sensitization and symptoms in response to aeroallergens compared with those who do not (Akdis et al. 2004). Therapeutic intervention also appears to be able to regulate T regulatory cell activity. For example, inhaled or systemic

T Cells and Cytokines in Asthma and Allergic Inflammation

glucocorticoid therapy of asthmatics was associated with elevated expression of both FoxP3 and IL-10 mRNA in peripheral blood CD4+ T cells (Karagiannidis et al. 2004), suggesting the induction of T regulatory cells, although the precise phenotype of these cells (natural or Tr1) could not be concluded from this study since it is still controversial whether the development of adaptive as opposed to natural T regulatory cells always requires expression of FoxP3 (Fehervari & Sakaguchi 2004; Yagi et al. 2004). Allergen immunotherapy may also induce adaptive, allergen-specific T regulatory cells. Studies have shown increases in allergenspecific IL-10-producing Tr1 and TGF-β-producing Tr3 type cells in the blood or airways following immunotherapy (Jutel et al. 2003; Nouri-Aria et al. 2004), although what role these cells play, if any, in mediating the clinical effects of immunotherapy (i.e., reduced responsiveness of mucosal surfaces to allergen exposure) is not clear (this is secondary to the fact that the immunologic processes underlying the clinical effects of allergen immunotherapy in general are poorly characterized). Furthermore, increased IL-10 production following allergen immunotherapy is not limited to T cells, but may also be observed in monocytes/macrophages and B cells (Akdis et al. 1998; Jutel et al. 2003). These are all potential antigen-presenting cells and could conceivably directly suppress T effector cells or contribute to the induction of adaptive T regulatory cells. Despite all these uncertainties, it would seem well worth pursuing therapeutic induction of adaptive T regulatory cells as a means of long-term, directed, and allergen-specific therapy for allergic diseases. Since allergen presentation by immature dendritic cells and production of cytokines such as IL-10 and TGF-β appear important in this respect, combination of allergen immunotherapy with administration of drugs that inhibit dendritic cell maturation and induce IL-10 production, such as 1,25-dihydroxyvitamin D3 or glucocorticoids, may be a fruitful strategy. Finally, a return to the hygiene hypothesis, which in essence suggests that lack of exposure to environmental infectious agents is one factor responsible for the increasing prevalence of allergy in the past 30 or 40 years. As originally formulated, it cannot now apply to the concept of directing a battle between Th1 and Th2 cell supremacy. Environmental influences on the development and persistence of allergic disease, if they truly exist, must now be examined in the light of their possible influences on T regulatory cells. Interestingly, pathogen-specific Tr1 adaptive T regulatory cells are induced in the course of infections with many viruses, bacteria, and parasites (reviewed by Mills 2004). In some cases this results in incomplete elimination of the pathogen, which could theoretically result in “bystander” suppression of allergic responses by both natural and adaptive T regulatory cells. Such findings may necessitate investigation of the hygiene hypothesis in the context of a much broader range of infectious agents, not only pathogens but also commensal bacteria such as the intestinal flora (Kalliomaki & Isolauri 2003).

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TIMs and SOCS The TIM family of proteins was first recognized in mice during a random search for markers that would differentiate between Th1 and Th2 cells. The protein now called TIM-3 is one of very few found to be uniquely expressed on Th1 differentiated T cells (Monney et al. 2002). Subsequent positional cloning techniques uncovered eight related TIM genes in the mouse, although only four of them, TIM1–4, are known to be expressed. Corresponding genes were identified in humans. Human TIM-1 shows homology with mouse TIM-1 and TIM-2 and may have evolved to serve the purposes of both, although this is not certain. Human TIM-3 and TIM-4 show reasonable homology with their mouse counterparts. These genes encode type 1 transmembrane proteins with an immunoglobulin variable domain, and an intracellular signaling sequence with tyrosine phosphorylation motifs (TIM-4 exceptionally lacks such sequences, supporting the suggestion, referred to below, that it may serve as a ligand for the other TIM molecules). In humans, the genes encoding the TIM proteins are on chromosome 5q33.2, not far from the IL-4/IL-5/IL-13 cluster: indeed linkage studies in mice suggest that it is this locus and not the IL-4/IL-5/IL-13 cluster that is linked most closely to susceptibility to experimental asthma (McIntire et al. 2001). Experiments with TIM-3–immunoglobulin fusion protein in mice suggest that the TIM-3 ligand is found predominantly on naive CD4+ T cells. Blockade of TIM-3 stimulation in mice with this fusion protein results in highly augmented Th1 responses (Sabatos et al. 2003). The function of its putative human homolog is as yet poorly characterized. In mice, TIM-2 is preferentially expressed on Th2 cells, whereas TIM-3 is present to an extent on all activated T cells. The use of a TIM-2–immunoglobulin fusion protein has demonstrated a ligand for TIM-2 on activated antigen-presenting cells. Administration of this fusion protein in various models of inflammation tends to augment Th2 responses. The putative human analog of TIM-1 and TIM-2 is the hepatitis A virus receptor (Feigelstock et al. 1998). Epidemiologic studies suggest that patients previously infected with hepatitis A are less likely to have asthma and allergy (Matricardi et al. 2002). In addition, TIM-1 is preferentially expressed on human Th2 cells, whereas TIM-3 is preferentially expressed on Th1 cells (Khademi et al. 2004). A polymorphism of TIM-1 resulting in a six-amino-acid insertion has been linked to the risk of hepatitis A infection and atopy in a North American population (McIntire et al. 2003). Recently, it has been reported that another member of the TIM family, TIM-4, serves as a natural ligand for TIM-1 in mice. Accordingly, TIM-4 is not expressed on T cells but instead on antigen-presenting cells, particularly mature dendritic cells (Meyers et al. 2005). In general, engagement of TIM-1 with a soluble TIM-4–immunoglobulin fusion protein produces a general increase in T-cell proliferation and cytokine production, although the effect can be inhibitory in vitro

60

at lower concentrations (Meyers et al. 2005). The mechanism of this effect has not been elucidated, although it suggests there may be more than one ligand for TIM-4 on T cells. Understanding the mechanisms by which the TIM gene family contributes to immune regulation might uncover new therapeutic opportunities. Because all the TIM molecules studied so far seem to be involved with the balance of expression of Th1- and Th2-type cytokines, they could act as useful drug targets in any system where one would hope to shift this balance, as in allergic diseases. Finally, the TIM genes are highly polymorphic in humans, and one or more of these polymorphisms may be particularly important in directing the strength of T-cell polarization in diseases including allergy and asthma. Cytokines generally signal through the Janus family kinases Jak1–3 and Tyk2, and the STAT (signal transducer and activator of transcription) proteins 1–6. Interaction of a cytokine with its receptor results in reciprocal tyrosine phosphorylation of receptor-associated Jaks and Jak-mediated tyrosine phosphorylation of a cytoplasmic domain of the receptor. The STAT molecules then dock with the latter and are themselves tyrosine phosphorylated, which allows them to dimerize and translocate to the nucleus where they act as transcriptional regulators. The SOCS (suppressor of cytokine signaling) proteins appear to act as negative regulators of this mechanism. Eight members of the SOCS family have been identified: cytokine inducible SH2-containing protein (CIS) and SOCS1–7. They are induced by activation of STATs and limit, by negative feedback, docking of STATs to activated cytokine receptors, thus turning off the initial activation signal. SOCS proteins are induced by a variety of cytokines, growth factors, and PAMPs such as lipopolysaccharide and bacterial DNA sequences acting on TLRs. SOCS1 appears to be particularly important for regulation of IFN-γ-mediated signaling. SOCS1-deficient mice die early with widespread activation of peripheral T cells, an effect that can be delayed by removal of IFN-γ-producing T and NKT cells (Alexander et al. 1999). However, SOCS1 is also capable of inhibiting Jak/STAT signaling initiated by a wide variety of cytokines other than IFN-γ, including IL-2, IL-4, IL-6, IL-7, IL-9, and IL-13 as well as the α and β interferons. SOCS1deficient T cells exhibit sustained phosphorylation of STAT6 or STAT4 when stimulated with IL-4 or IL-12 respectively, accompanied by extreme polarization toward a Th2 or Th1 phenotype (Fujimoto et al. 2002), but these cells spontaneously revert to a high IFN-γ-producing Th1 phenotype. This net effect may represent a complex balance of untamed Th1- and Th2-inducing signals from cytokines such as IFN-γ, IL-12, IL-6, and IL-4. SOCS5 is more clearly implicated in enhancing Th1 T-cell polarization, since it may limit Jak1/Jak3/STAT6 signaling induced by engagement of the IL-4 receptor α chain, which is selectively impaired in Th1 cells (Huang & Paul 1998) although the expression of Jak1, Jak3, and STAT6 is similar

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may come from in the first place before Th2 differentiation has taken place (it certainly does not come from dendritic cells). Work from Yong-Jun Liu’s group (Liu et al. 2006) suggests TSLP as a candidate for the counterpart of IL-12 in promoting Th2 responses. If ratified by scientific consensus, this finding may move TSLP to center stage as a prime molecular target in allergic diseases. The critical difference between TSLP and other dendritic cell stimuli such as CD40L and TLR ligands is that TSLP does not induce the Th1-polarizing cytokines IL-12, or members of the IL-12 family, or other proinflammatory cytokines such as IFN-8, IL-1β, and IL-6, but does induce chemokines such as TARC and MDC which may attract Th2 differentiated T cells. Further to this, when TSLP-activated dendritic cells stimulate naive CD4+ T cells in vitro, they induce a unique type of Th2 cell that produces the “signature” Th2 cytokines IL-4, IL-5 and IL-13, and large amounts of TNF-α, but not IL-10 (Soumelis et al. 2002). That TNF-α also plays a role in asthmatic inflammation has been confirmed by the therapeutic success of TNF-α blockade in this disease (see below). Conversely, IL-10, although conventionally classified as a Th2type cytokine, exerts a number of antiinflammatory actions in asthma as described below. Liu has proposed that Th2 cells producing large amounts of TNF-α, in addition to the “signature” cytokines IL-4, IL-5 and IL-13, may be regarded as inflammatory Th2 cells. Conversely, those Th2 cells producing large amounts of IL-10 but relatively little TNF-α in addition to these signature cytokines could exert a regulatory function. A similar principle may apply with Th1 cells (Fig. 3.5). As described above, interaction of OX40L expressed on TSLP-activated dendritic cells with OX40 on T cells may be a critical trigger for the differentiation of inflammatory Th2 cells. This effect is independent of IL-4 but may be overridden by IL-12, which provides a mechanism whereby environmental stimuli enhancing IL-12 production could turn off development of inflammatory Th2 cells, which is the basis of the hygiene hypothesis. In this scenario IL-4, while acting as an autocrine promoter of Th2 cell differentiation once initiated, is not a critical signal for this initiation. TSLP is expressed in “stromal” cells, such as skin keratinocytes, bronchial epithelial cells, and lung smooth muscle cells

in both Th1 and Th2 cells. Furthermore, SOCS5 is expressed in fully committed Th1 but not Th2 cells, in which its expression appears to be driven by IL-12 (Seki et al. 2002). Only Th1 cells characteristically express a functional IL-12 receptor. Thus, selective induction of SOCS5 during initial T-cell activation might play a role in regulating the direction of Th1 cell differentiation. A caveat is that T cells from SOCS5 gene-deleted mice did not show a tendency toward Th2 differentiation (Brender et al. 2004). Conversely, SOCS3 is implicated in inhibiting Th1 cell differentiation. It is selectively expressed in a Th2-type cytokine environment and in Th2 cells (Seki et al. 2003). SOCS3 can block STAT4 activation by the IL-12 receptor β chain in the presence of IL-12 (Seki et al. 2003). Furthermore, its expression in circulating T cells in patients with asthma correlates with disease severity, while SOCS3 overexpression in transgenic mice enhances Th2-type cytokine expression and airway eosinophilia in experimentally induced asthma (Seki et al. 2003). These observations suggest that SOCS3 blockade may be a worthwhile goal for pharmacologic and other approaches to limiting the Th2 responses in diseases such as asthma, although the consequences may be wide ranging, nonspecific, and possibly ultimately deleterious.

Finale: beyond the Th1/Th2 paradigm Th2 cytokines have been implicated in IgE switching, eosinophil infiltration, and mucous hyperplasia in the target mucosa in allergic diseases and asthma. Dendritic cells play a critical role in directing these responses, which in turn depend on developmental signals acting on these dendritic cells as they mature. As discussed earlier, a link between dendritic cells and induction of Th1 responses is relatively well defined. Microorganism-derived PAMPs activate dendritic cells through TLRs inducing IL-12 production, which primes naive CD4+ T cells to undergo Th1 differentiation. The situation has currently been less clear with induction of Th2 responses. It is not clear whether environmental PAMPs acting through TLRs are involved in initiation of Th2 responses. Furthermore, a clear cytokine counterpart of IL-12 in promoting Th2 responses is not clear. The cytokine IL-4 has been presumed to serve this role, but the vexing question is where this IL-4

Th2

Th2 IL-10

Fig. 3.5 The new Th1/Th2 paradigm. Whereas Th2 cells produce the “signature” cytokines IL4, IL-5, and IL-13, and Th1 cells produce the “signature” cytokine IFN-g, subsets of these cells may serve overall proinflammatory or inhibitory/regulatory functions according to their additional production of TNF-a or IL-10 respectively.

Regulatory IL-4, IL-5, IL-13

TNF-a

Inflammatory IL-4, IL-5, IL-13

Th1

Th1

Regulatory IFN-g

Inflammatory IFN-g

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and fibroblasts, although it may also be expressed by at least some blood leukocytes. The stimuli leading to its expression are as yet uncharacterized, but induction by environmental agents such as allergens, pollutants, and viral infections could provide an important link between environmental influences and induction and exacerbation of allergic diseases such as atopic dermatitis, atopic rhinitis, and asthma. A recent study from our own group shows that TSLP mRNA expression is increased in asthmatic airways and correlates with the expression of both Th2-attracting chemokines and disease severity (Ying et al. 2005). Finally mast cells activated by surface IgE cross-linkage also produce TSLP, which could provide a link between mast cell activation and induction of inflammatory Th2 cells following acute allergen exposure of atopic individuals.

Role of T cells and cytokines in asthma pathogenesis As recently as the late 1980s, asthma was seen as a disease driven by smooth muscle contraction as a result of release of mast cell mediators such as histamine, and the proposition that T cells might be involved was treated with some derision. In the past 25 years, overwhelming evidence, to which the author of this chapter has made a substantial contribution, has accumulated for a critical role for T cells and their cytokine products in asthma, and the proposition is now generally accepted. Indeed, this discovery was hailed as one of the significant milestones in asthma research in the 200th centenary publication of the American Thoracic Society. Asthma is now regarded as a chronic inflammatory disease of the bronchial mucosa characterized by eosinophil infiltration and airway remodeling. Despite these findings, the evidence for a role for T cells has remained largely circumstantial in the sense that there remains a great gulf between descriptive studies of the nature of the inflammatory changes in the bronchial mucosa in asthma and how precisely these are related to the clinical features of the disease, namely variable airways obstruction (causing wheeze and shortness of breath) and nonspecific airway hyperresponsiveness (AHR) (causing cough and inappropriate bronchial constriction in response to environmental stimuli such as cold air, smoke, and exercise). Another major question which remains to be answered is what activates T cells in asthma. While allergen exposure clearly exacerbates asthma in atopic subjects, not all asthmatics are atopic and, even in atopic asthmatics, it cannot be assumed, as it largely has been, that T-cell activation is exclusively initiated by allergens. It has been suggested, for example, that self antigens might also drive T-cell responses in asthma (Lassalle et al. 1993; Nahm et al. 2002). It is possible that T-cell activation in asthma may occur initially in response to allergens, but that other (hypothetical) circumstances intervene in those patients

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in whom it persists, rather than regresses, to maintain chronic T-cell activation and thereby chronic disease.

