Immunology: An Illustrated Outline [6 ed.] 0367684640, 9780367684648, 9780367681395, 9781003137658

Table of contents :
Cover
Half Title
Title Page
Copyright Page
Preface
Contents
Index of Terms
Chapter 1: The Immune System
Introduction
Lymphocytes
Innate lymphoid cells
Markers
Antigen-presenting cells
Phagocytes and auxiliary cells
Lymphoid system
Leukocyte development
Thymus and T-cell development
Lymph nodes
Spleen
Gut-associated lymphoid tissue (GALT)
Chapter 2: Immune Recognition
Antigen receptors
Antibody structure
Antibody-structural variations
Antibody functions
Antibody genes
Antibody biotechnology
Immunotherapeutic agents
Antigen-antibody interaction
T-cell antigen receptor (TCR)
T-cell receptor genes
MHC molecules
MHC genes
Immune recognition by NK cells
Innate immune recognition
Chapter 3: Immune Responses
Adaptive and innate immunity
Antibody response
Cell cooperation
Antigen presentation
T-cell activation
B-cell activation
Cytokines and cytokine receptors
Phagocytosis
Complement receptors
Fc receptors
Phagocyte microbicidal systems
Intracellular receptors for pathogens
Cytotoxicity
Inflammation
Mechanisms of cell migration
Chemokines and chemokine receptors
Complement
Immunoregulation
Neuroendocrine regulation
Tolerance
Genetic polymorphism in the immune response
Immunosuppression
Immunopotentiation
Vaccines
Chapter 4: Immunopathology
Immunodeficiency
Transplantation
MHC disease associations
MHC typing
Autoimmune disease
Animal models and mutant strains
Hypersensitivity
Type I (immediate) hypersensitivity
Type II (antibody-mediated) hypersensitivity
Type III (immune-complex-mediated) hypersensitivity
Type IV (delayed) hypersensitivity (DTH)
Chapter 5: Immunological Techniques
Antibodies and antigens
Clones and cell lines
Isolation of cells
Cellular functions

Citation preview

Immunology An Illustrated Outline

Immunology An Illustrated Outline Sixth Edition

David Male

CRC Press Boca Raton and London Sixth edition published 2021 by CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 and by CRC Press 2 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN © 2021 Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, LLC The right of David Male to be identified as author of this work has been asserted by him in accordance with sections 77 and 78 of the Copyright, Designs and Patents Act 1988. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact mpkbookspermissions@ tandf.co.uk Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. ISBN: [978-0-367-68464-8] (hbk) ISBN: [978-0-367-68139-5] (pbk) ISBN: [978-1-003-13765-8] (ebk) Typeset in Helvetica by KnowledgeWorks Global Ltd.

Preface This book serves three different functions. It provides a concise overview of basic immunology for readers who have not studied the subject previously, but need an understanding of the subject to support undergraduate or postgraduate work. It can also be used as a reference for science and medical students who have studied immunology, but require a refresher on specific content or to aid revision for exams. Finally, the book can be used as a dictionary of immunological terms. Readers who already know some immunology and require a summary of particular aspects should consult the contents pages. The book is divided into five sections, each of which contains a number of related topics that are generally set out on double-page spreads. These topics are arranged in a logical sequence, so that Sections 1–3 are a short course in basic immunology, Section 4 provides the basis for clinical immunology, and Section 5 outlines important immunological techniques. To use the book as a dictionary, look up the word or abbreviation in the “Index of Terms.” This gives a single page number where a definition of the word will be found; associated terms can be found on the same page. Page references to particular topics set out over several pages are indicated in bold. Items found as entries in tables are given in italics. This edition of the book has been fully revised to highlight the latest understanding of the subject, particularly in the areas of therapeutic antibodies, innate immune defenses, and control of immune responses. Naturally, a book of this kind cannot include everything of interest to immunologists. I have tried to cover all essential areas of the subject, but I should be pleased to know when readers consider that particular subjects deserve further coverage. I am most grateful to colleagues, acknowledged in the figure legends, who have allowed me to use micrographs or photographs. For this edition, I am very pleased to have worked with a new editorial team, including Jo Koster and Jordan Wearing at CRC Press/ Taylor & Francis and I also thank the illustrator, Nigel Orme.

