Eales - immunology for life scientists 2003

IMMUNOLOGY for Life Scientists SECOND EDITION LESLEY-JANE EALES University of Surrey, Guildford, UK Copyright u 2003 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777 First Edition published 1997 Reprinted October 1997, January 1999, May 2001 Email (for orders and customer service enquiries): cs-books@wiley.co.uk Visit our Home Page on www.wileyeurope.com or www.wiley.com 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, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1T 4LP, UK, without the permission in writing of the Publisher. 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Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 33 Park Road, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 22 Worcester Road, Etobicoke, Ontario, Canada M9W 1L1 Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Library of Congress Cataloging-in-Publication Data Eales, Lesley-Jane. Immunology for life scientists / Lesley-Jane Eales. – 2nd ed. p. cm. Includes bibliographical references and index. ISBN 0-470-84523-6 (cloth : alk. paper) – ISBN 0-470-84524-4 (pbk. : alk. paper) 1. Immunology. 2. Immunopathology. 3. Immunity. I. Title. QR181.E24 2003 616.07’9–dc21 2003050184 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0 470 84523 6 ISBN 0 470 84524 4 (pbk) Typeset in Times 11/13pt by Dobbie Typesetting Ltd, Tavistock, Devon Printed and bound in Great Britain by T J International, Padstow, Cornwall This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production. DEDICATION For my dad who gave me patience and for Scott who taught me the skills CONTENTS Preface to the 2nd edition xvii Preface to the 1st edition xix Glossary xxi 1 Cells and tissues of the immune system 1 1.1 Cells involved in the immune response 1 1.1.1 Cellular origins – the pluripotent stem cell 2 1.1.2 Cells principally involved in the innate immune response 4 Polymorphonuclear leukocytes 4 Neutrophils 4 Eosinophils 5 Basophils and mast cells 6 Megakaryocytes and platelets 9 1.1.3 Antigen presenting cells and large granular lymphocytes 10 Monocytes and macrophages 1 0 Dendritic cells 11 Large granular lymphocytes 12 1.1.4 Cells involved in the specific immune response 13 Lymphocytes 13 Tcells 15 Bcells 16 Key points for review 18 1.2 Lymphoid tissues 18 1.2.1 Primary lymphoid tissues 19 The thymus 19 Mammalian ‘‘bursa equivalents’’ 21 B cell development in the bone marrow 21 1.2.2 Secondary lymphoid tissues 21 Thelymphaticsystem 21 Lymph nodes 23 Spleen 24 1.2.3 Tertiary lymphoid tissues 24 Mucosa-associated lymphoid tissue 24 Intraepithelial lymphocytes 25 Key points for review 25 Bibliography 26 Now test yourself! 26 2 Antigens and their receptors 29 2.1 Characteristics of antigens and immunogens 30 2.1.1 Factors affecting immunogenicity 30 Foreignness 30 Size 31 Chemical complexity 31 Route of administration 31 Dose 31 Host genetic make-up 32 Approaches used to increase immunogenicity 32 Key points for review 33 2.2 The major histocompatibility complex 33 2.2.1 Class I MHC molecules 35 2.2.2 Class II MHC molecules 37 2.2.3 Non-classical HLA molecules 39 Key points for review 39 2.3 Antigen receptors on cells 40 2.3.1 The B cell antigen receptor 40 Immunoglobulins 41 Antibody structure 42 Isotypes 44 Allotypes 45 Idiotypes 45 2.3.2 Antibody classes 46 Immunoglobulin G 46 Immunoglobulin M 46 Immunoglobulin A 47 Immunoglobulin D 49 Immunoglobulin E 49 2.3.3 Antibody function 49 2.3.4 Fc receptors 50 2.3.5 The T cell antigen receptor 50 gdTcells 52 The CD3 complex 52 Function of the TCR-CD3 complex 54 2.3.6 The natural killer cell receptor 55 Key points for review 56 2.4 Generation of antigen receptor diversity 57 2.4.1 Theories concerning antibody diversity 57 2.4.2 The genetic basis of antibody diversity 58 V, D and J region heavy chain genes 58 The light chain V and J genes 59 2.4.3 Generation of antibody diversity 59 Combinatorial and junctional diversity 60 Control of VDJ gene rearrangement 61 Mechanisms of V(D)J rearrangement 61 viii CONTENTS Diversity due to somatic mutation 61 2.4.4 Antibody maturation 63 2.4.5 Genetic basis of T cell antigen receptor diversity 63 ‘‘Similarity to self rule’’ – limited diversity 63 Diverse TCR repertoire 64 Genomic organisation – the TCRa chain 65 Genomic organisation – the TCRb chain 65 Genomic organisation – the TCRg chain 65 Genomic organisation – the TCRd chain 66 2.4.6 Generation of T cell antigen receptor diversity 66 Size of the T cell repertoire 66 Key points for review 67 Bibliography 67 Now test yourself! 