T cells and Th2 cytokines in asthma The concept of T-cell involvement in asthma arose from the known involvement of these cells in allergen-specific IgE synthesis by B cells in atopic subjects, and the belief that T-cell products might also have direct effects on the airways through recruitment of inflammatory cells, particularly eosinophils. My early studies demonstrated activation of CD4+ T cells in the peripheral blood of patients with acute severe asthma, as shown by expression of the activation marker CD25 (now a source of some uncertainty since this is now also recognized as a marker of T regulatory cells) and correlations of the percentages of activated T cells with disease severity (Corrigan et al. 1988; Corrigan & Kay 1990). Since glucocorticoids are powerful inhibitors of T-cell activation, it was reassuring that T-cell activation was inhibited by systemic glucocorticoid therapy in asthmatics to a degree which correlated with clinical improvement, as measured by changes in spirometry (Corrigan et al. 1991a). Indeed, a subgroup of patients relatively clinically resistant to glucocorticoid therapy failed to show inhibition of T-cell activation, although this could be effected by other immunosuppressive drugs such as cyclosporin A (Corrigan et al. 1991a,b). Activated T cells could similarly be demonstrated in other compartments of asthmatic airways such as the bronchial mucosa and bronchoalveolar lavage fluid, and again the degree of activation could be correlated with eosinophil infiltration and impairment of lung function (Azzawi et al. 1990; Walker et al. 1991; Robinson et al. 1992, 1993a). After the description of the Th1/Th2 dichotomy, and the development of the technique of in situ hybridization to investigate expression of mRNA encoding cytokines in T cells, it became apparent that the overall profile of expression of cytokine mRNA in CD4+ T cells in asthmatics was Th2-type, that is IL-4, IL-5 and IL-13 predominant, in the peripheral blood (Doi et al. 1994; Corrigan et al. 1995), in bronchoalveolar lavage fluid (Robinson et al. 1992, 1993a,b; Till et al. 1995; Ying et al. 1995), and in the bronchial mucosa (Ying et al. 1995, 1997; Humbert et al. 1997a) of asthmatics as compared with controls. The prominent features of these studies were that expression of the cytokine IL-5 most consistently correlated with the degree of airways obstruction in asthma and, where studied, cytokine expression was reduced concomitantly with glucocorticoid therapy and clinical improvement. Some of these Th2-type T cells were shown to be allergen-specific (Till et al. 1998), although interestingly at least some of them retained the ability to respond to IL-12 (Varga et al. 2000). Again, cytokine production was inhibited by antiasthma glucocorticoids (Powell et al. 2001a). As mentioned, however, these experiments do not necessarily indicate that allergens are the sole or even the most important stimulus to CD4+ T-cell activation in asthma.

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Histamine Bronchospasm

Prostaglandin D2 Leukotrienes Mast cell

IL-4, IL-13, TGF-b

IgE

ACUTE CHRONIC

Allergen Other antigens?

B

Epi Fib ASM

B cell

TSLP IL-4, IL-13

TSLP IL-4

IL-13

AHR Remodeling Narrowing TGF-b

IL-5 Major basic proteins Leukotrienes

CD4+ DC Th2 T cell

Eosinophil

Fig. 3.6 Working hypothesis of asthma pathogenesis. Mast cells sensitized by surface allergen-specific IgE release acute mediators of bronchoconstriction on allergen exposure, which may serve as a mechanism for acute exacerbation of asthma in atopic patients. Th2 T-cell differentiation in the airways is driven by dendritic cells (DC) which present allergens and possibly other antigens to T cells in an MHC class II restricted fashion, possibly under the influence of thymic stromal lymphopoietin (TSLP) produced by mast cells, epithelial cells, and other cells. Th2 cytokines control IgE synthesis by B cells (IL-4, IL-13) and encourage recruitment and

activation of eosinophils (IL-5), which may damage the mucosa through release of major basic protein, and are also a source of remodeling cytokines such as TGF-b. Th2 cytokines such as IL-4 and IL-13 also induce release of growth factors by structural cells in the airways such as epithelial cells (Epi), myofibroblasts (Fib), and airway smooth muscle cells (ASM) causing remodeling changes (fibrous protein deposition, mucous hyperplasia, smooth muscle hypertrophy/hyperplasia). Mast cells are also a source of remodeling cytokines. See text for definition of other abbreviations.

These findings resulted in the concept that asthma is driven by Th2-type T cells, and that IL-5 expression by these cells drives eosinophil recruitment to, and selective accumulation in, the airways (Fig. 3.6). They also linked IL-4 and IL-13 production by these cells as promoters of IgE synthesis by inducing B-cell switching to IgE. Despite this explosion of knowledge in a period of 10 years, important questions remain. Because all the aforementioned studies represent a “snapshot” of a single period in time, they have provided no information as to how asthma severity is regulated on a day-to-day basis, and even today there is very little information on how environmental stimuli (with the possible exception of allergen exposure in those asthmatics who are also atopic) interact with this T-cell/Th2-type cytokine/ eosinophil axis to alter disease severity in the short term (such stimuli would include viral infections, exercise, cold air, smoke, and others). Furthermore, as mentioned, although eosinophil products such as basic proteins have been hypothesized to “damage” the bronchial mucosa in asthma, there is little or no understanding of how this “damage” results in the clinical features of the disease. It has also become apparent that CD4+ T cells are not the only possible sources of Th2-type cytokines in asthma. Eosinophils, mast cells, and basophils are also potential sources (Moqbel et al. 1995; Kon et al. 1998a; Lacy & Moqbel 2001; Pawankar 2001), while airway smooth muscle cells may also produce Th2-type cytokines and chemokines (see below and other chapters in this volume).

Is all asthma the same? Several clinical phenotypes of asthma have been described (atopic, nonatopic, occupational), although the fundamental clinical features of asthma (variable airways obstruction and AHR) in all these phenotypes appears to be similar. The question arises as to whether the T-cell/cytokine/eosinophil paradigm of inflammation plays a similar role in all these phenotypes. In cross-sectional studies of bronchial biopsies from patients with these phenotypes of asthma, the cellular immunopathology of the disease, at least in terms of numbers of infiltrating cells, appeared to be virtually identical (Bentley et al. 1992a,b; Humbert et al. 1996), and in every case characterized by evidence of T-cell activation and eosinophil infiltration. We have performed exhaustive comparisons of the cellular and molecular immunopathology of the bronchial mucosal infiltrate in atopic and nonatopic asthma (Humbert et al. 1996, 1997a,b,c; Ying et al. 1997) and have found that the profiles of cytokine expression, with predominant expression of IL-4, IL-5 and IL-13, as well as the cellular provenance of the cytokines (predominantly CD4+ T cells) are remarkably similar in asthma regardless of the atopic status of the patient. At first sight, this might suggest that IgEmediated mechanisms such as mast cell degranulation are neither necessary nor sufficient for the development of asthma, and that when asthma and atopy coexist, as they often do, mast cell degranulation serves merely to exacerbate the disease acutely by release of bronchoconstricting mediators such as histamine and leukotrienes into airways already

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rendered hyperresponsive by chronic T cell-mediated inflammation. The situation has been complicated, however, by our recent observation (Takhar et al. 2007) that IgE class-switch recombination in B cells may occur in the bronchial mucosa of both atopic and nonatopic asthmatics, suggesting that the latter patients may manufacture IgE, allergen-specific or otherwise, in the bronchial mucosa even though this is not detectable by conventional tests (skin-prick tests or in vitro tests) in the periphery. Thus, while the precise role of IgE in asthma pathogenesis remains to be elucidated, these experiments nevertheless stress the similarity of the immunopathologic mechanisms across the spectrum of clinical phenotypes. Studies on child asthma seem to support the T-cell hypothesis. We observed activated peripheral blood CD4+ T cells in child asthmatics, correlations with blood eosinophils and disease severity, and increased Th2-type cytokine mRNA expression that were reduced concomitantly with glucocorticoid therapy and disease improvement (Gemou-Engesaeth et al. 1994, 1997, 2002). Other phenotypes of asthma which have been much discussed are the “severe” and “difficult to treat” phenotypes (these are not synonymous since the clinical responsiveness of asthma to therapy does not necessarily parallel its severity). One problem with studying patients with severe asthma is that it is difficult to discriminate a priori abnormalities from the effects of the high dosages of glucocorticoid that these patients inevitably receive. Making a case for “severe” asthma forming a distinct immunopathologic phenotype, Wenzel et al. (1997, 1999) have shown that it is possible to delineate groups of severe, glucocorticoid-dependent asthmatics with numbers of bronchial mucosal eosinophils within the range observed in normal controls. One of these studies suggested that these patients also had increased numbers of airway neutrophils, whereas the other did not. Pursuing this theme, it has recently been suggested that milder asthmatics with “noneosinophilic” asthma respond less well, at least in the short term, to inhaled glucocorticoid therapy (Berry et al. 2007). There is intense interest in linking (if possible) particular immunopathologic changes with particular clinical phenotypes of asthma, since this has obvious implications for distinct approaches to therapy, and doubtless these studies will multiply. Nevertheless, aside from these isolated (though intriguing) observations, there is as yet no extensive evidence base supporting the hypothesis that asthma can be subdivided on molecular or cellular pathologic grounds, or that clinical phenotypes of asthma have distinct immunopathologic features.

Airway remodeling There has been much discussion about the possible role of changes in the airways, collectively termed “remodeling,” that may be observed in association with asthmatic inflammation. These changes include deposition of new fibrous

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proteins, hyperplasia of mucous glands, neovascularization, and airway smooth muscle hypertrophy and hyperplasia. In theory such changes, once established, might be resistant to therapy and could cause irreversible blockage of the airways and AHR, although none of these possibilities has yet been convincingly demonstrated. Experiments in animals (see below) suggest that all the changes characteristic of remodeling, as well as AHR and inflammatory cell infiltration, can be recapitulated in the airways by the transgenic expression of single cytokines such as IL-5, IL-11, or IL-13 in the airways. In the case of transgenic IL-13 expression (Kibe et al. 2003), glucocorticoid administration abolished the associated cellular infiltrate but not the remodeling changes. In human studies, anti-IL-5 therapy was shown to reduce deposition of extracellular proteins in the bronchial mucosa while partly but not completely abolishing the infiltration of eosinophils (FloodPage et al. 2003). Together these experiments strongly suggest that Th2-type and other cytokines may participate in remodeling, but leave open the question of whether leukocytes such as eosinophils are necessarily involved in the process. In humans, Th2-type cytokines such as IL-5 and IL-13 have been shown to have the ability to increase airway smooth muscle contractility to cholinergic agonists in vitro (Hakonarson et al. 1999; Laporte et al. 2001), and it has been suggested that such changes alone might be sufficient to sustain AHR (Maclem 1996). Bronchial biopsies from asthmatics compared with those from patients with eosinophilic bronchitis (characterized by cough without reversible airways obstruction or AHR) showed no differences in bronchial mucosal T cell or eosinophil infiltration, but mast-cell invasion of smooth muscle cells only in the asthmatics, suggesting AHR may be more related to mast cell/smooth muscle interactions than the T-cell/cytokine/eosinophil axis (Brightling et al. 2002). This mast-cell myositis was also observed in a second study (Berry et al. 2007). If reinforced by scientific consensus, and if specific for asthma, these findings suggest that mechanisms other than those mediated by T cells may contribute to AHR (although cytokines may still be involved), and even that attention might be better focused on inflammatory changes in airway smooth muscle rather than the mucosa. Having said all this, there is no firm evidence, as with postulated “damage” to the bronchial mucosa by eosinophil products, that remodeling changes contribute to the clinical features of asthma. If they do, one might expect that remodeling changes, which might be less susceptible to reversal once established, would be more prominent in those asthmatics who show a poor response to T cell-directed therapy, such as glucocorticoid, compared with those who show a good response. This possibility remains to be investigated. Two sets of experiments provide more direct evidence for T-cell involvement in ongoing regulation of asthma severity. Treatment of severe, glucocorticoid-dependent asthmatics with a single infusion of a chimeric anti-CD4 monoclonal antibody, which temporarily ablated circulating CD4+ T cells,

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resulted in measurable improvement in lung function compared with a parallel group treated with placebo (Kon et al. 1998b). Such an approach is unlikely to be used in routine clinical practice, but it does provide “relatively” clear proof of principle that direct inhibition of CD4+ T cells can ameliorate asthma. Conversely, it was shown that intradermal injection of short peptides derived from the cat allergen Fel d 1 could induce an isolated late bronchoconstrictor response in asthmatics with cat allergy (Haselden et al. 1999, 2001). These peptides bound to MHC class II molecules, but did not activate basophils by IgE cross-linking in a histamine release assay. The phenomenon was MHC class II-restricted in the sense that it was observed only in individuals whose MHC class II molecules were able to bind to the injected peptides. These interesting data show not only that a presumably “pure” CD4 + T-cell stimulus can cause bronchoconstriction in asthmatics, but also that this stimulus is capable of being transmitted from the site of injection, presumably to the lungs, within hours. The mechanism of this phenomenon remains unclear since it was not accompanied by any detectable T-cell activation within the airways, cellular infiltration, or changes in the production of IL-5, IL-13, histamine or leukotrienes, although inhaled challenge with the same peptides was accompanied by increased eosinophils in induced sputum (Ali et al. 2002).

New cytokines in asthma In addition to the “classical” Th2-type cytokines, many other cytokines have been implicated in the mechanism of asthma (Table 3.3). Many of these demonstrations have relied on mouse models of asthma, which usually involve relatively short-term sensitization of the animals to a protein (typically ovalbumin) by intraperitoneal injection of the protein in adjuvant, followed by repeated inhalational challenge with the same protein. Although animals challenged in this way develop “AHR,” usually demonstrated by increased airways resistance and/or reduced compliance in response to aerosolized bronchoconstricting drugs such as methacholine, the data obtained are very dependent on the precise protocol employed, not to mention the strain of mouse. Rather than being truly representative of the mechanism of chronic human asthma, these models have provided insight into how individual cytokines may effect airway changes when either overexpressed (as in transgenic animals) or ablated (by gene deletion or blocking antibodies). One of the most striking realizations from these models is that many cytokines may cause airway changes associated with AHR and remodeling apparently through direct effects on the airways, pushing effector granulocytes somewhat out of the limelight, at least in this context although, as has been discussed, direct interactions of granulocytes such as mast cells with airway smooth muscle cells may yet have an important role to play in the generation of AHR. In addition to these animal models, studies of cytokine expression have been performed

T Cells and Cytokines in Asthma and Allergic Inflammation

in human asthma, although many of these have been simply observational. In mouse models, adoptive transfer of differentiated allergen-specific Th2, but not Th1, cells to naive mice can induce airway eosinophil infiltration and AHR on allergen rechallenge (reviewed by Lloyd et al. 2001). The idiosyncratic nature of these models was well demonstrated by two studies published in the Journal of Experimental Medicine in 1996, one of which (Foster et al. 1996) suggested that IL-5 blockade abolished airway eosinophil infiltration, AHR, and remodeling changes, while a second (Corry et al. 1996) suggested that IL-4 but not IL-5 blockade had the same range of effects. IL-5 appears to have an important eosinophil-regulating function in asthma, as do the cytokines IL-3 and GM-CSF. The heterodimeric receptors for all three of these cytokines share a common β chain, although the IL-5 receptor is expressed among the granulocytes only on eosinophils and basophils, unlike IL-3 and GM-CSF receptors which are expressed on a wider range of granulocytes, as well as monocyte/macrophages and dendritic cells. All three cytokines activate eosinophils by signaling through p38 MAPK, causing increased expression of integrins such as ICAM-1, α6β2 integrin (CD18), and CD44 (Ip et al. 2005). Once activated, eosinophils in asthmatics release IL-5 in an autocrine fashion, which prolongs their life through upregulation of the antiapoptotic factor Bcl-2 (Huang et al. 2005). IL-3 upregulates CD48 expression on eosinophils, cross-linking of which causes release of granule proteins (Munitz et al. 2006). This is an important observation since although eosinophil granule proteins have been postulated to damage the bronchial epithelium in human asthma, an effect that is in turn postulated to increase AHR, the precise physiologic stimulus to eosinophil degranulation in vivo in human asthma remains ill-defined. IL-5, IL-3, and GM-CSF also have an important regulatory role in the formation of eosinophil progenitors in the bone marrow (Dorman et al. 2004). There has been much interest in a possible role for IL-9 in asthma. In addition to Th2 cells, eosinophils, neutrophils and mast cells are potential sources. IL-9 is produced by allergenspecific T cells (Devos et al. 2006) and is implicated in inducing tissue infiltration with mast cells (Nouri-Aria et al. 2005). It is overexpressed in the bronchial mucosa of asthmatics (Ying et al. 2002). Interestingly, IL-9 was reported to be overexpressed in infants with respiratory syncytial virus bronchiolitis, which causes wheeze, where neutrophils appear to be a major source (McNamara et al. 2004). Bronchial epithelial cells express IL-9 receptors (Tsicopoulos et al. 2004), which control epithelial cell differentiation and repair by signaling through the transmembrane receptor tyrosine kinase family of receptors called the ErbBs. MUC-4, a large membranebound glycoprotein, is a potential ligand for the ErbB-2 receptor in epithelial cells. Thus IL-9 also causes increased MUC-4 expression, leading to increased production of mucous glycoproteins (Damera et al. 2006). Cultured human airway

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66

Th1

Th1/Th2

Th2

Th2

Th1/Th2

IL-2

IL-3

IL-4

IL-5

IL-6

Fibroblasts, macrophages, endothelial cells, epithelial cells

AHR, eosinophilia, mucus hypersecretion, airway remodeling

IL-16

Chemoattractant for CD4 cells, monocytes, eosinophils; reduces Th2-type cytokines but increases IL-10