Contents Index of Termsix

Chapter 1  The Immune System Introduction2 Lymphocytes4 Innate lymphoid cells8 Markers9 Antigen-presenting cells12 Phagocytes and auxiliary cells14 Lymphoid system16 Leukocyte development18 Thymus and T-cell development20 Lymph nodes22 Spleen24 Gut-associated lymphoid tissue (GALT)25

Chapter 2  Immune Recognition Antigen receptors26 Antibody structure28 Antibody-structural variations30 Antibody functions32 Antibody genes34 Antibody biotechnology38 Immunotherapeutic agents39 Antigen-antibody interactions40 T-cell antigen receptor (TCR)42 T-cell receptor genes43 MHC molecules44 MHC genes46 Immune recognition by NK cells48 Innate immune recognition50

Chapter 3  Immune Responses Adaptive and innate immunity54 Antibody response56 Cell cooperation58 Antigen presentation60 T-cell activation64

viii B-cell activation67 Cytokines and cytokine receptors70 Phagocytosis76 Complement receptors78 Fc receptors79 Phagocyte microbicidal systems80 Intracellular receptors for pathogens83 Cytotoxicity84 Inflammation87 Mechanisms of cell migration90 Chemokines and chemokine receptors94 Complement96 Immunoregulation100 Neuroendocrine regulation103 Tolerance104 Genetic polymorphism in the immune response106 Immunosuppression108 Immunopotentiation110 Vaccines111

Chapter 4  Immunopathology Immunodeficiency112 Transplantation116 MHC disease associations118 MHC typing120 Autoimmune disease121 Animal models and mutant strains124 Hypersensitivity126 Type I (immediate) hypersensitivity128 Type II (antibody-mediated) hypersensitivity130 Type III (immune-complex-mediated) hypersensitivity132 Type IV (delayed) hypersensitivity (DTH) 134

Chapter 5  Immunological Techniques Antibodies and antigens136 Clones and cell lines146 Isolation of cells148 Cellular functions150

Index of Terms Note: Bold page numbers identify topics set out on several pages; roman page numbers identify entries in the text, including definitions; italic page numbers indicate additional information in tables or figures. 12/23 rule  34

A

Ab (antibodies)  27 Abatercept  39 ABO blood group system  130 Accessory cells  3 Acquired immune deficiency syndrome (AIDS)  115 Acquired (adaptive) immunity  54 Activation-induced cytidine deaminase (AID)  37 Active immunization  57 Acute-phase proteins  54 Acute rejection  117 ADAMs  82 Adaptive immunity  54–55 ADCC (antibody-dependent cell mediated cytotoxicity)  85 Addison’s disease  119 Adenoids  17 Adherence  148 Adhesion  58 Adhesion assays  151 Adhesion molecules  91, 93 Adjuvants  110 AFC (antibody-forming cells)  6 Afferent lymphatics  23 Affinity, antibody  40 Affinity chromatography  142 Affinity maturation  56–57 Aflibercept  39 AID (activation-induced cytidine deaminase)  37 AIDS (acquired immune deficiency syndrome)  115 AIRE (autoimmune regulator)  21 Allelic exclusion  30 Allergens  128 Allergy  128 Allotypes  31 Alternative pathway, complement  96 Amplification loop, complement  96 Amyloid-P, serum (SAP)  53 Anaphylatoxins  98 Anaphylaxis  129 Anchor residues  62 Angioedema, hereditary  98