68 3 The innate immune response 74 3.1 The complement cascades 75 3.1.1 The classical complement pathway 75 C1 76 C4 77 C2 77 C3 77 3.1.2 The alternative complement pathway 79 3.1.3 The lectin pathway 81 3.1.4 The membrane attack complex 82 3.1.5 Regulation of complement activation 83 C1 inhibitor (C1INH) 84 Regulators of complement activation (RCA) family 84 Regulators of the membrane attack complex 85 Key points for review 85 3.2 Phagocytosis 86 3.2.1 Pattern recognition receptors 86 Complement receptor 3 (CR3) 87 CD14 87 Toll-like receptors 87 Macrophage scavenger receptors 88 3.2.2 Opsonisation 90 3.2.3 Ingestion 90 3.2.4 Digestion 92 3.2.5 The respiratory burst 94 3.2.6 Other antimicrobial activities of lysosomes 95 Defensins 96 Key points for review 96 3.3 Inflammation 97 3.3.1 Inflammatory mediators 98 3.3.2 Cellular responses in inflammation 99 3.3.3 Chemokines 102 Key points for review 104 CONTENTS ix 3.4 Haemostasis and thrombosis 104 3.4.1 Regulation of coagulation 105 3.4.2 The fibrinolytic system 106 Key points for review 106 Bibliography 107 Now test yourself! 108 4 The adaptive immune response 112 4.1 Antigen processing and presentation by MHC gene products 112 4.1.1 Generation of peptides presented by MHC Class I molecules 113 Assembly and intracellular transport of MHC Class I molecules 113 4.1.2 Generation of peptides presented by MHC Class II molecules 114 Assembly and intracellular transport of MHC Class II molecules 115 Key points for review 116 4.2 Antigen processing and presentation by CD1 117 4.2.1 Structure of CD1 117 4.2.2 Antigen presentation by CD1 117 Key points for review 118 4.3 Cell-mediated immunity 118 4.3.1 Antigen-specific T cell stimulation 118 T cell responses to antigen stimulation 119 Th 0 ,Th 1 and Th 2 cells 122 4.3.2 Other cells in cell-mediated immunity 123 Mechanisms of target cell death 125 Cytotoxic T cells 126 Macrophages 126 NK cells 128 Key points for review 129 4.4 B cell adaptiv e immunity 129 4.4.1 B cell differentiation and antibody production 130 Class switching 132 Key points for review 133 4.5 Lymphocyte memor y 134 Key points for review 136 4.6 The mucosal immune response 137 4.6.1 Structure of the mucosal immune system 137 Organised mucosal lymphoid tissue 138 Intraepithelial cells 139 Leukocytes in the lamina propria 139 4.6.2 Immunoglobulins and mucosal immunity 139 Production of other immunoglobulins in the mucosa 140 4.6.3 The mucosae and their role in immunity 140 Key points for review 140 4.7 Tolerance 141 x CONTENTS 4.7.1 Lymphocyte tolerance 141 Induction time 142 Antigen dose 143 Antigen persistence 144 Specificity 144 Duration 144 Route of administration 145 Tissue specificity 145 4.7.2 Mechanisms of tolerance induction 146 Clonal deletion 147 Clonal anergy 148 Clonal exhaustion 149 Clonal abortion 150 Antibody forming cell (AFC) blockade 150 4.7.3 Maintenance of tolerance 150 Regulatory T cells 150 Antibody-induced tolerance 151 4.7.4 Mechanisms involved in the development of incomplete tolerance 151 Key points for review 151 Bibliography 153 Now test yourself! 