Increased

Increased

Increased

CD8+, MC, eosinophils

T-cell growth factor; expands Treg

Th1

IL-15

Increased: soluble IL-13 receptor blocked AHR but not eosinophils or IgE. Transgene developed airways inflammation, remodeling, AHR

Decreased: exogenous IL-12 decreased eosinophils but not AHR

Increased

Deficient IL-10 response in therapy-resistant patients, restored by vitamin D3

Increased further by viral infection

Increased, especially by systemic glucocorticoid (along with IP-10)

Increased (in severe asthma)

Increased: antibody decreased eosinophils but not AHR

Increased: soluble IL-4 receptor had some steroid-sparing effect

Increased

Increased

Human asthma

Decreased

Th2 cells, eosinophils, MC, basophils

MC development, B-cell switch to IgE production, eosinophilia, AHR, mucus hypersecretion, reduced epithelial integrity, remodeling, reduced PGE2 production by epithelial cells

Th2

IL-13

Exogenous IL-12 blocked eosinophils and AHR

Transgene had AHR and changes of remodeling

Adenoviral transfer decreased inflammation

Transgene had eosinophils, AHR and mucus; knockout no effect

IL-8 receptor knockout decreased AHR and neutrophils

Transgene showed increased AHR and inflammation, knockout less; trans-signaling blockade reduces Th2 response; conventional signaling blockade favors Treg

Increased: knockout or blocking decreases eosinophils and AHR

Increased: blocking decreases AHR (but some residual)

Increased: blocking decreases eosinophilia

Decreased

Animal models of airway inflammation

Many non-T cells

DC, macrophages, B cells

Favors Th1 differentiation, inhibits IgE synthesis

Th1

IL-12

IL-11

T cells, macrophage

Endothelial cells, epithelial cells (induced by viral infection), macrophages, fibroblasts, T cells, ASM (increased by IL-17A)

Neutrophil activation and chemotaxis; weak eosinophil chemotaxis

Suppresses Th1/Th2 function, eosinophil/MC/basophil activation, favors Treg production, B-cell switch to IgG4

Th1/Th2 cells, macrophages, endothelial cells, DC, ASM, fibroblasts

T- and B-cell growth factor, cofactor for IgE synthesis, Th2 differentiation (trans-signaling), diversion of Treg to Th17 (conventional signaling)

“Regulatory” Th1/Th2, Treg (induced by glucocorticoid)

Th2 cells, eosinophils, MC, basophils

Eosinophil and basophil differentiation, maturation, and activation

IL-10

Th2 cells, eosinophils, MC, basophils

B-cell switch to IgE synthesis, MC development, eosinophil and basophil activation, mucus secretion, favors Th2 production, increased endothelial cell VCAM expression

Th2 cells, eosinophils, neutrophils, MC, basophils

Th1/Th2 cells, eosinophils, MC, basophils, macrophage/ monocytes, fibroblasts

Differentiation and activation of eosinophil, neutrophil, basophil, MC; eosinophil degranulation (CD48)

MC and eosinophil development, AHR, mucus secretion, chemokine expression by ASM

Th1 cells, eosinophils

T-cell growth factor

Th2

Producer cell in human patients

Actions

IL-9

IL-8

Th1/Th2/Th17/ Treg associated

PART 1

Cytokine

Table 3.3 Cytokines implicated in asthma.

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Suppresses Th1/Th2 function, favors Treg induction, cofactor for IgA secretion, increases mucin production and myofibroblast differentiation

Inhibits IgE synthesis, inhibits Th2 induction, activates eosinophils and macrophages

“Regulatory” Th1/Th2, Treg

Th1

TGF-b

IFN-g

Epithelial cells, endothelial cells, fibroblasts, ASM, IgE-activated MC, other leukocytes

Th1 cells, NK cells

Eosinophils, MC, basophils, T cells, monocytes, macrophages, ASM

Macrophages, NK cells, T cells

Transgene develops atopic dermatitislike phenotype and airways inflammation

Decreased

Increased

Increased

Increased: transgene has airway inflammation

Not studied

Not studied

Increased in mouse model of asthma; transgene (electroporation) had enhanced Th2-type cytokine expression

Knockout had increased eosinophils and AHR; exogenous IL-18 (with IL-12) decreased AHR and eosinophils; exogenous IL-18 alone increased Th2-type cytokines

Transgene showed augmented allergen-induced airways eosinophilia, Th2-type cytokines, mucus secretion

Wide variety of targets increasing cytokines, chemokines, and metalloproteinases

Increased in the bronchial mucosa; correlates with CC chemokine expression

Increased in viral infection and exacerbations

TGF-b2 increased (particularly in eosinophils), TGF-b1 and b2 after allergen challenge

Increased: blockade by antibody or soluble receptor improves asthma symptoms and AHR

Increased

Not studied

Not studied

Elevated in serum

Reduced

Not yet measured

Increased

ASM, airway smooth muscle cell; DC, dendritic cell; IFN, interferon; MC, mast cell; NK, natural killer; TGF, transforming growth factor; TNF, tumor necrosis factor; Treg, T regulatory cell; TSLP, thymic stromal lymphopoietin; VCAM, vascular cell adhesion molecule.

Activates DC to induce “inflammatory” Th2 cells and CC chemokines; induces OX40L on DC; may be primary trigger for Th2 differentiation

Activation of endothelial cells and epithelial cells

“Inflammatory” Th1/Th2

TNF-a

Th1/Th2 cells, macrophages, eosinophils, MC, basophils, fibroblasts, epithelial cells, endothelial cells

Macrophages, DC

Macrophages, DC

T cells

Macrophages, epithelial cells, DC

Th2 central memory cells

Th17 cells, CD8 T cells, gd cells, NK cells, neutrophils, epithelial cells, endothelial cells, fibroblasts

CHAPTER 3

TSLP

Differentiation and activation of eosinophils, neutrophils, basophils, MC

Th1/Th2

Acts conversely to IL-23 in limiting Th17 development of naive T cells

IL-27

GM-CSF

Amplifies Th17 development once initiated by TGF-b and IL-6

In presence of IL-12 induces IFN-g by T cells, NK cells, favors Th1 differentiation; with IL-2 alone increases Th2type cytokines in T and NK cells; with IL-3 increases Th2type cytokines in MC and basophils

IL-23

Th1

IL-18

Maintains Th2-type T-cell activation and central memory

T-cell growth factor

Th2

IL-17E (IL-25)

Induces inflammatory cytokine production by fibroblasts, macrophages, epithelial cells, endothelial cells; CXC chemokine production by ASM

IL-19

Th17

IL-17A/F

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smooth muscle cells also express IL-9 receptors, stimulation of which triggers release of Th2-type chemoattracting chemokines by these cells (Gounni et al. 2004). Overexpression of IL-9 in the airways of transgenic mice causes airway inflammation, mast cell hyperplasia, and AHR (Temann et al. 1998). As with IL-9, transgenic expression of IL-11 and IL-13 in the airways of mice was sufficient to cause eosinophil infiltration, mucus hypersecretion and remodeling changes (Tang et al. 1996; Zhu et al. 1999). IL-11 is produced by normal human lung fibroblasts in response to mediators of neovascularization such as endothelin A (Gallelli et al. 2005). It is also overexpressed in the asthmatic bronchial mucosa (Minshall et al. 2000). In addition to Th2-type cells, IL-13 may originate from mast cells, basophils, and eosinophils. It is induced in mast cells by TNF-α through an NF-κB-dependent pathway (Lee et al. 2004). IL-13 is highly implicated in remodeling (Wills-Karp 2004), increasing the production of remodeling mediators such as platelet-derived growth factor and periostin by lung fibroblasts (Ingram et al. 2006; Takayama et al. 2006). It may compromise epithelial cell basement membrane attachment by inhibiting production of proteins such as paxillin (Ramirez-Icaza et al. 2004). It also stimulates the release of chemokines such as eotaxin from human airway smooth muscle cells (Peng et al. 2004). In a mouse model of asthma, soluble IL-13 receptor abrogated AHR without affecting serum IgE concentrations or infiltration of the airways with eosinophils (Grunig et al. 1998; Wills-Karp et al. 1998), reinforcing the concept that cytokines such as IL-13 may act directly to cause AHR perhaps independently of granulocytic infiltration, at least in the airways mucosa. Most interestingly, IL-13 has been implicated in the aspirinsensitive phenotype of asthma. It reduces the production of prostaglandin (PG)E2 in airway epithelial cells by reducing the activities of the enzymes cyclooxygenase-2 and PGE synthase 1, while increasing the activity of the PGE2-catabolizing enzyme 15-prostaglandin dehydrogenase, as well as reducing expression of the PGE2 receptor EP2 (Trudeau et al. 2006). Finally, it has been shown to increase expression of the cysteinyl leukotriene receptors CysLT1 and CysLT2 in mouse lungs (Chavez et al. 2006). IL-16 is a CD4+ T-cell chemoattractant in vitro (Center et al. 1994) and is overexpressed in the asthmatic bronchial mucosa. IL-16 reduces production of IL-5 and IL-13 by allergen-stimulated T cells from atopic donors, while increasing production of IL-10 (El Bassam et al. 2006). Thus it may play a role in suppression of Th2 T-cell activation and, conceivably, induction of allergen-specific T regulatory cells. The role of the IL-17 family of cytokines has been discussed above. IL-25 (IL-17E), the most distant relative of the IL-17 cytokine family, may play a pivotal role in activating Th2 cells and, more importantly, maintaining Th2-type TCM cells. Overexpression of IL-25 in mice increased antigen-induced but not spontaneous eosinophil and T-cell recruitment to the

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airways, and also caused goblet cell hyperplasia (Tamachi et al. 2006). IL-17A has a number of effects on human airway smooth muscle cells, including induction of CC chemokines such as eotaxin (Rahman et al. 2006) and augmentation of TNF-α-induced production of CXC chemokines such as IL-8 (Henness et al. 2006). IL-6 is a member of a family of cytokines that includes IL-11 and ciliary neurotrophic factor. Although most soluble cytokine receptors act as antagonists and compete with their membrane-associated counterparts for binding to cytokine ligands, soluble receptors of the IL-6 family of cytokines can, when coupled with their cytokines, act as agonists by ligating the universal signal-transducing receptor for all IL-6 family cytokines called gp130 (Rose-John et al. 2006), which is expressed on a range of target cells that do not necessarily express the membrane-bound form of the receptors. This process has been termed “trans-signaling.” In some cells, transsignaling by soluble IL-6/IL-6R complexes ligating gp130, and “conventional” signaling, whereby IL-6 acts on its membranebound receptor, may exert very disparate effects. Thus IL-6 increases proliferation of Th2 cells by trans-signaling, but by conventional signaling through the membrane-bound receptor diverts the development of CD4+CD25+ T regulatory cells toward a more proinflammatory Th17 phenotype (see above). In mouse models, blockade of the soluble IL-6 receptor using a gp130–immunoglobulin heavy chain fusion protein reduced Th2 T-cell development in the airways, whereas direct blockade of the membrane-bound IL-6 receptor increased the development of T regulatory cells (Doganci et al. 2005a,b). The possible origins of IL-6 are manifold and include dendritic cells, airway smooth muscle cells (Shan et al. 2006), and fibroblasts (in which it is induced by Th2-type and other cytokines as well as TGF-β). Activated eosinophils have been reported to increase IL-6 release from human fibroblasts (Gomes et al. 2005), probably through release of cytokines including IL-1β and TGF-β. Endothelin-1, a profibrotic mediator, also increases production of IL-6, as well as IL-11 by human lung fibroblasts (Gallelli et al. 2005). Such observations link airway remodeling in asthma with cytokine products of airway smooth muscle cells and eosinophils. IL-8 is a CXC chemokine that attracts and activates neutrophils. Epithelial cell expression of IL-8 is increased in viral infections where it may contribute to viral-induced airways inflammation (Funkhouser et al. 2004; Newcomb et al. 2005). The cytokine IL-17A enhances the stability of TNF-α-induced IL-8 mRNA in human airway smooth muscle cells (Henness et al. 2006). Expression of IL-8 and its sister CXC chemokine IP-10 is increased in the human bronchial mucosa in association with systemic glucocorticoid therapy, in contradistinction to that of eosinophil-attracting CC chemokines such as eotaxin which is reduced (Fukakusa et al. 2005). This may contribute to the neutrophil infiltration of the airways observed in severe asthmatics treated with systemic glucocorticoid.

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IL-19 belongs to the IL-10 family of cytokines, which includes IL-10, IL-19, IL-20, IL-22, melanoma differentiationassociated gene 7 (IL-24), and AK155 (IL-26). Apart from IL-10 (see below), there have been few studies of a possible role of these cytokines in human asthma. Human asthmatics were found to have elevated serum concentrations of IL-19 compared with controls, and IL-19 expression was also elevated in a mouse model of asthma induced by house-dust mite allergen (Liao et al. 2004). Overexpression of the IL-19 gene by electroporation in this mouse model increased IL-4, IL-5, and IL-13 expression in a T cell-dependent fashion. Thus IL-19 must be added to the ever-expanding list of cytokines that may regulate Th2-type cytokine expression in human asthma. IL-18 is produced by epithelial cells and activated monocytes/ macrophages. It is traditionally regarded as an inducer of Th1 T-cell differentiation and increases IFN-γ production by Th1type T cells, CD8+ T cells, and NK cells. It synergizes with, but acts independently of, IL-12 (El-Mezayen & Matsumoto 2004). In mouse models of asthma, IL-12 administration inhibited AHR, airway cellular infiltration, and Th2-type cytokine expression (Gavett et al. 1995); coadministration of IL-12 and IL-18 had a similar effect (Hofstra et al. 1998). Expression of IL-12 and IL-18 has been shown to be deficient in human asthmatics compared with controls (Ho et al. 2002; McKay et al. 2004). However, there is a twist in the tale of the IL-18 story, since it has been reported that IL-18 in combination with IL-2 promotes Th2-type cytokine production by T cells and NK cells, while in combination with IL-3 it promotes the production of these cytokines by mast cells and basophils. Intranasal administration of IL-18 with IL-2 caused eosinophilic infiltration, AHR, and mucous hyperplasia in the airways of naive mice in a T cell-, STAT6-, and IL-13-dependent fashion (Ishikawa et al. 2006). Thus, in conditions where IL-18 may be produced independently of IL-12, as for example following direct activation of epithelial cells, IL-18 may actually enhance asthmatic inflammation. With the realization that IL-10 is a key mediator of suppression of both Th1 and Th2 T-cell proliferation and cytokine production by certain subsets of adaptive (Tr1) T regulatory cells, its importance in the regulation of disease severity and its potential for the long-term regulation of allergen-specific T-cell responses in human asthma has moved to center stage. IL-10 is one of the few cytokines whose expression is increased, rather than inhibited, by glucocorticoid. It has a wide range of inhibitory actions on cells of the immune system, including T cells and antigen-presenting cells and, when expressed by T regulatory cells, it can inhibit the function of both Th1 and Th2 cells (reviewed by Hawrylowicz & O’Garra 2005). Deficiency of IL-10 production, for example by dendritic cells, has been associated with the development of atopy (Gentile et al. 2004). We identified a defect in glucocorticoid-induced IL-10 production in clinically glucocorticoid-refractory asthmatics compared with responsive asthmatics, implying that