Angiotensin-converting enzyme (CD143)  11 Animal models  124–125 Ankylosing spondylitis  119 Antibodies (Ab)  27 assays for/using  136–145 biotechnology  38 classes and subclasses  30, 33 fragments  38 functions  32–33 generation of diversity  34 structural variations  30–31 structure  28–29 synthesis  37 therapeutic  109 see also Immunoglobulins Antibody affinity  40 Antibody avidity  41 Antibody/complement depletion  148 Antibody-dependent cell-mediated cytotoxicity (ADCC)  85 Antibody-drug conjugates  39 Antibody-forming cells (AFC)  6 Antibody genes  34–37 Antibody-mediated (type II) hypersensitivity  127, 130–131 Antibody-mediated immunoregulation  101 Antibody response  56–57 Antibody therapy  39 Antibody valency  41 Antigen(s)  26 assays for/using  136–145 Antigen-antibody bond  40 Antigen-antibody interactions  40–41 Antigen presentation  58, 60–63 class I (internal) pathway  62 class II (external) pathway  61 cross-presentation  63 Antigen-presenting cells (APCs)  12–13, 13 antigen processing and presentation  60 facultative  13 Antigen processing  60 Antigen receptors 26–27

x Antigen suicide  149 Antigenic determinants (epitopes)  26 Antigenic peptides  61 Antiviral proteins  55 APCs (antigen-presenting cells)  12–13, 13 APRIL  69 Arthus reaction  133 Atacicept  39 Ataxia telangiectasia  113 Atopy  129 Attenuated live vaccines  111 Autoimmune activation  122 Autoimmune disease  121–123 Autoimmune hemolytic anemia  131 Autoimmune regulator (AIRE)  21 Autoimmunity, genetic risk factors for,  122 Autoreactive cells  122 Autoregulatory failure  123 Auxiliary cells  14–15 Avidity, antibody  41 Azathioprine  108

B

BAFF (B-cell activating factor)  69 B (complement factor)  99 B cell(s)  6 antigen presentation  13 development  23 B-cell activation  67–69 B-cell activating factor (BAFF)  69 B-cell co-receptor complex  69 B-cell receptor  27 B-cell tolerance  104 B1 cells  6 B2 cells  6 B7  65 B7-1 (CD80)  11, 65 B7-2 (CD86)  11, 65 Bacillus Calmette-Guérin (BCG)  110 Bacterial endocarditis  133 BALT (bronchus-associated lymphoid tissue)  17 Bare leukocyte syndrome  113 Basophils  15 BB rat  125 BCG (bacillus Calmette-Guérin)  110 Bcl-2  23 Beige mouse (Bg)  125 Belatercept  39 β1 integrin (CD29)  10 β1H (H)  99 β2 integrin (CD18)  10 β2m (β2-microglobulin)  44 Bg (beige mouse)  125

Biological response modifiers (BRMs)  110 Biotechnology, antibody  38 Biotin reagents  138 Biozzi ABH mouse  125 Biozzi mice  107 Bispecific antibodies  39 Blood groups  130 Bone marrow  18 Bordetella pertussis toxin/toxoid (PTx)  110 Bradykinin  88 BRMs (biological response modifiers)  110 Bronchus-associated lymphoid tissue (BALT)  17 Bruton’s disease  114 Buffalo rat  125 BXSB mouse  125 Bystander lysis  98

C

C genes  37 C-reactive protein (CRP)  53 C (constant) regions  29 C1inh  99 C1q/C1r/C1s  99 C2  99 C3  99 C3 convertases  96 C3a  88, 98 C3bina (I)  99 C3H/HeJ mouse  125 C4  99 C4bp  99 C5  99 C5a  94 88 C5aR (CD88)  11 C6/C7/C8/C9  99 Calnexin  62 CAMs (Cell adhesion molecules)  92 Capping  144 Capture immunoassays  137 Carriers  68 Caspases  85 Cathelicidins  81 Cationic proteins  81 CBA/N mouse  125 CCL2 (MCP-1)  88 CCL3 (MIP-1α)  88 CCL5 (RANTES)  88 CCL11 (eotaxin)  88 CCR1–CCR9  95 CD markers  9, 10–11 CD1  10, 45 CD2 (LFA-2)  10, 65 CD3  10 CD3 complex  42

