Roitt’s Essential Immunology Peter J. Delves Professor Delves obtained his PhD from the University of London in 1986 and is a Professor of Immunology at UCL (University College London). His research has focused on molecular aspects of antigen recognition. He has authored and edited a number of immunology books, and teaches the subject at a broad range of levels. Seamus J. Martin Professor Martin received his PhD from Th e National University of Ireland in 1990 and trained as a post - doctoral fellow at University College London (with Ivan Roitt) and Th e La Jolla Institute for Allergy and Immunology, California, USA (with Doug Green). Since 1999, he is the holder of the Smurfi t Chair of Medical Genetics at Trinity College Dublin and is also a Science Foundation Ireland Principal Investigator. His research is focused on various aspects of programmed cell death (apoptosis) in the immune system and in cancer and he has received several awards for his work in this area. He has previously edited two books on apoptosis and was elected as a Member of Th e Royal Irish Academy in 2006 and as a member of Th e European Molecular Biology Organisation (EMBO) in 2009. Dennis R. Burton Professor Burton obtained his BA in Chemistry from the University of Oxford in 1974 and his PhD in Physical Biochemistry from the University of Lund in Sweden in 1978. After a period at the University of Sheffi eld, he moved to the Scripps Research Institute in La Jolla, California in 1989 where he is Professor of Immunology and Molecular Biology. His research interests include antibodies, antibody responses to pathogens and vaccine design, particularly in relation to HIV. Ivan M. Roitt Professor Roitt was born in 1927 and educated at King Edward ’ s School, Birmingham and Balliol College, Oxford. In 1956, together with Deborah Doniach and Peter Campbell, he made the classic discovery of thyroglobulin autoantibodies in Hashimoto ’ s thyroiditis which helped to open the whole concept of a relationship between autoimmunity and human disease. Th e work was extended to an intensive study of autoimmune phenomena in pernicious anaemia and primary biliary cirrhosis. In 1983 he was elected a Fellow of Th e Royal Society, and has been elected to Honorary Membership of the Royal College of Physicians and appointed Honorary Fellow of Th e Royal Society of Medicine. TWELFTH EDITION Roitt’s Essential Immunology Peter J. Delves PhD Division of Infection and Immunity UCL London, UK Seamus J. Martin PhD, FTCD, MRIA Th e Smurfi t Institute of Genetics Trinity College Dublin, Ireland Dennis R. Burton PhD Department of Immunology and Molecular Biology Th e Scripps Research Institute La Jolla, California, USA Ivan M. Roitt MA, DSc(Oxon), FRCPath, Hon FRCP (Lond), FRS Centre for Investigative and Diagnostic Oncology Middlesex University London, UK A John Wiley & Sons, Ltd., Publication Th is edition fi rst published 2011 © 1971, 1974, 1977, 1980, 1984, 1988, 1991, 1994, 1997, 2001, 2006 by Peter J Delves, Seamus J. Martin, Dennis R. Burton, Ivan M. Roitt Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientifi c, Technical and Medical business to form Wiley-Blackwell. 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Th e 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 c reated 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 Roitt’s essential immunology / Peter J. Delves ... [et al.]. – 12th ed. p. cm. – (Essentials ; 16) Rev. ed. of: Roitt’s essential immunology / Ivan M. Roitt, Peter J. Delves. Includes bibliographical references and index. ISBN 978-1-4051-9683-3 (pbk.) 1. Immunology. I. Delves, Peter J. II. Roitt, Ivan M. (Ivan Maurice) Roitt’s essential immunology. III. Title: Essential immunology. QR181.R57 2011 616.07'9–dc22 2010047392 A catalogue record for this book is available from the British Library. Set in 10/12 pt Adobe Garamond Pro by Toppan Best-set Premedia Limited 1 2011 Contents Acknowledgments vi Preface vii Abbreviations viii How to get the best out of your textbook xii PART 