T Cells and Cytokines in Asthma and Allergic Inflammation

glucocorticoid ameliorates human asthma at least partly through the actions of IL-10 (Hawrylowicz et al. 2002). Some of the IL-10 produced by glucocorticoid therapy of asthmatics originates from FoxP3-expressing Tr1 T regulatory cells (Karagiannidis et al. 2004). We have also shown that IL-10-secreting regulatory T cells can be induced in vitro by glucocorticoid and long-acting β2 agonist (Peek et al. 2005), providing one possible mechanistic explanation for the now well-recognized effects of concomitant long-acting β2-agonist therapy in sparing glucocorticoid therapy while improving symptoms and reducing disease exacerbations in moderate/ severe asthmatics. Finally, we have shown that the defect in glucocorticoid-induced IL-10 production by T cells from clinically glucocorticoid-resistant asthmatics is subject to reversal by therapeutic manipulation, for example by 1,25dyhidroxyvitamin D3 (Xystrakis et al. 2006). IL-10 has also been shown to be a key mediator of allergen-specific adaptive T regulatory cells induced in the course of allergen immunotherapy (Durham & Till 1998). Manipulation of the immune response by induction of IL-10 production, for example with drugs like vitamin D3 or by administration of glucocorticoid in the course of allergen immunotherapy, promises the possibility of long-term allergen-specific suppression of T-cell responses in asthma and allergic disease. Another cytokine implicated in mediating the functions of adaptive T regulatory cells is TGF-β, which exists in three isoforms: TGF-β1, TGF-β2, and TGF-β3 (reviewed by SchmidtWeber & Blaser 2004). TGF-β is produced by a wide variety of cells, including T cells, monocyte/macrophages, mast cells, and basophils. Eosinophils are also an important potential source in human asthma (Balzar et al. 2005). TGF-β plays a dichotomous role in inflammation, since in addition to being a mediator of T regulatory cell suppression it also exerts widespread effects on structural cells in the airways that may be relevant to remodeling (Howell & McAnulty 2006). In a group of severe asthmatics, expression of TGF-β2 but not the other isoforms was elevated in the airways and expressed prominently in eosinophils (Balzar et al. 2005). TGF-β2 but not TGF-β1 was also elevated in the asthmatic bronchial epithelium and increased mucin expression in cultured human bronchial epithelial cells (Chu et al. 2004). In a study in milder atopic asthmatics employing segmental allergen bronchial challenge, only TGF-β2 was elevated in lavage fluid at baseline, but both TGF-β1 and TGF-β2 were increased following allergen challenge. Both isoforms induced myofibroblast differentiation of fibroblasts, as measured by de novo expression of smooth muscle α-actin (Batra et al. 2004). It is not possible from these studies to determine whether any of this TGF-β expression reflects the activity of T regulatory cells. TGF-β1 has been reported to synergize with other profibrotic growth factors such as fibroblast growth factor (FGF)-2 to increase proliferation of human airway smooth muscle cells and increase production of connective tissue growth factor, which induces fibronectin and collagen I

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synthesis by fibroblasts (Burgess 2005; Bosse et al. 2006; Johnson et al. 2006). It is also itself produced by airway smooth muscle, for example in response to neutrophil elastase (Lee et al. 2006). The antiasthma glucocorticoid flunisolide has been reported to reduce TGF-β synthesis and fibronectin release by cultured induced sputum cells from asthmatics (Profita et al. 2004), suggesting that glucocorticoid may be able to inhibit at least some ongoing remodeling changes in asthma, even if it may not reverse established changes. Finally, leave cannot be taken of this section without reminding the reader of the increasing interest in the IL-7like cytokine TSLP as a “master switch” of Th2-type T-cell development through its priming effects on dendritic cells, and in maintaining Th2-type T-cell memory. Mice expressing a TSLP transgene have been shown to develop an atopic dermatitis-like phenotype (Yoo et al. 2005) and airways inflammation resembling that of asthma (Al Shami et al. 2005; Zhou et al. 2005). TSLP expression is increased in lesional skin of human patients with atopic dermatitis (Soumelis et al. 2002) and the bronchial mucosa of asthmatics (Ying et al. 2005). TSLP may prove to be a key therapeutic target in allergic disease since its elimination might not only block the development of allergen-specific Th2-type T-cell activation but also the maintenance of allergen-specific TCM cells. Furthermore, these effects would be expected to be considerably greater in extent than those of blocking single cytokines released by activated “inflammatory” Th2-type end effector cells. New data regarding the role of TNF-α in asthma are discussed below. An overview of the putative roles of the cytokines produced by inflammatory Th2 cells is presented in Fig. 3.7.

Microbial fragments

Table 3.4 Responsiveness of subsets of T cells to chemokines. (Modified after Sebastiani et al. 2002) Chemokine

Th1-type

Th2-type

IP-10 Mig I-TAC RANTES MIP-1b MCP-1 Eotaxin TARC MDC I-309

+++ +++ +++ +++ +++ ++ + + + +

+ + + + + ++ +++ +++ +++ +++

T regulatory cells are more sensitive to I-309, MCP-1, MIPs and TARC.

Do T cells home to the airways in asthma? Homing receptors that attract activated T cells to particular organs are obviously of great interest when considering new therapeutic approaches to putative T cell-mediated diseases such as asthma. Although homing receptors that preferentially attract T cells to the lymph nodes, skin, and gut mucosa have been identified, a search for homing receptors directing T cells to the airway mucosa has so far been fruitless. In the absence of a specific set of homing receptors, attention has switched to the possibility that particular functional subsets of T cells may express receptors for particular chemoattractant molecules. Chemokines, which pay a particular role in diapedesis of leukocytes into and out of tissues, have been particularly studied in this regard (Table 3.4). Dogma has

IL-9, IL-13 IL-4, IL-9, IL-13

TLR Blockade

OX40L NF-AT TSLP

DC

AHR

IL-12

DC

IL-4, IL-13

IL-4

Mucus hypersecretion IgE switching

OX40 IL-4, IL-5, IL-9, IL-13 Eosinophil and basophil activation

GATA-3 STAT6 C-maf

TSLPR

Mast cell activation Smooth muscle activation, remodeling

IL-4, IL-9, IL-13 IL-4R IL-25

IL-25R

CD4+ inflammatory Th2 T cell (IL-4, IL-5, IL-13, TNF-a high, IL-10 low)

Fig. 3.7 Activation and functions of inflammatory Th2 cells in asthma. Thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DC) promote the induction of inflammatory Th2 cells through OX40/OX40L costimulatory molecule interaction, which induces nuclear factor of activated T cells (NF-AT), which triggers IL-4 production and then IL-4dependent GATA-3 transcription. This process is reinforced by IL-25

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TNF-a

but overridden by IL-12 produced, for example, by DC exposed to microbial fragments and activated through Toll-like receptors (TLR). Cytokine products of inflammatory Th2 cells exhibit considerable pleiotropism and have been implicated in all the pathophysiologic changes that characterize asthma. TSLPR, TSLP receptor. See text for definition of other abbreviations.

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it that human Th2-type T cells preferentially express the chemokine ligands CCR3, CCR4, and CCR8 (Bonecchi et al. 1998). CCR4 in particular is said to be a marker of Th2-type central memory and effector cells (Rivino et al. 2004), and indeed we have identified preferential expression of CCR4 and CCR3 on IL-4-expressing bronchoalveolar lavage T cells from both asthmatics and controls (Morgan et al. 2005). Furthermore, in another study (Panina-Bordignon et al. 2001) it was observed that nearly all T cells in bronchial mucosal biopsies from atopic asthmatics obtained 24 hours after allergen challenge expressed IL-4 and CCR4, while CCR8 was coexpressed only on a minority of these cells (28%), and CCR3 was not expressed at all on T cells but was prominent on eosinophils. Thus, while CCR3 may play an important role in the recruitment of granulocytes such as eosinophils and basophils to sites of inflammation (see other chapters of this volume), its role in attracting T cells in human asthma is less certain. Despite these observations, other studies do not paint a clear picture of preferential bronchial mucosal expression of chemokines that attract Th2-type cells in human asthma. We (Ying et al. 2005) and others (Miotto et al. 2001; Bochner et al. 2003) have described elevated expression not only of chemokines whose ligands are said to be preferentially expressed on Th2-type T cells, such as TARC/CCL17 and MDC/CCL22 (both CCR4 ligands), but also of chemokines whose ligands are said to be preferentially expressed on Th1type T cells, in particular IP-10/CXCL10 (a CXCR3 ligand), both in “steady-state” asthma and following bronchial allergen challenge. At the same time, expression of CCR4 as a marker of Th2-type T cells has been questioned. For example, CCR4 expression has been detected on both Th1 and Th2 differentiated T cells, as well as T regulatory cells (Andrew et al. 2001; Iellem et al. 2001). If T cells are attracted to sites of inflammation according to their expression of chemokine receptors and the types of chemokines expressed in that particular type of inflammation, one would expect to be able to correlate expression of chemokines with infiltration of T cells bearing their receptors. In addressing this, however, we showed (Ying et al. 2005) that while expression of the chemokine CCR4 ligands TARC/CCL17 and MDC/CCL22 was elevated in the bronchial mucosa of asthmatics compared with controls, the total number of cells expressing CCR4 was no different in the two groups of subjects, although slightly elevated percentages of CD4+ T cells expressed CCR4 in the asthmatics as compared with the controls. Overall, these data support a scenario, at least in the case of T cells, in which cells are attracted to the bronchial mucosa in health and disease according to a particular pattern of chemokine expression, rather than one in which selective expression of chemokines results in selective influx of cells bearing their particular ligands. Examination of the effects of deletion of the genes encoding CCR3, CCR4, and CCR8 in mouse models of asthma has provided similarly

T Cells and Cytokines in Asthma and Allergic Inflammation

disappointing equivocal results with regard to Th2 T-cell infiltration (Chensue et al. 2001; Humbles et al. 2002; Schuh et al. 2002). As mentioned above, the CRTH2 receptor, which is a receptor for PGD2, may be a better marker for Th2 central and effector memory cells (Cosmi et al. 2000; Wang et al. 2006) but whether this molecule is involved in T-cell trafficking is unknown. In summary, then, there is at present little justification for the hope that specific blockade of chemokine receptors will provide a practical approach to blocking infiltration of the asthmatic bronchial mucosa by Th2-type cells, although it still holds some promise for the prevention of infiltration of other leukocytes such as eosinophils and basophils.

CD8, gd, and NKT cells in asthma This account has dealt principally with CD4+ T cells. Although traditionally regarded as cytotoxic cells, CD8+ T cells might play a proinflammatory role in the airways of asthmatics. For example, we showed that, in both atopic and nonatopic asthmatics, mRNA encoding IL-4 and IL-5, while localizing predominantly to CD4+ T cells, was also detectable in CD8+ T cells (Ying et al. 1997). Furthermore, we also found that CD8+ as well as CD4+ T-cell lines from the airways of asthmatic patients were capable of elaborating IL-5 protein (Till et al. 1995). All these observations are compatible with the concept of the population of CD8+ T cytotoxic type 2 (Tc2) lymphocytes. In a mouse model of asthma, viral infection was shown to induce virus-specific CD8+ T cells that were also capable of secreting IL-5 (Schwarze et al. 1999). Thus, CD8+ T cells may also contribute to the production of Th2type cytokines, perhaps under particular circumstances such as viral exacerbation of asthma (Dahl et al. 2004). As mentioned earlier, little is known about how cytokine production by T cells of any phenotype may contribute to the day-to-day regulation of severity of asthma, as for example when it is exacerbated by a rhinoviral infection. Studies in mouse models of asthma have implicated γδ T cells as having both regulatory and stimulatory roles in the genesis of airways inflammation (Zuany-Amorim et al. 1998; Lahn et al. 1999; Jin et al. 2005). There are currently only three observational reports of these cells in human asthma suggesting increased numbers of γδ T cells in bronchoalveolar lavage fluid of atopic asthmatics both at baseline and following segmental bronchial allergen challenge (Spinozzi et al. 1996; Krug et al. 2001), with corresponding reduced numbers in the blood (Chen et al. 1996). Although it is not inconceivable that these cells were allergen-specific as claimed in one of these reports (Spinozzi et al. 1996), very little is known about the antigen repertoire of γδ T cells, and those studies that do exist (see above) suggest that this repertoire is likely to be very limited. Consequently it is not possible to make any definitive statement about the role, if any, of γδ T cells in human asthma. With regard to NKT cells, the current hot topic is the controversial possibility that many of the CD4+ cells observed in

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the bronchial mucosa of moderate to severe asthmatics are not conventional T cells but NKT cells expressing the T-cell invariant receptor chain (Akbari et al. 2006; see above). NKT cells are certainly potentially abundant sources of Th2-type cytokines, and if these preliminary observations are verified by scientific consensus, they could force a change in our current thinking about how such cytokines are generated in the asthmatic airways, as well as the nature of the stimuli which cause their production.

What have new approaches to treatment taught us about the T-cell hypothesis of asthma? Glucocorticoids remain the cornerstone of asthma therapy, and we and many others have consistently demonstrated evidence of T-cell inhibition in asthmatics in association with clinical improvement (see above). There are similarly many studies showing reduction of Th2-type cytokine expression and eosinophil infiltration in the airways of asthmatics following glucocorticoid therapy (Robinson et al. 1993b; Bentley et al. 1996). Conversely, patients who are refractory to glucocorticoid therapy have T cells that are refractory to the inhibitory effects of glucocorticoid both in vitro and in vivo (Corrigan et al. 1991a; Leung et al. 1995). The mechanisms of this refractoriness are likely multifactorial and depend on interaction of positive T-cell regulatory signals induced by the inflammatory milieu and the environment, and negative regulatory signals influenced by glucocorticoid. For example, we have recently shown (Loke et al. 2006) that systemic glucocorticoid reduces bronchial mucosal activation of the components of the transcriptional regulator activator protein (AP)-1 in glucocorticoid-sensitive but not glucocorticoidresistant asthmatic patients, which may be one mechanism accounting for glucocorticoid refractoriness in some patients and which is likely centered on T cells. One stimulus for the activation of AP-1 components is excessive oxidative stress, which could conceivably arise from dietary deficiency or other environmental influences such as cigarette smoking, which has been reported to impair glucocorticoid responsiveness in asthma (Chaudhuri et al. 2003). Other investigators have reported signaling through p38 MAPK (Irusen et al. 2002) or following exposure to bacterial superantigens (Hauk et al. 2000) as stimuli that induce glucocorticoid refractoriness of T cells. Such interactions are likely complex and dynamic, but will likely repay further dissection since they may clarify how glucocorticoid exerts its inhibitory actions on T cells, how this may be confounded by environmental influences, and how these in turn might be overcome by new therapeutic approaches. Notwithstanding this paucity of knowledge, all these experiments reinforce the concept that, within individual asthmatics, glucocorticoid inhibition of T cells can be correlated with clinical responsiveness. They do not, however, indicate what the critical aspects of this responsiveness are or, as mentioned above, whether all the

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changes effected by T cells in asthma can be fully reversed by glucocorticoid. Other immunomodulatory drugs have also been assessed for a possible therapeutic role in asthma. Since many of these agents have potentially serious unwanted effects, attention has been focused on severe asthmatics requiring systemic glucocorticoid therapy (i.e., those in whom the risk–benefit ratio of therapy is most likely to be acceptable). Methotrexate is a folic acid analog used at low dosage for its immunomodulatory activity in a variety of chronic diseases. It exerts a delayed but sustained therapeutic effect even with intermittent weekly dosing, probably because it accumulates in cells as polyglutamate complexes, resulting in accumulation of S-adenosyl methionine and adenosine, both of which are inhibitory to T-cell function. Indeed, we have shown that methotrexate therapy of oral glucocorticoid-dependent asthmatics increases the sensitivity of their blood T cells to glucocorticoid inhibition (Corrigan et al. 2003). A metaanalysis (Marin 1997) of the effects of concomitant methotrexate therapy of oral glucocorticoid-dependent asthmatics suggested an oral glucocorticoid sparing effect (overall about 20%, but only in about 60% of responsive patients) if used for a minimum of 3–6 months, but with no significant improvement in lung function. Cyclosporin A is a lipophilic cyclic undecapeptide. In a complex with the cytoplasmic binding protein cyclophilin, it inhibits calcineurin-mediated dephosphorylation and nuclear translocation of the cytoplasmic subunit of the T-cell transcriptional activator NF-AT, thus inhibiting T-cell proliferation and cytokine production relatively specifically. Two blinded placebo-controlled trials in severe, oral glucocorticoid-dependent asthmatics (Alexander et al. 1992; Lock et al. 1996) both showed that concomitant cyclosporin A therapy improved lung function (slightly) while reducing oral glucocorticoid requirements. It was further shown that pretreatment of mild atopic asthmatics with cyclosporin A inhibited the late-phase bronchoconstrictor response of these patients following bronchial allergen challenge (Sihra et al. 1997). These approaches to therapy have not been widely embraced because the overall effects of these drugs have proven small. Not all patients respond, and response cannot be predicted a priori (Alexander et al. 1996). Furthermore, they have a high incidence of unwanted effects and chronic immunosuppression raises the specter of possible increased malignancy and opportunistic infection. Because they affect T cells they provide broad support for the T-cell hypothesis of asthma, although it is somewhat disappointing that they have not proven more effective, suggesting that, as with glucocorticoid, external unidentified influences may confound their activity in certain individuals or that there is more to the antiasthma activity of glucocorticoid than turning off cytokine production. The precise effects of these drugs in vivo in the airways of asthmatics have not been systematically studied, although one study showed that attenuation by