xi CD4  10, 63 CD5  10 CD8  10, 63 CD11a  10 CD11a/CD18 (LFA-1)  64, 93 CD11b  10 CD11b/CD18 (CR3)  78, 93 CD11c  10 CD11c/CD18 (p150/95, CR4)  78, 93 CD13  10 CD14  10, 52 CD15 (Lewisx/sialyl Lex)  10 CD16 (FcγRIII)  10, 79 CD18 (β2 integrin)  10 CD19  10, 68–69 CD20  10 CD21 (CR2)  10, 69 CD23 (FcεRII)  10 CD25 (IL-2R α chain)  10, 74 CD28  10, 65 CD29 (β1 integrin)  10 CD30  10 CD31 (PECAM)  10, 92, 93 CD32 (FcγRII)  10, 79 CD34  10 CD35 (CR1)  10, 78 CD37  10 CD38  10 CD40  10, 68 CD40L (CD154)  11 CD43 (leukosialin)  10, 92 CD44  10, 92 CD45 (leukocyte common antigen, LCA)  10, 68 CD45R  10 CD46 (membrane cofactor protein, MCP)  10, 98 CD47  102 CD48  10 CD49a (VLA-1)  10 CD49b (VLA-2)  10 CD49c (VLA-3)  10 CD49d (VLA-4)  10, 93 CD49e (VLA-5)  10 CD49f (VLA-6)  10 CD50 (ICAM-3)  10, 64 CD53  11 CD54 (ICAM-1)  11, 92, 93 CD55 (decay-accelerating factor)  11, 98 CD56 (NCAM)  11 CD57 (HNK)  11 CD58 (LFA-3)  11, 65 CD59 (protectin)  11, 98 CD62 (selectins)  11, 92, 93 CD64 (FcγRI)  11, 79 CD68 (macrosialin)  11 CD71 (transferrin receptor)  11 CD72  69

CD73 (ecto 5′-nucleotidase)  11 CD74 (invariant chain)  11, 61 CD79ab (Igα and Igβ)  11, 27 CD80 (B7-1)  11, 65 CD81 (TAPA)  11, 68–69 CD85  11 CD86 (B7-2)  11, 65 CD87 (urokinase plasminogen activator receptor)  11 CD88 (C5aR)  11 CD89 (FcαR)  11, 79 CD90 (Thy-1)  11 CD93  78 CD94 (NKG2A)  11 CD95 (Fas)  11, 84 CD95L (CD178, Fas ligand)  11, 84 CD100  69 CD102 (ICAM-2)  11, 92, 93 CD103  11 CD105 (endoglin)  11 CD106 (VCAM-1)  11, 92, 93 CD117 (c-Kit)  19 CD143 (angiotensin-converting enzyme)  11 CD144 (VE-cadherin)  11 CD152 (CTLA-4)  11, 66 CD153  11 CD154 (CD40L)  11 CD158  11 CD159a  11 CD162 (PSGL-1)  11, 93 CD178 (Fas ligand, CD95L)  11, 84 CD200  11, 102 CD204  11 CD206 (mannose receptor)  11, 50 CD244  11 CD247  11 CD273  11 CD279 (PD1)  66 CD305  11 CDRs (complementarity-determining regions)  31 Celiac disease  119 Cell adhesion molecules (CAMs)  92 Cell cooperation  58–59, 59 Cell isolation  148 Cell lines  146–147 Cell-mediated immunity  55 Cell migration  90–93 Cell-surface markers  9 Cellular functions (assays)  150–151 Central tolerance  104 CFA (complete Freund’s adjuvant)  110 Cγ domain  29 CGD (chronic granulomatous disease)  115 CH1 domain  29 Charge neutralization  40