154 5 Abnormal it ies of the immun e sys tem 159 5.1 Hypersensitivity 159 5.1.1 Hypersensitivity reactions 160 5.1.2 Type I hypersensitivity 160 Regulation of type 1 hypersensitivity 161 Humoral events in allergy 163 5.1.3 Type II hypersensitivity 164 5.1.4 Type III hypersensitivity 165 5.1.5 Type IV hypersensitivity 166 Tuberculin-type DTH 167 Granuloma formation 168 Contact hypersensitivity 168 Key points for review 169 5.2 Autoimmunity and autoimmune diseases 170 5.2.1 Causes of autoimmunity 170 Genetic factors in autoimmune disease 171 Sex-linked factors in autoimmune disease 172 Stress and neurochemicals in autoimmune disease 172 Chemicals and pharmaceuticals in autoimmune disease 172 Viruses in autoimmune disease 172 Antigen mimicry 173 5.2.2 Classification of autoimmune disease 175 5.2.3 Immunopathology of autoimmune diseases 176 5.2.4 The immunology of autoimmune disease 176 Target antigens 177 CONTENTS xi Non-specific immunity in autoimmune disease 177 Mononuclear phagocytes in non-specific immunity 178 Mononuclear phagocytes in specific immunity 178 Dentritic cells in autoimmune disease 179 Role of T cells in autoimmune disease 179 B cells in autoimmune disease 180 Cytokine defects 182 Chemokines in autoimmune disease 182 Key points for review 182 5.3 Immunodeficiency diseases 183 5.3.1 Classification of immunodeficiency diseases 184 5.3.2 Primary immunodeficiency diseases 185 5.3.3 B cell abnormalities 185 Selective immunoglobulin A deficiency 185 X-linked agammaglobulinaemia (XLA) 186 CD40 ligand deficiency 187 X-linked lymphoproliferative disease (Duncan’s syndrome) 187 5.3.4 T cell abnormalities 188 Congenital thymic aplasia (Di George syndrome) 188 Wiskott–Aldrich syndrome 189 5.3.5 T and B cell abnormalities 190 Severe combined immunodeficiency disease (SCID) 190 X-linked severe combined immunodeficiency (XSCID) 190 SCID with adenosine deaminase deficiency (ADA-SCID) 192 The bare lymphocyte syndrome 192 5.3.6 Abnormalities associated with phagocytic cells 192 Chediak–Higashi syndrome (CHS) 192 Chronic granulomatous disease (CGD) 193 5.3.7 Abnormalities of the complement pathway 194 Deficiencies of complement components 194 The alternative pathway 195 The classical pathway 195 C1INH defici ency – hereditary angioede ma (H A E) 195 5.3.8 Acquired immunodeficiencies 196 Iatrogenic immunodeficiencies 196 5.3.9 The acquired immunodeficiency syndrome (AIDS) 197 The human immunodeficiency virus (HIV) 198 Key points for review 201 Bibliography 202 Now test yourself! 204 6 Infection, immunity, immunopathogenesis 209 6.1 The innate immune system in infection 210 6.1.1 The skin 210 6.1.2 The mucosae 211 6.1.3 Protective chemicals 211 Lysozyme 211 Alimentary fluids 212 xii CONTENTS Complement 212 Defensins 212 Natural antibodies 213 6.1.4 The role of normal body flora 214 Key points for review 214 6.2 Infection – the role of the innate immune system 214 6.2.1 Attachment 215 6.2.2 The body’s response to invasion – fever 215 6.2.3 Cells involved in innate immunity in infection 216 Phagocytic cells 216 Natural killer cells 218 Platelets 220 6.2.4 Inflammation and immunopathology 221 Endotoxin 221 Endotoxin-induced injury 222 Key points for review 222 6.3 Infection – the role of the specific immune response 223 6.3.1 Intracellular pathogens and fungi 223 6.3.2 Parasitic infections 223 6.3.3 The role of antibody in immunity to infection 224 Opsonisation 224 Complement activation 225 Inhibition of adherence 225 Toxin neutralisation 225 Virus neutralisation 226 Inhibition of microbial enzyme activity 226 Inhibition of microbial growth 226 6.3.4 Pathology due to specific antibody 226 Polyclonal B cell activation 226 Immune complex formation 227 6.3.5 T cell-mediated immunity 229 Parasitic infections 230 Viral infections 230 Th 1 and Th 2 cells 230 Cytotoxic T cell activity 231 Cytolytic mechanisms 232 6.3.6 Pathology caused by the cell-mediated immune response 234 Key points for review 236 6.4 Cytokines in immunity to infection 236 Key points for review 239 Bibliography 239 Now test yourself! 240 7 Immunity and the MHC 243 7.1 Transplantation 243 7.1.1 Tissue typing 244 7.1.2 Cross-matching 244 7.1.3 Rejection 245 CONTENTS xiii [...]... to visit the site on a regular basis as it will be constantly updated with new information and useful material L.