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cyclosporin A of allergen-induced late-phase bronchoconstriction in atopic asthmatics was accompanied by reduced infiltration of eosinophils as well as asthma-relevant cytokines and chemokines (Khan et al. 2000). We have shown (Haczku et al. 1994; Powell et al. 2001b) that other immunomodulatory drugs such as sirolimus (rapamycin) and mycophenolate mofetil exert inhibitory effects on T cells from glucocorticoidresistant asthmatics, but the data from existing trials have so far dampened enthusiasm for clinical trials of these newer drugs in severe asthma. As discussed above, in the new concept of “inflammatory” Th2 cells, IL-5, IL-4, IL-13, and TNF-α may be regarded as key effector cytokine products. It was disappointing, therefore, when a single infusion of a humanized monoclonal IL-5blocking antibody (mepolizumab), while markedly reducing circulating blood eosinophils and recruitment of eosinophils to the airway lumen following allergen bronchial challenge of patients with mild asthma, had no effect on the ensuing bronchoconstrictor response or on basal AHR (Leckie et al. 2000). More prolonged studies of anti-IL-5 antibody in patients with moderate/severe asthma were similarly disappointing in terms of improvements in asthma symptoms or lung function. A biopsy study (Flood-Page et al. 2003) showed that while anti-IL-5 antibody profoundly reduced circulating eosinophils, it was less effective in removing eosinophils from the bronchial mucosa, but did appear to reduce deposition of extracellular structural remodeling proteins (see also discussion above). These data have provided asthma researchers with much food for thought. They do not entirely discount a role for eosinophils in regulating asthma severity or AHR, since in none of the studies has eosinophils been completely removed from the bronchial mucosa (although in view of the many factors regulating eosinophil recruitment to the airways, IL-5 blockade alone may never accomplish this). They also suggest, however, the possibility that direct effects of cytokines on the structure of the airways are more important that effects mediated through granulocytes such as eosinophils, which might be acting in a subservient role or even as innocent bystanders. Soluble humanized IL-4 receptor (altrakincept), administered by nebulization, has been tested in clinical trials and shown to prevent deterioration in lung function induced by withdrawal of glucocorticoid in patients with moderately severe asthma (Borish et al. 1999, 2001) but these relatively promising data have not so far been pursued. Nebulized therapy is cumbersome and wasteful, and may be followed in the future by trials of blocking monoclonal antibodies or soluble IL-4 receptor (which would also incidentally be expected to block the actions of IL-13). The pivotal role of IL-13 in airway remodeling has been discussed above, and trials of IL-13 blockade in asthma might be of interest. In addition, apart from the IL-4 receptor, IL-13 has two other specific receptors named IL-13Rα1 and IL-13Rα2. The latter

T Cells and Cytokines in Asthma and Allergic Inflammation

receptor exists naturally in a soluble form, and may act as a “decoy” receptor, scavenging active IL-13. Human soluble IL-13Rα2 is currently in clinical development. As will be apparent from the discussion above, IL-9 and IL-25 are also relatively promising theoretical targets for cytokine blockade in the treatment of asthma. A blocking humanized anti-TNF-α antibody (infliximab) and soluble TNF-α “decoy” receptor (etanercept) have been shown in preliminary studies to have remarkable (and somewhat unprecedented) clinical efficacy in human asthma (Berry et al. 2006; Erin et al. 2006; Howarth et al. 2006). In one study (Howarth et al. 2006), treatment of moderate/severe asthmatics with etanercept 25 mg subcutaneously twice weekly for 12 weeks was associated with improvements in symptoms and reductions in AHR comparable to that seen with systemic glucocorticoid therapy. This therapy seems therefore to hold considerable promise, although experience with the use of TNF-α blockade in other diseases has shown that this approach is not without its dangers (such as reactivation of tuberculosis, opportunistic infection, and possible increased malignancy). Because this therapy has to be given by injection, a search is on for small-molecule TNF-α inhibitors. TNF-α-converting enzyme (TACE) is a matrix metalloproteinase-related enzyme required for the release of TNF-α from cell surfaces where it is stored as an extracellular matrix “reservoir.” Small-molecule TACE inhibitors are currently in development. The importance of IL-10 as an inhibitory cytokine in asthma has already been emphasized. Recombinant IL-10 has proven effective in controlling other inflammatory diseases such as inflammatory bowel disease and psoriasis, where it is given by weekly injection. It is reasonably well tolerated, although hematologic unwanted effects have been noted. The possibility of manipulation of IL-10 production through the induction of T regulatory cells, for example by modified allergens (Klinman 2004; Simons et al. 2004) or by the use of relatively innocuous agents such as vitamin D, as distinct from therapy with IL-10 itself, offers considerable promise for future asthma therapy. As mentioned above, T-cell IL-10 production is increased rather than inhibited by glucocorticoid, and it could possibly prove that this is a critical effect of glucocorticoid not shared by other immunosuppressive drugs, which might explain the disappointing antiasthma efficacy of the latter. The reverse strategy to blocking asthma-relevant cytokines is to attempt to reduce their production by cytokines that inhibit Th2-type T-cell development. IL-12 is a “master regulator” of Th1 T-cell development, as emphasized above. IL-12 and Th1-type cytokines such as IFN-γ strongly inhibit Th1 responses. Recombinant human IL-12 has been administered to humans but it has a range of toxic effects that are somewhat minimized by slow acceleration of the dosage. In a single study on atopic asthmatics (Bryan et al. 2000), weekly

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infusion of IL-12 over 4 weeks, at escalating dosage, caused a progressive fall in circulating eosinophils and also reduced ingress of eosinophils into induced sputum following allergen bronchial challenge. Unfortunately, as with anti-IL-5, there was no evidence of reduction of the allergen-induced bronchoconstrictor response or of the associated increase in AHR. Most of the patients suffered with malaise and one with cardiac dysrhythmia. Consequently, IL-12 alone is unlikely to be developed as a therapeutic agent for asthma. Cytokines such as IL-18 and IL-23, which share some of the effects of IL-12 but have a rather ambiguous role in the disease at present (see above), are other possible therapeutic agents, although problems with unwanted effects similar to those seen with IL-12 seem likely. In summary, these studies have done little more than highlight the chasm of ignorance about how the cellular, immunologic, and structural changes one can observe in asthma are related, if at all, to the clinical manifestations of disease. After more than 25 years of the T-cell/cytokine hypothesis of asthma, there still remains a pressing need to delineate those precise functions of cells and cytokines that are clearly related to causation of the disease, otherwise other breakthroughs in cytokine-directed therapy will remain serendipitous. It is essential to understand what mechanisms cause irreversible airways obstruction in asthma so that therapy can be directed against these. Specific, cytokinedirected therapies offer perhaps the best chance of removing particular cytokines from the equation, but owing to the redundancy of cytokine action, as evidenced by the ventures into anticytokine therapy thus far attempted, they may not necessarily offer viable therapeutic solutions.

Back to the future In summary, there is considerable evidence that T cells and their cytokine products play a role in asthma pathogenesis, but key questions, which have not so much been generated by extant work but have always been lurking in the wings, remain. These may be summarized as follows: • Do T-cell products cause the clinical features of asthma, and if so how? • Will T cell-directed therapy cure asthma or will irreversible changes induced by T-cell products preclude this? • What drives T-cell activation in asthma? • What drives T-cell refractoriness to inhibition in asthma? • Can new forms of therapy, which target multiple cytokines but are nevertheless more specific than glucocorticoids, be developed? • Can we keep effector T cells out of asthmatic airways? • Can we abolish T-cell memory of allergenic and other antigenic, asthma-relevant triggers? • Does the development of asthma in certain individuals reflect alterations in immunology or underlying heterogeneity, as yet uncharacterized, in the structure of the bronchial mucosa?

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Addressing all these challenges provides exciting prospects for future studies.

Acknowledgment I wish to thank my excellent assistants Pamela Robertin and Christine Grace for their many hours of work on this manuscript.

References Abbas, A.K., Murphy, K. & Sher, A. (1996) Functional diversity of helper T lymphocytes. Nature 383, 787–93. Agea, E., Russano, A., Bistoni, O. et al. (2005) Human CD1-restricted T cell recognition of lipids from pollens. J Exp Med 202, 295–308. Aggarwal, S. & Gurney, A.L. (2003) IL-17: prototype member of an emerging cytokine family. J Leukoc Biol 71, 1– 8. Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J. & Gurney, A.L. (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278, 1910–14. Akbari, O., Freeman, G.J., Meyer, E.H. et al. (2002) Antigen-specific regulatory T cells develop via the ICOS–ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8, 1024–32. Akbari, O., Stock, P., Meyer, E. et al. (2003) Essential role of NKT cells producing IL-4 and IL-13 in the development of allergeninduced airway hyperreactivity. Nat Med 9, 582– 8. Akbari, O., Faul, J.K., Hoyte, E.G. et al. (2006) CD4+ invariant T-cell receptor+ natural killer T cells in bronchial asthma. N Engl J Med 354, 1117–29. Akdis, C.A., Blesken, T., Akdis, M., Wuthrich, B. & Blaser, K. (1998) Role of interleukin 10 in specific immunotherapy. J Clin Invest 102, 98–106. Akdis, M., Verhagen, J., Taylor, A. et al. (2004) Immune responses in healthy and allergic individuals are characterised by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med 199, 1567–75. Akdis, M., Blaser, K. & Akdis, C.A. (2005) T regulatory cells in allergy: novel concepts in the pathogenesis, prevention, and treatment of allergic diseases. J Allergy Clin Immunol 116, 961–8. Alexander, A.G., Barnes, N.C. & Kay, A.B. (1992) Trial of cyclosporine in corticosteroid-dependent chronic severe asthma. Lancet 339, 324–8. Alexander, A.G., Barnes, N.C., Kay, A.B. & Corrigan, C.J. (1996) Can clinical response to cyclosporin in chronic severe asthma be predicted by an in vitro T-lymphocyte proliferation assay? Eur Respir J 9, 1421–6. Alexander, W.S., Starr, R., Fenner, J.E. et al. (1999) SOCS1 is a critical inhibitor of interferon gamma signalling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98, 597– 608. Ali, F.R., Bylanski, M., Arbery, J., Larche, M. & Kay, A.B. (2002) Inhalation of allergen-derived T cell epitopes induces isolated late asthmatics reactions with associated local eosinophilia. J Allergy Clin Immunol 109, S167.

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CHAPTER 3

Al Shami, A., Spolski, R., Kelly, J., Keane-Myers, A. & Leonard, W.J. (2005) A role for TSLP in the development of inflammation in an asthma model. J Exp Med 202, 829–39. Amsen, D., Blander, J.M., Lee, G.R., Tanigaki, K., Honjo, T. & Flavell, R.A. (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117, 515–26. Anderson, M.S., Venanzi, E.S., Klein, L. et al. (2002) Projection of an immunological self shadow within the thymus by the Aire protein. Science 298, 1395– 401. Andrew, D.P., Ruffing, N., Kim, C.H. et al. (2001) C-C chemokine receptor 4 expression defines a major subset of circulating nonintestinal memory T cells of both Th1 and Th2 potential. J Immunol 166, 103–11. Azzawi, M., Bradley, B., Jeffery, P.K. et al. (1990) Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. Am Rev Respir Dis 142, 1407–13. Balzar, S., Chu, H.W., Silkoff, P. et al. (2005) Increased TGF-beta2 in severe asthma with eosinophilia. J Allergy Clin Immunol 115, 110–17. Barrat, F.J., Cua, D.J., Boonstra, A. et al. (2002) In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)and Th2-inducing cytokines. J Exp Med 195, 603–16. Batra, V., Musani, A.I., Hastie, A.T. et al. (2004) Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)beta1, TGF beta2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on smooth muscle actin and collagen III synthesis by primary human lung fibroblasts. Clin Exp Allergy 34, 437– 44. Bellinghausen, I., Klostermann, B., Knop, J. & Saloga, J. (2003) Human CD4CD25 T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J Allergy Clin Immunol 111, 862– 8. Bennett, C.L., Christie, J., Ramsdell, F. et al. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FoxP3. Nat Genet 27, 20–21. Bentley, A.M., Maestrelli, P., Saetta, M. et al. (1992a) Activated T-lymphocytes and eosinophils in the bronchial mucosa in isocyanate-induced asthma. J Allergy Clin Immunol 89, 821–9. Bentley, A.M., Menz, G., Storz, C. et al. (1992b) Identification of T lymphocytes, macrophages, and activated eosinophils in the bronchial mucosa in intrinsic asthma. Relationship to symptoms and bronchial responsiveness. Am Rev Respir Dis 146, 500–6. Bentley, A.M., Hamid, Q., Robinson, D.S. et al. (1996) Prednisolone treatment in asthma. Reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5 and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med 153, 551–6. Berry, M.A., Hargadon, B., Shelley, M. et al. (2006) Evidence of a role of tumour necrosis factor alpha in refractory asthma. N Engl J Med 354, 697–708. Berry, M.A., Morgan, A., Shaw, D.E. et al. (2007) Pathological features and inhaled corticosteroid response of eosinophilic and noneosinophilic asthma. Thorax 62, 1043–9. Bettelli, F., Carrier, Y., Gao, W. et al. (2006) Reciprocal developmental pathways for the generation of pathogenic effector Th17 and regulatory T cells. Nature 441, 235– 8. Bilenki, L., Yang, J., Fan, Y., Wang, S. & Yang, X. (2004) Natural killer T cells contribute to airway eosinophilic inflammation in-

T Cells and Cytokines in Asthma and Allergic Inflammation

duced by ragweed through enhanced IL-4 and eotaxin production. Eur J Immunol 34, 345–54. Bluestone, J.A. & Tang, Q. (2005) How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol 17, 638–42. Bochner, B.S., Hudson, S.A., Xiao, H.Q. & Liu, M.C. (2003) Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. J Allergy Clin Immunol 112, 930–4. Bohle, B., Schwihla, H., Hu, H.-Z. et al. (1998) Long-lived Th2 clones specific for seasonal and perennial allergens can be detected in blood and skin by their TCR-hypervariable regions. J Immunol 160, 2022–7. Bonecchi, R., Bianchi, G., Bordignon, P.P. et al. (1998) Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med 187, 129– 34. Borish, L.C., Nelson, H.S., Lanz, M.J. et al. (1999) Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 160, 1816–23. Borish, L.C., Nelson, H.S., Corren, J. et al. (2001) IL-4R Asthma Study Group. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 107, 963–70. Bosse, Y., Thompson, C., Stankova, J. & Rola-Pleszczynski, M. (2006) Fibroblast growth factor 2 and transforming growth factor beta 1 synergism in human smooth muscle cell proliferation. Am J Respir Cell Mol Biol 34, 746–53. Brandes, M., Williman, K. & Moser, B. (2005) Professional antigenpresenting function by human gamma delta T cells. Science 309, 264– 8. Brender, C., Columbus, R., Metcalf, D. et al. (2004) SOCS5 is expressed in primary B and T lymphoid cells but is dispensable for lymphocyte production and function. Mol Cell Biol 24, 6094–103. Brightling, C.E., Bradding, P., Symon, F.A., Holgate, S.T., Wardlaw, A.J. & Pavord, I.D. (2002) Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med 346, 1699–705. Brigl, M. & Brenner, M.B. (2004) CD1: antigen presentation and T cell function. Annu Rev Immunol 22, 817–90. Bryan, S.A., O’Connor, B.J., Matti, S. et al. (2000) Effects of recombinant interleukin-12 on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet 356, 2149–53. Burgess, J.K. (2005) Connective tissue growth factor: a role in airway remodelling in asthma? Clin Exp Pharmacol Physiol 32, 988–94. Center, D.M., Kornfeld, H., Wu, M.J. et al. (1994) Cytokine binding to CD4+ inflammatory cells: implications for asthma. Am J Respir Crit Care Med 150, S59–S62. Chaudhuri, R., Livingston, E., McMahon, A.D. et al. (2003) Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 168, 1308–11. Chavez, J., Young, H.W., Corry, D.B. & Lieberman, M.W. (2006) Interactions between leukotriene C4 and interleukin 13 signalling pathways in a mouse model of airway disease. Arch Pathol Lab Med 130, 440–6. Chen, K.S., Miller, K.H. & Hengehold, D. (1996) Diminution of T cells with gamma delta receptor in the peripheral blood of allergic asthmatic individuals. Clin Exp Allergy 26, 295–302. Chensue, S.W., Lukacs, N.W., Yang, T.Y. et al. (2001) Aberrant in vivo T helper type 2 cell response and impaired eosinophil recruitment CC chemokine receptor 8 knockout mice. J Exp Med 193, 573– 84.