xii Chediak-Higashi syndrome  115 Chemokine receptors  94–95, 95 Chemokines  88, 94–95 Chemokinesis  91 Chemotaxis  91 Chimeric antibodies  38 Chlorambucil  108 Chromium release assay  151 Chronic granulomatous disease (CGD)  115 Chronic rejection  117 CL domain  29 CLA  93 Class I (internal) pathway  62 Class II (external) pathway  61 Class switching  36 Classes (isotypes), antibody  30, 33 Classical pathway, complement  96 Clonal restriction  107 Clonal selection  6 Clones  146–147 Cloning  147 Cμ domain  29 Costimulation  58 Collectins  53 Colony-stimulating factors (CSFs)  19 Combined vaccines  111 Common variable immunodeficiency (CVID)  114 Competition radioimmunoassay  137 Complement  54, 96–99 activation, control of  98 components  99 depletion  148 reaction pathways  97 Complement fixation  98 Complement fixation test  140 Complement receptors  78 Complementarity-determining regions (CDRs)  31 Complete Freund’s adjuvant (CFA)  110 Congenic strains  124 Conjugate vaccines  111 Connective tissue mast cells (CTMCs)  15 Constant (C) regions  29 Contact hypersensitivity  134 Contact residues  40 Continuous epitopes  40 Coombs tests, direct and indirect  140 Cortex lymph node  22 thymic  20 CR1 (CD35)  10, 78 CR2 (CD21)  10

CR3 (CD11b/CD18)  78, 93 CR4 (CD11c/CD18, p150/95)  78, 93 Cross-matching  117 Cross-presentation  63 Cross-reaction, antigen/antibody  41 CRP (C-reactive protein)  53 CSFs (colony-stimulating factors)  19 CTLA-4 (CD152)  11, 66 CTMCs (connective tissue mast cells)  15 Cutaneous vasculitis  133 CVID (common variable immunodeficiency)  114 CX3CL1 (fractalkine)  102 CX3CR1  95 CXCL8 (IL-8)  72, 88 CXCL10 (IP-10)  88 CXCR1–CXCR5  95 Cyclophosphamide  108 Cyclosporin-A  108 Cysteine aspartic acid proteases  85 Cytokine inhibitors, soluble  75 Cytokine receptors  70–75, 74 soluble  75 Cytokine storm  71 Cytokines  59, 70–75 B-cell development  69 leukocyte differentiation  18 Cytotoxic T cells (Tc cells)  4 Cytotoxicity  84–86 Cytotoxicity assay  151

D

D (complement factor)  99 D genes  34 DAF (decay-accelerating factor, CD55)  11, 98 Damage-associated molecular patterns (DAMPs)  50 Danger signal  100 DAMPs (damage-associated molecular patterns)  50 DBA/2 mouse  125 DC-SIGN  51 DCs (dendritic cells)  12 Decay-accelerating factor (DAF, CD55)  11, 98 Dectins  51 Defensins  81 Delayed (type IV) hypersensitivity  127, 134–135 Dendritic cells (DCs)  12 Dermatitis herpetiformis  119 Dermatomyositis  133 Desensitization  129 Diabetes, insulin-dependent  119 Diapedesis  91 DiGeorge syndrome  113

xiii Direct Coombs test  140 Direct immunofluorescence  144 Discontinuous epitopes  40 Diversity of antibody genes, generation of  34 DM molecules  61 DNA vaccines  111 Dominant idiotypes  30 Drug-induced reactions  131 Duffy blood group system  130

E

E-selectin (CD62E)  11, 93 ECP (eosinophil cationic protein)  86 Ecto 5′-nucleotidase (CD73)  11 Education of T cells  21 Efferent lymphatics  23 Eicosanoids  89 Electrophoretic mobility-shift assays (EMSA)  143 ELISA (enzyme-linked immunosorbent assay)  138 ELISPOT assays  150 EMSA (electrophoretic mobility shift assays)  143 Endocarditis, bacterial  133 Endocrine regulation  103 Endocytosis  76 Endoglin (CD105)  11 Endotoxin  110 see also Lipopolysaccharide Enhancement  117 Enzyme-linked immunosorbent assay (ELISA)  138 Eosinophil cationic protein (ECP)  86 Eosinophil-mediated cytotoxicity  86 Eosinophil peroxidase  86 Eosinophils  3, 15 Eotaxin (CCL11)  88 Epithelial cells, thymic  20 Epithelioid cells  135 Epitopes (antigenic determinants)  40 Equilibrium dialysis  140 Etanercept  39 Extended haplotype  118 External pathway, antigen presentation  61 Exudate  87