1: Fundamentals of Immunology 1. Innate immunity 3 2. Specifi c acquired immunity 35 3. Antibodies 53 4. Membrane receptors for antigen 79 5. The primary interaction with antigen 113 6. Immunological methods and applications 141 7. The anatomy of the immune response 188 8. Lymphocyte activation 205 9. The production of effectors 226 10. Control mechanisms 263 11. Ontogeny and phylogeny 283 PART 2: Applied Immunology 12. Adversarial strategies during infection 313 13. Vaccines 345 14. Immunodefi ciency 369 15. Allergy and other hypersensitivities 394 16. Transplantation 423 17. Tumor immunology 445 18. Autoimmune diseases 475 Glossary 511 Index 522 Companion website www.roitt.com Acknowledgments Th e input of the editorial team of Elizabeth Johnston, Laura Murphy and Cathryn Gates at Wiley - Blackwell and the project management of Ruth Swan is warmly acknowledged. We are much indebted to the co - editors of Immunology, J. Brostoff , D. Roth and D. Male, together with the publishers, Mosby, and the following individuals for permission to utilize or modify their fi gures: J. Brostoff and A. Hall for fi gure 15.11 ; J. Horton for figure 11.19 ; a nd J. Taverne for fi gures 12.23 and 12.24 . I MR would like to acknowledge the indefatigable secretarial assistance of Christine Griffi n. DRB wishes to particularly acknowledge the invaluable contributions of Amandeep Gakhal, Erin Scherer, Rena Astronomo and Wendelien Oswald. He is grateful to Jenny Woof, Ann Feeney, Beatrice Hahn, Jim Marks, Don Mosier, Paul Sharp, Robyn Stanfi eld, James Stevens and Mario Stevenson for many very helpful comments. PJD would particularly like to thank Per Brandtzaeg, Volker Brinkmann, Greg Campbell, Peter Lydyard, Rand Swenson and Ulrich Wahn. SJM is indebted to Ed Lavelle, Sean Cullen, Cristina Munoz - Pinedo and all of the members of his laboratory for comments, suggestions and support. He would also like to thank Mia, Madeleine and Jamie for their support and indulgence. Every eff ort has been made by the authors and the publisher to contact all the copyright holders to obtain their permission to reproduce copyright material. However, if any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the fi rst opportunity. A number of scientists very generously provided illustrations for inclusion in this edition, and we have acknowledged our gratitude to them in the relevant fi gure legends. Companion website Th is book is accompanied by a companion website: w ww.roitt.com Th e website includes: • Interactive MCQs and SBA questions for each chapter, with feedback on all answers selected • Animations and videos showing key concepts • Fully downloadable fi gures and illustrations, further reading and useful links • Extracts from the Encyclopaedia of Life Sciences • Podcasts to reinforce the key principles explained in the text: ideal for revision ‘ o n the go ’ Preface W elcome to this new edition! When Ivan wrote the fi rst edition some 40 years ago, he wanted to feel that he was chatting to the reader almost informally, rather than preaching, and it has been our intention to maintain this style. As a subject, immunol- ogy is exciting and dynamic and to persuade you that it is absolutely worthwhile for you to tackle this new edition we have made very extensive changes to update the previous edition. Accordingly, apart from the introduction of numerous new illustra- tions, we have: ■ Expanded discussion of pathogen - and danger - associated molecular patterns (PAMPs & DAMPs) ■ Introduced a new section on dendritic cells and their role in antigen processing including cross - presentation ■ Updated sections on B - cell and NK receptors ■ Enhanced discussion of lymphocyte traffi cking ■ Incorporated the latest fi ndings on T - cell subsets, particularly Th 17 and the diversity of regulatory T - cells ■ Recorded newer information on NK and cytotoxic T - cell killing mechanisms ■ Given more insight into the eff ects of aging on immune responses ■ Carried out a major rewrite of the vaccine