75

9781405157209_4_003.qxd 4/1/08 14:26 Page 76

PART 1

Immunology of the Allergic Response

Chu, H.W., Balzar, S., Seedorf, G.J. et al. (2004) Transforming growth factor-beta2 induces bronchial epithelial mucin expression in asthmatics. Am J Pathol 165, 1097–106. Conti, L., Casetti, R., Cardone, M. et al. (2005) Reciprocal activating interaction between dendritic cells and pamidronate-stimulated gammadelta T cells: role of CD86 and inflammatory cytokines. J Immunol 174, 252– 60. Corrigan, C.J. & Kay, A.B. (1990) CD4 T-lymphocyte activation in acute severe asthma: relationship to disease severity and atopic status. Am Rev Respir Dis 141, 970–7. Corrigan, C.J., Hartnell, A. & Kay, A.B. (1988) T-lymphocyte activation in acute severe asthma. Lancet i, 1129–32. Corrigan, C.J., Brown, P.H., Barnes, N.C. et al. (1991a) Glucocorticoid resistance in chronic asthma: glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. Am Rev Respir Dis 144, 1016–25. Corrigan, C.J., Brown, P.H., Barnes, N.C., Tsai, J.J., Frew, A.J. & Kay, A.B. (1991b) Glucocorticoid resistance in chronic asthma: peripheral blood T-lymphocyte activation and a comparison of the T-lymphocyte inhibitory effects of glucocorticoids and cyclosporin A. Am Rev Respir Dis 144, 1026– 32. Corrigan, C.J., Hamid, Q., North, J. et al. (1995) Peripheral blood CD4, but not CD8 T lymphocytes in patients with exacerbation of asthma transcribe and translate messenger RNA encoding cytokines which prolong eosinophil survival in the context of a Th2-type pattern: effect of glucocorticoid therapy. Am J Respir Cell Mol Biol 12, 567–78. Corrigan, C.J., Shiner, R., Shakur, B.H. & Ind, P.W. (2003) Methotrexate therapy in asthma increases T cell susceptibility to corticosteroid inhibition. Clin Exp Allergy 33, 1090–6. Corry, D.B., Folkesson, H.G., Warnock, M.L. et al. (1996) Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J Exp Med 183, 109–17. Cosmi, L., Annunziato, F., Iwasaki, M. et al. (2000) CRTh2 is the most reliable marker for the detection of circulating human type 2 Th2 and type 2 T cytotoxic cells in health and disease. Eur J Immunol 30, 2972–9. Coyle, A.J., Lehar, S., Lloyd, C. et al. (2000) The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13, 95–105. Croft, M. (2003) Costimulation of T cells by OX40, 4-1BB and CD27. Cytokine Growth Factor Rev 14, 265–73. Dahl, M.E., Dabbagh, K., Liggitt, D., Kim, S. & Lewis, D.B. (2004) Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Nat Immunol 5, 337– 43. Damera, G., Xia, B., Ancha, H.R. & Sachdev, G.P. (2006) IL-9 modulated MUC4 gene and glycoprotein expression in airway epithelial cells. Biosci Rep 26, 55– 67. De Libero, G., Moran, A.P., Glober, H.-J. et al. (2005) Bacterial infections promote T cell recognition of self-glycolipids. Immunity 22, 763–72. Devos, S., Cormont, F., Vrtala, S., Hooghe-Peters, E., Pirson, F. & Snick, J. (2006) Allergen-induced interleukin-9 production in vitro: correlation with atopy in human adults and comparison with interleukin-5 and interleukin-13. Clin Exp Allergy 36, 174–82. Doganci, A., Sauer, K., Karwet, R. & Finotto, S. (2005a) Pathological role of IL-6 in the experimental allergic bronchial asthma in mice. Clin Rev Allergy Immunol 28, 257–70.

76

Doganci, A., Eigenbrod, T., Krug, N. et al. (2005b) The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo. J Clin Invest 115, 313–25. Doi, S., Gemou-Engesaeth, V., Kay, A.B. & Corrigan, C.J. (1994) Polymerase chain reaction quantification of cytokine messenger RNA expression in peripheral blood mononuclear cells of patients with acute exacerbations of asthma: effect of glucocorticoid therapy. Clin Exp Allergy 24, 854 –7. Dong, C., Juedes, A.E., Temann, U.A. et al. (2001) ICOS co-stimulatory receptor is essential for T cell activation and function. Nature 409, 97–101. Donskoy, E. & Goldschneider, I. (2003) Two developmentally distinct populations of dendritic cells inhabit the adult mouse thymus: demonstration by differential importation of haematogenous precursors under steady state conditions. J Immunol 170, 3514–21. Dorman, S.C., Sehmi, R., Gauvreau, G.M. et al. (2004) Kinetics of bone marrow eosinophilopoiesis and associated cytokines after allergen inhalation. Am J Respir Crit Care Med 169, 565–72. Duez, C., Gosset, P. & Tonnel, A. (2006) Dendritic cells and Toll-like receptors in allergy and asthma. Eur J Dermatol 16, 12–16. Durham, S.R. & Till, S.J. (1998) Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol 102, 157–64. El Bassam, S., Pinsonneault, S., Kornfield, H., Ren, F., Menezes, J. & Laberge, S. (2006) Interleukin-16 inhibits interleukin-13 production by allergen-stimulated blood mononuclear cells. Immunology 117, 89–96. El-Mezayen, R.E. & Matsumoto, T. (2004) In vitro responsiveness to IL-18 in combination with IL-12 or IL-2 by PBMC from patients with bronchial asthma and atopic dermatitis. Clin Immunol 111, 61–8. Epstein, M.M. (2005) Targeting memory Th2 cells for the treatment of allergic asthma. Pharmacol Ther 109, 107–36. Erin, E.M., Leaker, B.R., Nicholson, G.C. et al. (2006) The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med 174, 753–62. Faith, A., McDonald, J., Peek, E. et al. (2005) Functional plasticity of human respiratory tract dendritic cells: GM-CSF enhances Th2 development. J Allergy Clin Immunol 116, 1136–43. Fallon, P.G., Ballantyne, S.J., Mangan, N.E. et al. (2006) Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5 and IL-13 at the onset of helminth expulsion. J Exp Med 203, 1105–16. Fehervari, Z. & Sakaguchi, S. (2004) Development and function of CD25+CD4+ regulatory T cells. Curr Opin Immunol 16, 203–8. Feigelstock, D., Thompson, P., Mattoo, P., Zhang, Y. & Kaplan, G.G. (1998) The human homolog of HAVcr-1 codes for a hepatitis A virus cellular receptor. J Virol 72, 6621– 8. Flood-Page, P.T., Menzies-Gow, A.N., Kay, A.B. & Robinson, D.S. (2003) Anti-IL-5 (mepolizumab) only partially depletes eosinophils from asthmatic airway tissue. Am J Respir Crit Care Med 167, 199– 204. Fort, M.M., Cheung, J., Yen, D. et al. (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985–95. Foster, P.S., Hogan, S.P., Ramsay, A.J., Matthaei, K.I. & Young, I.G. (1996) Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity and lung damage in a mouse asthma model. J Exp Med 183, 195–201.

9781405157209_4_003.qxd 4/1/08 14:26 Page 77

CHAPTER 3

Fujimoto, M., Tsutsui, H., Yumikura-Futatsugi, S. et al. (2002) A regulatory role for suppressor of cytokine signaling-1 in T(h) polarization in vivo. Int Immunol 14, 1343–50. Fukakusa, M., Bergeron, C., Tulic, M.K. et al. (2005) Oral corticosteroids decrease eosinophil and CC chemokine expression but increase neutrophil, IL-8, and IFN-gamma-inducible protein 10 expression in asthmatic airway mucosa. J Allergy Clin Immunol 115, 280– 6. Funkhouser, A.W., Kang, J.A., Tan, A. et al. (2004) Rhinovirus 16 3C protease induces interleukin-8 and granulocyte-macrophage colony-stimulating factor expression in human bronchial epithelial cells. Pediatr Res 55, 13–18. Fuss, I.J. (2004) Nonclassical CD1d-restricted NK T cells that produce IL-13 characterise an atypical Th2 response in ulcerative colitis. J Clin Invest 113, 1490–7. Gadue, P. & Stein, P. (2002) NKT cell precursors exhibit differential cytokine regulation and require ltk efficient maturation. J Immunol 169, 2397– 406. Gallelli, L., Pelaia, G., D’Agostino, B. et al. (2005) Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ET(A) receptor-dependent activation of MAP kinases. J Cell Biochem 96, 858– 68. Gavett, S.H., O’Hearn, D.J., Li, X., Huang, S.K., Finkelman, F.D. & Wills-Karp, M. (1995) Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med 182, 1527–36. Geginat, J., Sallusto, F. & Lanzavecchia, A. (2001) Cytokine-driven proliferation and differentiation of human naïve, central memory and effector memory CD4( + ) T cells. J Exp Med 194, 1711–19. Gemou-Engesaeth, V., Kay, A.B., Bush, A. & Corrigan, C.J. (1994) Activated peripheral blood CD4 and CD8 T lymphocytes in childhood asthma: correlation with eosinophilia and disease severity. Pediatr Allergy Immunol 5, 170– 7. Gemou-Engesaeth, V., Bush, A., Kay, A.B., Hamid, Q. & Corrigan, C.J. (1997) Inhaled glucocorticoid therapy of childhood asthma is associated with reduced peripheral blood T cell activation and “Th2-type” cytokine mRNA expression. Pediatrics 99, 695–703. Gemou-Engesaeth, V., Fagerhol, M.K., Toda, M. et al. (2002) Expression of activation markers and cytokine mRNA by peripheral blood CD4 and CD8 T cells in atopic and nonatopic childhood asthma: effect of inhaled glucocorticoid therapy. Pediatrics 109, E24. Gentile, D.A., Schreiber, R., Howe-Adams, J. et al. (2004) Diminished dendritic cell interleukin 10 production in atopic children. Ann Allergy Asthma Immunol 92, 538– 44. Godfrey, D., Hammond, K., Poulton, L., Smyth, M. & Baxter, A. (2000) NKT cells: facts, functions and fallacies Immunol Today 21, 573–83. Gomes, I., Mathur, S.K., Espenshade, B.M., Mori, Y., Varga, J. & Ackerman, S.J. (2005) Eosinophil–fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: implications in fibrogenesis. J Allergy Clin Immunol 116, 796–804. Gonzalo, J.A., Tian, J., Delaney, T. et al. (2001) ICOS is critical for T helper cell-mediated lung mucosal inflammatory responses. Nat Immunol 2, 597– 604. Gounni, A.S., Hamid, Q., Rahman, S.M., Hoeck, J., Yang, J. & Shan, L. (2004) IL-9-mediated induction of eotaxin 1/CCL11 in human airway smooth muscle cells. J Immunol 173, 2771–9. Grimbacher, B., Hutloff, A., Schlesier, M. et al. (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4, 261–8.

T Cells and Cytokines in Asthma and Allergic Inflammation

Grunig, G., Warnock, M., Wakil, A.E. et al. (1998) Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–3. Haczku, A., Alexander, A., Brown, P. et al. (1994) The effect of dexamethasone, cyclosporine and rapamycin on T-lymphocyte proliferation in vitro: comparison of cells from patients with glucocorticoid-sensitive and glucocorticoid-resistant chronic asthma. J Allergy Clin Immunol 93, 510–19. Hakonarson, H., Maskeri, N., Carter, C., Chuang, S. & Grunstein, M.M. (1999) Autocrine interaction between IL-5 and IL-1beta mediates altered responsiveness of atopic asthmatic sensitised airway smooth muscle. J Clin Invest 104, 657–67. Hansen, G., Berry, G., Dekruyff, R.H. & Umetsu, D.T. (1999) Allergenspecific Th1 cells fail to counterbalance Th2 cell-induced airway hyperactivity but cause severe airway inflammation. J Clin Invest 103, 175–83. Haselden, B.M., Kay, A.B. & Larché, M. (1999) Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med 189, 1885–94. Haselden, B.M., Larché, M., Meng, Q. et al. (2001) Late asthmatic reactions provoked by intradermal injection of T cell peptide epitopes are not associated with bronchial mucosal infiltration of eosinophils or Th2-type cells or with elevated concentrations of histamine or eicosanoids in bronchoalveolar fluid. J Allergy Clin Immunol 108, 394–401. Hauk, P.J., Hamid, Q.A., Chrousos, G.P. et al. (2000) Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol 105, 782–7. Hawrylowicz, C.M. & O’Garra, A. (2005) Potential role of interleukin10 secreting regulatory T cells in allergy and asthma. Nat Rev Immunol 5, 271–83. Hawrylowicz, C., Richards, D., Loke, T.-K., Corrigan, C. & Lee, T. (2002) A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. J Allergy Clin Immunol 109, 369–70. Hayday, A. & Tigelaar, R. (2003) Immunoregulation in the tissues by gamma delta T cells. Nat Rev Immunol 3, 233–42. Henness S., van Thoor, E., Ge, Q., Armour, C.L., Hughes, J.M. & Ammit, A.J. (2006) IL-17A acts via p38 MAPK to increase stability of TNF-alpha-induced IL-8 mRNA in human ASM. Am J Physiol 290, L1283–L1290. Hirai, H., Tanaka, K., Yoshie, O. et al. (2001) Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTh2. J Exp Med 193, 255–61. Ho, L.P., Davis, M., Denison, A., Wood, F.T. & Greening, A.P. (2002) Reduced interleukin-18 levels in BAL specimens from patients with asthma compared to patients with sarcoidosis and healthy control subjects. Chest 121, 1421–6. Hofstra, C.L., Van Ark, I., Hofman, G., Kool, M., Nijkamp, F.P. & Van Oosterhout, A.J. (1998) Prevention of Th2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels. J Immunol 161, 5054–60. Howarth, P.H., Babu, K.S., Arshad, H.S. et al. (2006) Tumour necrosis factor (TNF-alpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 61, 1012–18. Howell, J.E. & McAnulty, R.J. (2006) TGF-beta: its role in asthma and therapeutic potential. Curr Drug Targets 7, 547–65.

77

9781405157209_4_003.qxd 4/1/08 14:26 Page 78

PART 1

Immunology of the Allergic Response

Hsieh, C.S., Liang, Y., Tyznik, A.J., Self, S.G., Liggitt, D. & Rudensky, A.Y. (2004) Recognition of the peripheral self by naturally arising CD25+CD4+ T cell receptors. Immunity 21, 267–77. Huang, C.D., Wang, C.H., Liu, C.Y. et al. (2005) Eosinophils from asthmatics release IL-5 in an autocrine fashion to prevent apoptosis through upregulation of Bcl-2 expression. J Asthma 42, 395– 403. Huang, H. & Paul, W.E. (1998) Impaired interleukin 4 signaling in T helper type 1 cells. J Exp Med 187, 1305–13. Humbert, M., Durham, S.R., Ying, S. et al. (1996) IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against “intrinsic” asthma being a distinct immunopathologic entity. Am J Respir Crit Care Med. 154, 1497–504. Humbert, M., Durham, S.R., Kimmitt, P., Till, S.J., Kay, A.B. & Corrigan, C.J. (1997a) The relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J Respir Crit Care Med 156, 704– 8. Humbert, M., Durham, S.R., Kimmitt, P. et al. (1997b) Elevated expression of messenger ribonucleic acid encoding interleukin-13 in the bronchial mucosa of atopic and non-atopic subjects with asthma. J Allergy Clin Immunol 99, 657– 65. Humbert, M., Ying, S., Corrigan, C. et al. (1997c) Bronchial mucosal expression of the genes encoding chemokines RANTES and MCP-3 in symptomatic atopic and non-atopic asthmatics: relationship to the eosinophil-active cytokines interleukin (IL)-5, granulocyte/ macrophage colony-stimulating factor and IL-(3). Am J Respir Cell Mol Biol 16, 1– 8. Humbles, A.A., Lu, B., Friend, D.S. et al. (2002) The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. Proc Natl Acad Sci USA 99, 1479– 84. Hurst, S.D., Muchamuel, T., Gorman, D.M. et al. (2002) New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol 169, 443–53. Iellem, A., Mariani, M., Lang, R. et al. (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+ CD25+ regulatory T cells. J Exp Med 194, 847–53. Infante-Duarte, C., Horton, H.F., Byrne, M.C. & Kamradt, T. (2000) Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 165, 6107–15. Ingram, J.L., Antao-Menezes, A., Mangum, J.B. et al. (2006) Opposing actions of Stat1 and Stat6 on IL-13-induced up-regulation of early growth response gene and platelet derived growth factor ligands in pulmonary fibroblasts. J Immunol 177, 4141–8. Ip, W.K., Wong, C.K., Wang, C.B., Tian, Y.P. & Lam, C.W. (2005) Interleukin-3, -5 and granulocyte macrophage colony-stimulating factor induce adhesion and chemotaxis of human eosinophils via p38 mitogen-activated protein kinase and nuclear factor kappaB. Immunopharmacol Immunotoxicol 27, 371– 93. Irusen, E., Matthews, J.G., Takatiashi, A. et al. (2002) MAP kinaseinduced glucocorticoid-receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol 109, 649–57. Ishikawa, Y., Yoshimoto, T. & Nakanishi, K. (2006) Contribution of IL-18-induced innate T cell activation to airway inflammation with mucus hypersecretion and airway hyperresponsiveness. Int Immunol 18, 847–55.