F

f-Met (formyl-methionyl) peptides  89 Fab region  29 FACS (fluorescence-activated cell sorter)  145 Facultative APCs  13 Fas (CD95)  11, 84 Fas ligand (CD178, CD95L)  11, 84

Fc fusion proteins  39 Fc receptors  79 Fc region  29 FcαR (CD89)  11, 79 FcεRI  79 FcεRII (CD23)  10, 79 FcγRI (CD64)  11, 79 FcγRII (CD32)  10, 79 FcγRIII (CD16)  10, 79 FcRn  32 FDCs (follicular dendritic cells)  13 FIA (fluorescence immunoassay)  136 Fibrinopeptides/fibrin breakdown products  88 Ficolins  53 Ficoll gradients  148 First-set rejection  116 FK506  108 Flow cytometry  145 Fluorescence-activated cell sorter (FACS)  145 Fluorescence immunoassay (FIA)  136 fMLP  89 Follicular dendritic cells (FDCs)  13 Formyl-methionyl (f-Met) peptides  89 FPIAs (fusion proteins for immune applications)  39 Fractalkine (CX3CL1)  102 Framework segments, antibody  31 Frustrated phagocytosis  77 Fusion proteins for immune applications (FPIAs)  39

G

GALT (gut-associated lymphoid tissues)  25 γδ T cells  4 Generation of diversity, antibody genes  34 Genetic polymorphism  106–107 Germinal centers  23 Giant cells  135 gld mouse  125 GlyCAM-1  93 Goodpasture’s syndrome  119, 131 Graft rejection  116 Graft-versus-host disease (GvHD)  117 Granules, phagocyte  81 Granulocytes  15 Granulomatous reactions  135 Granzymes  84 Graves’ disease  119 Gut-associated lymphoid tissues (GALT)  25 GvHD (graft-versus-host disease)  117

xiv H

H (β1H)  99 H-2  47 H-2A  47 H-2D  47 H-2E  47 H-2K  47 H-2S  47 H-2T region  47 Haptens  68 Hashimoto’s thyroiditis  119 Hassall’s corpuscles  20 HDNB (hemolytic disease of the newborn)  131 Heavy chains  28 Helper ILCs  8 Helper T cells (Th cells)  4 Hemagglutination  140 Hemochromatosis  119 Hemolytic disease of the newborn (HDNB)  131 Hepatitis  133 chronic active  119 Hepatitis B  106 Hereditary angioedema  98 High endothelial venules (HEVs)  16 High-zone tolerance  105 HIGM (X-linked hyper-IgM)  114 Hinge region  29 Histamine  88 Histocompatibility genes  116 HIV infection  106, 115 HLA (human leukocyte antigen)  46 genetic polymorphism 106–107 see also MHC HLA-A  46 HLA-B  46 HLA-C  46 HLA-class III genes  47 HLA-DM  47 HLA-DP  47 HLA-DQ  47 HLA-DR  47 HLA-E  46 HLA-G  46 HNK (CD57)  11 5-HT (5-hydroxytryptamine)  88 Human leukocyte antigen (HLA)  46 Humanized antibodies  38 Humoral immunity  55 Hybridomas  146 5-Hydroxytryptamine (5-HT)  88 Hyper-IgE syndrome  114 Hyper-IgM (HIGM), X-linked  114 Hyperacute rejection  117 Hypersensitivity  126–127 contact  134 tuberculin-type  134

type I (immediate)  127, 128–129 type II (antibody-mediated)  127, 130–131 type III (immunecomplex-mediated)  127, 132–133 type IV (delayed)  127, 134–135 Hypervariable regions  31