-J E Supplementary material can be obtained from www.wiley.co.uk/ealesimmunology PREFACE TO THE 1ST EDITION Immunology for Life Scientists is, as its title suggests, a textbook for students who are studying immunology as part of another degree course If you consider how we first begin to... section, try the self-assessment programme that you can download from the web site Do not try and cover too much new ground at one go! 1.1 CELLS INVOLVED IN THE IMMUNE RESPONSE For many years, the immune response has been described as comprising the non-specific or innate response and the acquired or specific response The innate Immunology for Life Scientists, Second Edition Lesley-Jane Eales & 2003 John Wiley... precursor mast cells proliferate, and differentiate into either mucosa-associated mast cells (MMC) or connective tissue mast cells (CTMC) 8 IMMUNOLOGY FOR LIFE SCIENTISTS CELLS AND TISSUES OF THE IMMUNE SYSTEM 9 Figure 1.3 Involvement of mast cells and basophils in antibody-mediated response to allergen Antibody (IgE) binds to specific receptors on mast cells and basophils When cross-linked by allergen,... be life- threatening Antibody: A globular, serum protein formed in response to stimulation with an immunogen They are capable of highly specific discrimination between xxii GLOSSARY antigens and perform a variety of biological functions They may also be found on the surface of B cells as part of the B cell antigen receptor (see BCR) Antibody-dependent cellular cytotoxicity (ADCC): Cells expressing foreign... cell responsible for binding antigen and signalling the fact to the T cell It comprises a bimolecular complex the abTCR or the gdTCR, which binds antigen and the CD3 molecular complex, which is responsible for the intracellular signalling T-dependent antigen: An antigen that depends upon the activation of effector T cells for the production of cytokines required for B cell activation, proliferation and... tissues of the body and comprise only 4% of the white cells in the blood Their life span is about 13 days and they are about 8 mm in diameter Differentiation of precursors in the bone marrow is influenced by the cytokines interleukin 3 (IL-3) and granulocyte–monocyte colony-stimulating factor (GM-CSF) In addition, interleukin 5 (IL-5) specifically promotes the expansion of eosinophil (and basophil) numbers... interleukin 5 (IL-5) specifically promotes the expansion of eosinophil (and basophil) numbers The release of mature eosinophils from the bone marrow reserves is promoted by both IL-5 and the chemokine known as eotaxin 6 IMMUNOLOGY FOR LIFE SCIENTISTS In early development, their nuclei are bilobed but with maturation, they can become multilobed like other polymorphs Like neutrophils, they contain intracellular... believe how much our understanding of immunology has progressed in the few short years since the first edition of this book was produced Like its predecessor, this edition is very much aimed at students who have no clinical background and no prior knowledge of immunology It is for students who are doing immunology as part of another discipline such as biomedical scientists and is strictly designed to... carboxypeptidase, cathepsin G Basogranin MCTC only Basophils only 1^30 minutes Leukotriene C4 (LTC4) Prostaglandin D2 (PGD2) MC and basophils MC Minutes to hours IL-5, 6, 8, 16,TNFa, monocyte chemotactic protein-1 (MCP-1), monocyte inhibitory protein1a(MIP-1a) IL-4, 13 MC and basophils MC MC MC and basophils MEGAKARYOCYTES AND PLATELETS Megakaryocytic progenitor cells are derived from haematopoietic stem cells... is maintained in the bone marrow to replenish stocks in the blood when required This may be controlled by the lymphokine interleukin 3 (IL-3), a potent stimulator of megakaryocyte progenitor cells Megakaryocytes give rise to platelets by a 10 IMMUNOLOGY FOR LIFE SCIENTISTS process that appears to involve cytoplasmic fragmentation of the cell Platelet production depends on the number and size of megakaryocytes