78

Ito, T., Wang, Y.H., Duramand, O. et al. (2005) TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med 202, 1213–23. Ivanov, I.I., McKenzie, B.S., Zhou, L. et al. (2006) The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–33. Iwakura, Y. & Ishigame, H. (2006) The IL-23/IL-17 axis in inflammation. J Clin Invest 116, 1218–22. Jaffar, Z.H., Stanciu, L., Pandit, A., Lordan, J., Holgate, S.T. & Roberts, K. (1999) Essential role for both CD80 and CD86 costimulation, but not CD40 interactions, in allergen-induced Th2 cytokine production from asthmatic bronchial mucosal tissue: role for alphabeta, but not gammadelta T cells. J Immunol 163, 6283–91. Jin, N., Taube, C., Sharp, L. et al. (2005) Mismatched antigen prepares γδ T cells for suppression of airway hyperresponsiveness. J Immunol 174, 2671–9. Johnson, P.R., Burgess, J.K., Ge, Q. et al. (2006) Connective tissue growth factor induces extracellular matrix in asthmatic airway smooth muscle. Am J Respir Crit Care Med 173, 32–41. Jonuleit, H., Schmitt, E., Steinbrink, K. & Enk, A.H. (2001) Dendritic cells as a tool to induce anergic and regulatory T cells. Trends Immunol 22, 394–400. Jordan, M., Fletcher, J. & Baxter, A. (2004) Genetic control of NKT cell numbers. Immunol Cell Biol 82, 276–84. Jutel, M., Akdis, M., Budak, F. et al. (2003) IL-10 and TGF-β cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 33, 1205–14. Kalliomaki, M. & Isolauri, E. (2003) Role of intestinal flora in the development of allergy. Curr Opin Allergy Clin Immunol 3, 15–20. Karagiannidis, C., Akdis, M., Holopainen, P. et al. (2004) Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114, 1425–33. Karlsson, M.R., Rugtveit, J. & Brandtzaeg, P. (2004) Allergenresponsive CD4+CD25+ regulatory T cells in children who have outgrown cow’s milk allergy. J Exp Med 199, 1679–88. Kawaguchi, M., Adachi, M., Oda, N., Kokubu, F. & Huang, S.K. (2004) IL-17 cytokine family. J Allergy Clin Immunol 114, 1265–73. Kawai, T., Andrews, D., Colvin, R.B., Sachs, D.H. & Cosimi, A.B. (2000) Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 6, 114. Khademi, M., Illés, Z., Gielen, A.W. et al. (2004) T cell Ig- and mucindomain-containing molecule-3 (TIM-3) and TIM-1 molecules are differentially expressed on human Th1 and Th2 cells and in cerebrospinal fluid-derived mononuclear cells in multiple sclerosis. J Immunol 172, 7169–76. Khan, L.N., Kon, O.M., Macfarlane, A.J. et al. (2000) Attenuation of the allergen-induced late asthmatic reaction by cyclosporin A is associated with inhibition of bronchial eosinophils, interleukin-5, granulocyte macrophage colony-stimulating factor and eotaxin. Am J Respir Crit Care Med 162, 1377–82. Kibe, A., Inoue, H., Fukuyama, S. et al. (2003) Differential regulation by glucocorticoid of interleukin-13-induced eosinophilia, hyperresponsiveness, and goblet cell hyperplasia in mouse airways. Am J Respir Crit Care Med. 167, 50–6. Klinman, D.M. (2004) Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4, 1–10. Kolls, J.K. & Linden, A. (2004) Interleukin-17 family members and inflammation. Immunity 21, 467–76. Kon, O.M., Sihra, B.S., Till, S.J., Corrigan, C.J., Kay, A.B. & Grant, J.A.

9781405157209_4_003.qxd 4/1/08 14:26 Page 79

CHAPTER 3

(1998a) Unstimulated basophils in atopic and non-atopic subjects express intracellular interleukin-4: detection by flow cytometry. Allergy 53, 891– 6. Kon, O.M., Sihra, B.S., Compton, C.H., Leonard, T.B., Kay, A.B. & Barnes, N.C. (1998b) Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma. Lancet 352, 1109–13. Kroczek, R.A., Mages, H.W. & Hutloff, A. (2004) Emerging paradigms of T cell co-stimulation. Curr Opin Immunol 16, 321–7. Krug, N., Erpenbeck, V.J., Balke, K. et al. (2001) Cytokine profile of bronchoalveolar lavage-derived CD4+, CD8+, and gammadelta T cells in people with asthma after segmental allergen challenge. Am J Respir Cell Mol Biol 25, 125– 31. Lacy, P. & Moqbel, R. (2001) Immune effector functions of eosinophils in allergic airway inflammation. Curr Opin Allergy Clin Immunol 1, 79– 84. Lahn, M., Kanehiro, A., Takeda, K. et al. (1999) Negative regulation of airway responsiveness that is dependent on gammadelta T cells and independent of alphabeta T cells. Nat Med 5, 1150–6. Lametschwandtner, G., Biedermann, T., Schwarzler, C. et al. (2004) Sustained T-bet expression confers polarized human Th2 cells with Th1-like cytokine production and migratory capacities. J Allergy Clin Immunol 113, 987– 94. Lane, P. (2000) Role of OX40 signals in costimulating CD4 T cell selection, migration and cytokine differentiation in T helper (Th)1 and Th2 cells. J Exp Med 191, 201– 6. Laporte, J.C., Moore, P.E., Baraldo, S. et al. (2001) Direct effects of interleukin-13 on signalling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med 164, 141– 8. Larche, M., Till, S.J., Haselden, B.M. et al. (1998) Costimulation through CD86 is involved in airway antigen-presenting cell and T cell responses to allergen in atopic asthmatics. J Immunol 161, 6375–82. Lassalle, P., Delneste, Y., Gosset, P. et al. (1993) T and B-cell immune response to a 55 kDa endothelial cell-derived antigen in severe asthma. Eur J Immunol 23, 796– 803. Leckie, M.J., ten Brinke, A., Khan, J. et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144– 8. Lee, K.Y., Ho, S.C., Lin, H.C. et al. (2006) Neutrophil-derived elastase induces TGF-beta 1 secretion in human airway smooth muscle NF-kappaB pathway. Am J Respir Cell Mol Biol 35, 407–14. Lee, S.A., Fitzgerald, S.M., Huang, S.K. et al. (2004) Molecular regulation of interleukin-13 and monocyte chemoattractant protein-1 expressed in human mast cells by interleukin-1beta. Am J Respir Cell Mol Biol 31, 283– 91. Letuve, S., Lajoie-Kadoch, S., Audusseau, S. et al. (2006) IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts. J Allergy Clin Immunol 117, 590–6. Leung, D.Y., Martin, R.J., Szefler, S.J. et al. (1995) Dysregulation of interleukin 4, interleukin-5, and interferon gamma gene expression in steroid-resistant asthma. J Exp Med 181, 33–40. Liao, S.C., Cheng, Y.C., Wang, Y.C. et al. (2004) IL-19 induced Th2 cytokines and was up-regulated in asthma patients. J Immunol 173, 6712–18. Ling, E.M., Smith, T., Nguyen, X.D. et al. (2004) Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–15.

T Cells and Cytokines in Asthma and Allergic Inflammation

Liu, Y.-J., Soumelis, V., Watanabe, N. et al. (2006) TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol 25, 193–219. Lloyd, C.M., Gonzalo, J.A., Coyle, A.J. & Gutierrez-Ramos, J.C. (2001) Mouse models of allergic airway disease. Adv Immunol 77, 263– 95. Lock, S.H., Kay, A.B. & Barnes, N.C. (1996) Double-blind, placebocontrolled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 153, 509–14. Lohning, M., Hutloff, A., Kallinich, T. et al. (2003) Expression of ICOS in vivo defines CD4+ effector T cells with high inflammatory potential and a strong bias for secretion of interleukin 10. J Exp Med 197, 181–93. Loke, T.K., Mallett, K.H., Ratoff, J. et al. (2006) Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J Allergy Clin Immunol 118, 368–75. Lutz, M.B. & Schuler, G. (2002) Immature, semi-mature and fully mature dendritic cells: which signals induce intolerance or immunity? Trends Immunol 23, 445–9. McIntire, J.J., Umetsu, S.E., Akbari, O. et al. (2001) Identification of Tapr (an airway hyperreactivity regulator locus) and the linked Tim gene family. Nat Immunol 2, 1109–16. McIntire, J.J., Umetsu, S.E., Macaubas, C. et al. (2003) Immunology: hepatitis A virus link to atopic disease. Nature 425, 576. McKay, A., Komai-Koma, M., MacLeod, K.J. et al. (2004) Interleukin18 levels in induced sputum are reduced in asthmatic and normal smokers. Clin Exp Allergy 34, 904–10. Maclem, P.T. (1996) A theoretical analysis of the effect of airway smooth muscle load on airway narrowing. Am J Respir Crit Care Med 153, 83–9. McNamara, P.S., Flanagan, B.F., Baldwin, L.M., Newland, P., Hart, C.A. & Smyth, R.L. (2004) Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis. Lancet 363, 1031–7. Marin, M.G. (1997) Low dose methotrexate spares steroid usage in steroid-dependent chronic asthma. Chest 112, 29–33. Matricardi, P.M., Rosmini, F., Panetta, V., Ferrigno, L. & Bonini, S. (2002) Hay fever and asthma in relation to markers of infection in the United States. J Allergy Clin Immunol 110, 381–7. Mellor, A.L. & Munn, D.H. (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4, 762–74. Mercer, J.C., Ragin, M.J. & August, A. (2005) Natural killer T cells: rapid responders controlling immunity and disease. Int J Biochem Cell Biol. 37, 1337–43. Meyers, J.H., Chakravarti, S., Schlesinger, D. et al. (2005) TIM-4 is the ligand for TIM-1, and the TIM-1–TIM-4 interaction regulates T cell proliferation. Nat Immunol 6, 455– 64. Mills, K.H. (2004) Regulatory T cells: friend or foe in immunity to infection? Nat Rev Immunol 4, 841–55. Minshall, E., Chakir, J., Laviolette, M. et al. (2000) IL-11 expression is increased in severe asthma: association with epithelial cells and eosinophils. J Allergy Clin Immunol 105, 232–8. Miotto, D., Christodoulopoulos, P., Olivenstein, R. et al. (2001) Expression of IFN-gamma-inducible protein; monocyte chemoattractant proteins 1, 3 and 4; and eotaxin in Th1- and Th2-mediated lung diseases. J Allergy Clin Immunol 107, 664–70.

79

9781405157209_4_003.qxd 4/1/08 14:26 Page 80

PART 1

Immunology of the Allergic Response

Monney, L., Sabatos, C.A., Gaglia, J.L. et al. (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536– 41. Moqbel, R., Ying, S., Barkans, J. et al. (1995) Identification of mRNA for interleukin-4 in human eosinophils with granule localisation and release of the translated product. J Immunol 155, 4939–47. Morgan, A.J., Symon, F.A., Berry, M.A., Pavord, I.D., Corrigan, C.J. & Wardlaw, A.J. (2005) IL-4-expressing bronchoalveolar T cells from asthmatics and healthy subjects preferentially express CCR3 and CCR4. J Allergy Clin Immunol 116, 594– 600. Moseley, T.A., Haudenschild, D.R., Rose, L. & Reddi, A.H. (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14, 155–74. Munitz, A., Bachelet, I., Eliashar, R. et al. (2006) CD48 is an allergen and IL-3 induced activation molecule on eosinophils. J Immunol 177, 77–83. Mutalithas, K., Croudace, J., Guillen, C. et al. (2007) Bronchoalveolar lavage invariant natural killer T cells are not increased in asthma. J Allergy Clin Immunol 119, 1274– 6. Nagata, K., Tanaka, K., Ogawa, K. et al. (1999) Selective expression of a novel surface molecule by human Th2 cells in vivo. J Immunol 162, 1276–86. Nahm, D.H., Lee, Y.E., Yim, E.J. et al. (2002) Identification of cytokeratin 18 as a bronchial epithelial autoantigen associated with nonallergic asthma. Am J Respir Crit Care Med. 165, 1536–9. Nakamura, K., Kitani, A. & Strober, W. (2001) Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by surface-bound transforming growth factor β. J Exp Med 194, 629–44. Newcomb, D.C., Sajjan, U., Nanua, S. et al. (2005) Phosphatidylinositol 3-kinase is required for rhinovirus-induced airway epithelial cell interleukin-8 expression. J Biol Chem 280, 36952–61. Nouri-Aria, K.T., Wachholz, P.A., Francis, J.N. et al. (2004) Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol 172, 3252–9. Nouri-Aria, K.T., Pilette, C., Jacobson, M.R., Watanabe, H. & Durham, S.R. (2005) IL-9 and c-Kit+ mast cells in allergic rhinitis during seasonal allergen exposure: effect of immunotherapy. J Allergy Clin Immunol 116, 73– 9. Oda, N., Canelos, P.B., Essayan, D.M., Plunkett, B.A., Myers, A.C. & Huang, S.K. (2005) Interleukin-17F induces pulmonary neutrophilia and amplifies antigen-induced allergic response. Am J Respir Crit Care Med 171, 12–18. Oflazoglu, E., Swart, D.A., Anders-Bartholo, P. et al. (2004) Paradoxical role of programmed death-1 ligand 2 in Th2 immune responses in vitro and in a mouse asthma model in vivo. Eur J Immunol 34, 3326–36. Panina-Bordignon, P., Papi, A., Mariani, M. et al. (2001) The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics. J Clin Invest 107, 1357–64. Park, H., Li, Z., Yang, X.O. et al. (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6, 1133– 41. Pawankar, R. (2001) Mast cells as orchestrators of the allergic reaction: the IgE–IgE receptor mast cell network. Curr Opin Allergy Clin Immunol 1, 3– 6. Peek, E.J., Richards, D.F., Faith, A. et al. (2005) Interleukin-10secreting “regulatory” T cells induced by glucocorticoids and β2agonists. Am J Respir Cell Mol Biol 33, 105–11.

80

Peng, Q., Matsuda, T. & Hirst, S.J. (2004) Signalling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle. Am J Respir Crit Care Med 169, 596–603. Pennington, D.J., Silva-Santos, B. & Hayday, A.C. 2005. γδ T cell development: having the strength to get there. Curr Opin Immunol 17, 108–15. Peterson, P. & Peltonen, L. (2005) Autoimmune polyendocrinopathy syndrome type 1 (APS1) and the AIRE gene: new views on the molecular basis of autoimmunity. J Autoimmun 25, 49–55. Powell, N., Till, S.J., Kay, A.B. & Corrigan, C.J. (2001a) The topical glucocorticoids beclomethasone dipropionate and fluticasone propionate inhibit human T cell allergen-induced production of IL-5, IL-3 and GM-CSF mRNA and protein. Clin Exp Allergy 31, 69–76. Powell, N., Till, S., Bungre, J. & Corrigan, C.J. (2001b) The immunomodulatory drugs cyclosporin A, mycophenolate mofetil and sirolimus (rapamycin) inhibit allergen-induced proliferation and IL-5 production by PBMCs from atopic asthmatic patients. J Allergy Clin Immunol 108, 915–17. Profita, M., Gagliardo, R., Di Giorgi, R. et al. (2004) In vitro effects of flunisolide on MMP-9, TIMP-1, fibronectin, TGF-beta 1 release and apoptosis of sputum cells freshly isolated from mild to moderate asthmatics. Allergy 59, 927–32. Radhakrishnan, S., Lijima, K., Kobayashi, T., Kita, H. & Pease, L.R. (2005) Dendritic cells activated by cross-linking B7-DC (PD-L2) block inflammatory airway disease. J Allergy Clin Immunol 116, 668–74. Rahman, M.S., Yamasaki, A., Yang, J., Shan, L., Halayko, A.J. & Gounni, A.S. (2006) IL-17A induces eotaxin-1/CC chemokine ligand 11 expression in human airway smooth muscle cells: role of MAPK (Erk1/2, JNK, and p38) pathways. J Immunol 177, 4064– 71. Ramirez-Icaza, G., Mohammed, K.A., Nasreen, N. et al. (2004) Th2 cytokines IL-4 and IL-13 downregulate paxillin expression in bronchial airway epithelial cells. J Clin Immunol 24, 426–34. Rivino, L., Messi, M., Jarrossay, D., Lanzavecchia, A., Sallusto, F. & Geginat, J. (2004) Chemokine receptor expression identifies pre-T helper (Th)1, pre-Th2 and nonpolarised cells among human CD4+ central memory cells. J Exp Med 200, 725–35. Robinson, D.S., Hamid, Q., Ying, S. et al. (1992) Predominant Th2type bronchoalveolar lavage T-lymphocyte population in atopic asthma. N Engl J Med 326, 298–304. Robinson, D.S., Bentley, A.M., Hartnell, A., Kay, A.B. & Durham, S.R. (1993a) Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness. Thorax 48, 26–32. Robinson, D., Hamid, Q., Ying, S. et al. (1993b) Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon-gamma cytokine gene expression. Am Rev Respir Dis 148, 401–6. Romagnani, P., Maggi, L., Mazzinghi, B. et al. (2005) CXCR3-mediated opposite effects of CXCL10 and CXCL4 on Th1 or Th2 cytokine production J Allergy Clin Immunol 116, 1372–9. Rose-John, S., Scheller, J., Elson, G. & Jones, S.A. (2006) Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 80, 227–36. Rudolph, M.G., Stanfield, R.L. & Wilson, I.A. (2006) How TCRs bind MHCs, peptides and coreceptors. Annu Rev Immunol 24, 419–66.