chapter with new emphasis on mechanisms of action of conventional and carbo- hydrate vaccines, and new approaches to vaccine development including reverse vaccinology, together with progress in malaria vaccines and adjuvant action ■ P rovided new information on novel genetic immunodefi ciency defects, on the origin of AIDS and the ever- e xpanding plethora of AIDS drugs plus results from the latest HIV vaccine trials ■ Clarifi ed the recent fi ndings on the cellular transformations leading to cancer, the manipulation of the immune system by tumors and the links between infection, infl ammation and cancer ■ Substantially rewritten the chapter on autoimmune diseases. It is our fond expectation that you will enjoy and benefi t from a reading of our off ering. Peter J. Delves Seamus J. Martin Dennis R. Burton Ivan M. Roitt Abbreviations AAV adeno - associated virus CMV cytomegalovirus Ab antibody Cn complement component “ n ” AChR acetylcholine receptor Cn activated complement component “ n ” ACT adoptive cell transfer iCn inactivated complement component “ n ” ACTH adrenocorticotropic hormone Cna small peptide derived by proteolytic ADA adenosine deaminase activation of Cn ADCC antibody - dependent cellular cytotoxicity CpG cytosine phosphate - guanosine dinucleotide AEP asparagine endopeptidase motif Ag antigen CR(n) complement receptor “ n ” AID activation- induced cytidine deaminase CRP C - reactive protein AIDS acquired immunodefi ciency syndrome CSF cerebrospinal fl uid AIRE autoimmune regulator CSR class switch recombination ALBA addressable laser bead assay CTLR C - type lectin receptor ANCA antineutrophil cytoplasmic antibodies D gene diversity minigene joining V and J APC antigen - presenting cell segments to form variable region ARRE - 1 antigen receptor response element - 1 DAF decay accelerating factor ARRE - 2 antigen receptor response element - 2 DAG diacylglycerol ART antiretroviral therapy DAMP danger - associated molecular pattern ASFV African swine fever virus DC dendritic cells AZT zidovudine (3 ′ - azido - 3 ′ - deoxythymidine) DMARD disease - modifying antirheumatic drug BAFF B - cell - activating factor of the tumor DNP dinitrophenyl necrosis factor family DTH delayed - type hypersensitivity B - cell lymphocyte which matures in bone DTP diphtheria, tetanus, pertussis triple marrow vaccine BCG bacille Calmette – Gu é rin attenuated form EAE experimental autoimmune (allergic) of tuberculosis encephalomyelitis BCR B - cell receptor EBV Epstein – Barr virus BM bone marrow ELISA enzyme - linked immunosorbent assay BSA bovine serum albumin EM electron microscope BSE bovine spongiform encephalopathy E ø eosinophil Btk Bruton ’ s tyrosine kinase EPO erythropoietin BUDR bromodeoxyuridine ER endoplasmic reticulum C complement ES embryonic stem (cell) C α ( β / γ / δ ) constant part of TCR α ( β / γ / δ ) chain ET exfoliative toxins CALLA common acute lymphoblastic leukemia F(B) factor (B, etc.) antigen Fab monovalent Ig antigen - binding fragment cAMP cyclic adenosine mono phosphate after papain digestion CCP complement control protein repeat F(ab ′ ) divalent antigen - binding fragment after 2 CD cluster of diff erentiation pepsin digestion CDR complementarity determining regions of Ig FasL Fas - ligand or TCR variable portion FACS fl uorescence - activated cell sorter CEA carcinoembryonic antigen Fc Ig crystallisable - fragment originally; now CFA complete Freund ’ s adjuvant non - Fab part of Ig cGMP cyclic guanosine monophosphate Fc γ R receptor for IgG Fc fragment ChIP chromatin immunoprecipitation FDC follicular dendritic cell CHIP chemotaxis inhibitory protein fl t - 3 fl k - 2 ligand C constant part of Ig heavy (light) chain (sc)Fv (single chain) V – V antigen binding H(L) H L CLA cutaneous lymphocyte antigen fragment CLIP class II - associated invariant chain peptide GADS GRB2 - related adapter protein CMI cell - mediated immunity g.b.m. glomerular basement membrane CML cell - mediated lympholysis G - CSF granulocyte colony - stimulating factor