9781405157209_4_003.qxd 4/1/08 14:26 Page 81

CHAPTER 3

Sabatos, C.A., Chakravarti, S., Cha, E. et al. (2003) Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 4, 1102–10. Sakaguchi, S. (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 14, 73– 99. Sallusto, F., Geginat, J. & Lanzavecchia, A. (2004) Central memory and effector memory T cell subsets: function, generation and maintenance. Annu Rev Immunol 22, 745–63. Schmidt-Weber, C.B. & Blaser, K. (2004) Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation. Curr Opin Immunol 16, 709–16. Schnyder-Candrian, S., Togbe, D., Couillin, I. et al. (2006) Interleukin17 is a negative regulator of established allergic asthma. J Exp Med 203, 2715– 25. Schuh, J.M., Power, C.A., Proudfoot, A.E., Kunkel, S.L., Lukacs, N.W. & Hogaboam, C.M. (2002) Airway hyperresponsiveness, but not airway remodelling, is attenuated during chronic pulmonary allergic responses to Aspergillus in CCR4–/– mice. FASEB J 16, 1313–15. Schwarze, J., Cieslewicz, G., Joetham, A., Ikemura, T., Hamelmann, E. & Gelfand, E.W. (1999) CD8 T cells are essential in the development of respiratory syncytial virus-induced lung eosinophilia and airway hyperresponsiveness. J Immunol 162, 4207–11. Scotet, E., Martinez, L.O., Grant, E. et al. (2005) Tumor recognition following Vγ9Vδ T cell receptor interactions with a surface F1ATPase-related structure and apolipoprotein A-1. Immunity 22, 71– 80. Sebastiani, S., Albanesi, C., De, P.O., Puddu, P., Cavani, A. & Girolomoni, G. (2002) The role of chemokines in allergic contact dermatitis. Arch Dermatol Res 293, 552– 9. Seki, Y., Hayashi, K., Matsumoto, A. et al. (2002) Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc Natl Acad Sci USA 99, 13003– 8. Seki, Y., Inoue, H., Nagata, N. et al. (2003) SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses. Nat Med 9, 1047–54. Sen, Y., Yongyi, B., Yuling, H. et al. (2005) V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ cells upon CD226 engagement. J Immunol 175, 4914–26. Shan, X., Hu, A., Veler, H. et al. (2006) Regulation of Toll-like receptor 4-induced proasthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signalling. Am J Physiol 291, L324–L333. Sheikh, A., Smeeth, L. & Hubbard, R. (2003) There is no evidence of an inverse relationship between TH2-mediated atopy and TH1mediated autoimmune disorders: lack of support for the hygiene hypothesis. J Allergy Clin Immunol 111, 131–5. Sihra, B.S., Kon, O.M., Durham, S.R., Walker, S., Barnes, N.C. & Kay, A.B. (1997) Effect of cyclosporin A on the allergen-induced late asthmatic reaction. Thorax 52, 447–52. Simons, F.E., Shikishima, Y., Van Nest, G., Eiden, J.J. & HayGlass, K.T. (2004) Selective immune redirection in humans with ragweed allergy by injecting Amb a1 linked to immunostimulatory DNA. J Allergy Clin Immunol. 113, 1144–51. Skapenko, A., Niedobitek, G.U., Kalden, J.R., Lipsky, P.E. & SchulzeKoops, H. (2004) IL-4 exerts a much more profound suppression of Th1 immunity in humans than in mice. J Immunol 172, 6427–34.

T Cells and Cytokines in Asthma and Allergic Inflammation

Smits, H.H., van Rietschoten, J.G., Hilkens, C.M. et al. (2001) IL-12induced reversal of human Th2 cells is accompanied by full restoration of IL-12 responsiveness and loss of GATA-3 expression. Eur J Immunol 31, 1055–65. So, T., Song, J., Sugie, K., Altman, A. & Croft, M. (2006) Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment. Proc Natl Acad Sci USA 103, 3740–5. Soumelis, V., Reche, P.A., Kanzler, H. et al. (2002) Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 3, 673– 80. Spinozzi, F., Agea, E., Bistoni, O. et al. (1996) Increased allergenspecific, steroid-sensitive gamma delta T cells in bronchoalveolar lavage fluid from patients with asthma. Ann Intern Med 124, 223–7. Starr, T.K., Jameson, S.C. & Hogquist, K.A. (2003) Positive and negative selection of T cells. Annu Rev Immunol 21, 139–76. Stetson, D., Molirs, M., Reinhardt, R. et al. (2003) Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J Exp Med 198, 1069–76. Stumhofer, J.S., Laurence, A., Wilson, E.H. et al. (2006) Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat Immunol 7, 937– 45. Su, M. & Anderson, M.S. (2004) AIRE: an update. Curr Opin Immunol 16, 748–52. Szabo, S.J., Kim, S.T., Costa, G.L., Zhang, X., Fathman, C.G. & Glimcher, L.H. (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–69. Tadokoro, C.E., Shakhar, G., Shen, S. et al. (2006) Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells. J Exp Med 203, 505–11. Takayama, G., Arima, K., Kanaji, T. et al. (2006) Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol 118, 98– 104. Takhar, P., Corrigan, C.J., Smurthwaite, L. et al. (2007) Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic asthmatics. J Allergy Clin Immunol. 119, 213–18. Tamachi, T., Maezawa, Y., Ikeda, K. et al. (2006) IL-25 enhances allergic airway inflammation by amplifying a Th2 cell-dependent pathway in mice. J Allergy Clin Immunol 118, 606–14. Tamada, K., Harada, M., Abe, K., Li, T. & Nomoto, K. (1998) IL-4producing NK1.1+ T cells are resistant to glucocorticoid-induced apoptosis: implications for the Th1/Th2 balance. J Immunol 161, 1239–47. Tang, W., Geba, G.P., Zheng, T. et al. (1996) Targeted expression of IL-11 in the murine airways causes lymphocytic inflammation, bronchial remodelling and airways obstruction. J Clin Invest 98, 2845–53. Tarkowski, M. (2003) Expression and role of CD30 in regulation of T cell activity. Curr Opin Hematol 19, 267–71. Temann, U.A., Geba, G.P., Rankin, J.A. & Flavell, R.A. (1998) Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia and bronchial hyperresponsiveness. J Exp Med 188, 1307–20. Till, S.J., Li, B., Durham, S. et al. (1995) Secretion of the eosinophilactive cytokines interleukin-5, granulocyte/macrophage colonystimulating factor and interleukin-3 by bronchoalveolar lavage CD4+ and CD8+ T cell lines in atopic asthmatics, and atopic and non-atopic controls. Eur J Immunol 25, 2727–31.

81

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Till, S.J., Durham, S.R., Rajakulasingam, K. et al. (1998) Allergeninduced proliferation and IL-5 production by bronchoalveolar lavage and blood T cells following segmental allergen challenge. Am J Respir Crit Care Med 158, 404–11. Trudeau, J., Hu, H., Chibana, K., Chu, H.W., Westcott, J.Y. & Wenzel, S.E. (2006) Selective downregulation of prostaglandin E2-related pathways by the Th2 cytokine IL-13. J Allergy Clin Immunol 117, 1446–54. Tsicopoulos, A., Shimbara A., de Nadai, P. et al. (2004) Involvement of IL-9 in the bronchial phenotype of patients with nasal polyposis. J Allergy Clin Immunol 113, 462– 9. Varga, E.M., Wachholz, P., Nouri-Aria, K. et al. (2000) T cells from human allergen-induced late asthmatic responses express IL-12 receptor β2 subunit mRNA and respond to IL-12 in vitro. J Immunol 165, 2877–85. Venkataraman, C., Schaefer, G. & Schindler, U. (2000) Cutting edge: Chandra, a novel four-transmembrane domain protein differentially expressed in helper type 1 lymphocytes. J Immunol 165, 632–6. Vijayanand, P., Sumois, G., Pickard, C. et al. (2007) Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 356, 1410– 22. Walker, C., Kaegi, M.K., Braun, P. & Blaser, K. (1991) Activated T cells and eosinophils in bronchoalveolar lavage from subjects with asthma correlated with disease severity. J Allergy Clin Immunol 88, 935–42. Wang, Y.-H., Ito, T., Wang, Y.-H. et al. (2006) Maintenance and polarisation of human Th2 central memory cells by thymic stromal lymphopoietin-activated dendritic cells. Immunity 24, 827–38. Watanabe, N., Hanabuchi, S., Soumelis, V. et al. (2004) Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion. Nat Immunol 5, 426– 34. Watanabe, N., Wang, Y.H., Lee, H.K., Ito, T., Cao, W. & Liu, Y.J. (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+ CD25+ regulatory T cells in human thymus. Nature 436, 1181–5. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677– 88. Weiner, H.L. (2001) The mucosal milieu creates tolerogenic dendritic cells and Tr1 and Tr3 regulatory cells. Nat Immunol 2, 671–2. Wenzel, S.E., Szefler, S.J., Leung, D.Y. et al. (1997) Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 156, 737–43. Wenzel, S.E., Schwartz, L.B., Langmack, E.L. et al. (1999) Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160, 1001– 8. Wills-Karp, M. (2004) Interleukin-13 in asthma pathogenesis. Immunol Rev 202, 175–90. Wills-Karp, M., Luyimbazi, J., Xu, X. et al. (1998) Interleukin-13: central mediator of allergic asthma. Science 282, 2258–61.

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Worth, A., Thrasher, A.J. & Gaspar, B. (2006) Autoimmune lymphoproliferative syndrome: molecular basis of disease and clinical phenotype. Br J Haematol 133, 124–40. Xystrakis, E., Kusumakar, S., Boswell, S. et al. (2006) Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid resistant asthma. J Clin Invest 116, 146–55. Yagi, H., Nomura, T., Nakamura, K. et al. (2004) Crucial role of FoxP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 16, 1643–56. Yazdanbakhsh, M., Kremsner, P.G. & van Ree, R. (2002) Allergy, parasites, and the hygiene hypothesis. Science 296, 490–4. Ying, S., Durham, S.R., Corrigan, C.J., Hamid, Q. & Kay, A.B. (1995) Phenotype of cells expressing mRNA for Th2-type (interleukin-4 and interleukin-5) and Th1-type (interleukin-2 and interferongamma) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatics and normal control subjects. Am J Respir Cell Mol Biol 12, 477–87. Ying, S., Humbert, M., Barkans, J. et al. (1997) Expression of IL-4 and IL-5 mRNA and protein product by CD4+ and CD8+ T cells, eosinophils and mast cells in bronchial biopsies obtained from atopic and non-atopic (intrinsic) asthmatics. J Immunol 158, 3539–44. Ying, S., Meng, Q., Kay, A.B. & Robinson, D.S. (2002) Elevated expression of interleukin-9 mRNA in the bronchial mucosa of atopic asthmatics and allergen-induced cutaneous late-phase reaction: relationships to eosinophils, mast cells and T lymphocytes. Clin Exp Allergy 32, 866–71. Ying, S., O’Connor, B., Ratoff, J. et al. (2005) Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 174, 8183–90. Yoo, J., Omori, M., Gyamati, D. et al. (2005) Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med 202, 541–9. Zheng, W. & Flavell, R.A. (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89, 587–96. Zhou, B., Comeau, M.R., De Smedt, T. et al. (2005) Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol 6, 1047–53. Zhou, D., Mattner, J., Cantuli, C. et al. (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–9. Zhu, J., Min, B., Hu-Li, J. et al. (2004) Conditional deletion of Gata3 sshows its essential function in TH1-TH2 responses. Nat Immunol 5, 1157–65. Zhu, Z., Homer, R.J., Wang, Z. et al. (1999) Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities and eotaxin production. J Clin Invest 103, 779–88. Zuany-Amorim, C., Ruffie, C., Haile, S., Vargaftig, B.B., Pereira, P. & Pretolani, M. (1998) Requirement for gammadelta T cells in allergic airway inflammation. Science 280, 1265–7.

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Regulatory T Cells and Other Tolerogenic Mechanisms in Allergy and Asthma Catherine Hawrylowicz and Cezmi A. Akdis

Summary The induction of immune tolerance and specific immune suppression are essential processes in the control of immune responses. Regulatory T cells (Treg) play a central role in immune control in the periphery. Two broad categories of Treg have been described: naturally occurring Treg that are present in all individuals and antigen-induced Treg that secrete inhibitory cytokines such as interleukin (IL)-10 and/or transforming growth factor (TGF)-β. In allergic disease, the balance between allergen-specific Treg and disease-promoting T helper 2 (Th2) cells appears to be decisive in the development of an allergic versus a nondisease-promoting or “healthy” immune response against allergen. Treg specific for common environmental allergens represent the dominant subset in healthy individuals, arguing for a state of natural tolerance to allergen in these individuals. In contrast, there is a high frequency of allergenspecific Th2 cells in allergic individuals. Treg function appears to be impaired in active allergic disease. Both allergen-specific immunotherapy and certain nonspecific therapies, such as glucocorticoids, enhance Treg function. For example, induction of IL-10- and TGF-β-producing Treg cells, IgG4 isotype blocking antibodies, and suppression of mast cells, basophils and eosinophils represent major components of a relatively normalized immune response after allergen-specific immunotherapy. Through the application of recent advances in our knowledge of Treg biology and related mechanisms of peripheral tolerance, the hope is that more rational and safer approaches for improved prevention and cure of allergic diseases will emerge.

Prevention of the development of allergic responses Many common biological mechanisms are likely to exist to prevent immune responsiveness to innocuous substances or allergens in our environment and to self-antigens, for which an extensive literature exists (Hogquist et al. 2005). While the Allergy and Allergic Diseases, 2nd edition. Edited by A.B. Kay, A.P. Kaplan, J. Bousquet, P.G. Holt. © 2008 Blackwell Publishing. ISBN: 978-1-405-15720-9.

majority of autoreactive T cells undergo selection and clonal deletion in the thymus (central tolerance), a minority escape and are detectable in the periphery. The importance of thymic selection in control of immune responses to allergen is unclear since allergens themselves are unlikely to be present at the time of thymic selection, although negative selection on some cross-reactive determinants may occur. Additional immunologic controls are therefore in place to eliminate or inactivate potentially hazardous effector cells that emerge from the thymus into the periphery. Allergens themselves are often not highly immunogenic compounds. Many allergens enter the body via the respiratory tract or the gut which, unlike other routes of immunization, in the steady state generally results in the induction of tolerance (Macaubas et al. 2003). In addition to this, specialized T-cell subsets, broadly termed regulatory T cells (Treg), play an essential and protective role in immune suppression in the periphery. This review focuses on the evidence that Treg cells play a central role in the prevention of disease-promoting allergen-specific Th2 responses in health, that Treg function may be impaired in allergic disease, and how therapeutic strategies aim to restore, boost and/or induce de novo Treg activity.

Regulatory T cells (Fig. 4.1) The existence of suppressor cells, which limit ongoing immune responses and prevent autoimmune disease, was postulated over 30 years ago (Gershon 1975). The recent phenotypic and functional characterization of these cells has led to a resurgence of interest in their therapeutic application in a number of immune-mediated diseases. Two broad subsets of CD3+CD4+ suppressive or Treg cells have been described: constitutive or naturally occurring versus adaptive or inducible Treg. Subsets of Treg cells and their suppressor mechanisms are shown in Table 4.1. There are other Treg populations, including CD8+ Treg cells with the reported capacity to both inhibit and exacerbate allergic airway disease (Stock et al. 2004a; Noble et al. 2006). In addition, double-negative (CD4− CD8−) T-cell receptor (TCR)αβ+ Treg cells that mediate tolerance in several experimental autoimmune diseases (Strober

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Fig. 4.1 Suppression of Th2 and Th1 cell-mediated features of allergic inflammation by Treg cells. Treg cells utilize multiple suppressor factors to regulate undesired activity of effector Th2 cells. Interleukin (IL)-10 and transforming growth factor (TGF)-b suppress IgE production and induce noninflammatory immunoglobulin isotypes IgG4 and IgA, respectively. Furthermore, these two cytokines directly suppress allergic inflammation induced by effector cells such as mast cells, basophils, and eosinophils. In addition, Th2 cells are suppressed by Treg cells and can therefore no longer provide cytokines such as IL-3, IL-4, IL-5, IL-9, and IL-13. These c