I

I (C3bina)  99 Ia antigens (MHC class II molecules)  45 ICAM-1 (CD54)  11, 92, 93 ICAM-2 (CD102)  11, 92, 93 ICAM-3 (CD50)  10, 64 Iccosomes  13 IDCs (interdigitating dendritic cells)  12, 13 Idiotopes  30 Idiotypes (Ids)  30 Ids (idiotypes)  30 IELs (intraepithelial lymphocytes)  4 IFNs (interferons)  55 IFNγ (interferon-γ)  71 Ig see Immunoglobulins IgA  32 IgA1  33 IgA2  33 Igα (CD79a)  11, 27 Igβ (CD79b)  11, 27 IgD  32 IgE  33 IgG  32 IgG1  33 IgG2  33 IgG3  33 IgG4  33 IgM  32, 33 IgSF (immunoglobulin supergene family)  31 Ii (invariant chain, CD74)  11, 61 IL see Interleukins ILC1  8 ILC2  8 ILC3  8 ILCs (innate lymphoid cells)  8 Immediate (type I) hypersensitivity  127, 128–129 Immediate-phase reactions  128 Immortalization  146 Immune adherence  76 Immune-complex diseases  133 Immune-complex-mediated (type III) hypersensitivity  127, 132–133 Immune-complex-mediated immunoregulation  101 Immune checkpoints  66

xv Immune complexes  132 clearance  132 deposition  132 Immune deviation  105 Immune recognition  26–53 Immune recognition by NK cells  48–49 Immune response  54–111 cell cooperation  58–59 genetic polymorphism  106–107 neuroendocrine regulation  103 Immune response (Ir) genes  107 Immune system  2–25 Immunity adaptive  54–55, 55 cell-mediated  55 humoral  55 innate  54–55, 55 Immunization active  57 passive  57 Immuno-coprecipitation  141 Immunoabsorption  142 Immunoblotting  141 Immunochromatography (lateral flow test)  139 Immunodeficiency  112–115 Immunofluorescence  144 Immunogens  67 Immunoglobulin supergene family (IgSF)  31 Immunoglobulins (Ig)  27 membrane  28 secreted  28 see also Antibodies; specific classes/subclasses Immunogold labeling  144 Immunohistochemistry  144 Immunological synapse  65 Immunological techniques 136–151 Immunomagnetic beads  149 Immunopathology  112–135 Immunopotentiation  110 Immunoprecipitation  141 Immunoradiometric assay (IRMA)  137 Immunoreceptor tyrosine activation motifs (ITAMs)  27 Immunoregulation  100–102 by Tregs,  102, 102 Immunosuppression  108–109 Immunotherapeutic agents  39 In situ hybridization  151 Inbred strains  124 Indirect Coombs test  140 Indirect immunofluorescence  144 Induced fit  40 Inflammasomes  83

Inflammation  87–89 elements of  87 mediators  88, 89 Innate immune recognition  50–53 Innate immunity  54–55 Innate lymphoid cells (ILCs)  8 characteristics of  8 helper  8 Integrins  92 Interdigitating dendritic cells (IDCs)  12, 13 Interferon-γ (IFNγ)  71 Interferons (IFNs)  55 α chain (CD25)  10, 65 Interleukins (IL-1 to IL-40)  71, 72–73 IL-2  72 IL-2 receptor (IL-2R)  74 IL-4  72 IL-7  72 IL-8 (CXCL8)  72, 88 IL-12  72 Internal (class I) pathway, antigen presentation  62 Intracellular receptors for pathogens  83 Invariant chain (Ii, CD74)  11, 61 IPEX syndrome  113 IP-10 (CXCL10)  88 Ir (immune response) genes  107 IRMA (immunoradiometric assay)  137 Isolation of cells  148–149 Isotype (class) switching  37 Isotypes, immunoglobulin  30, 33 ITAMs (immunoreceptor tyrosine activation motifs)  27

J

J chain  32 J genes  34 JAKs  70 Junctional diversity  35 Juvenile rheumatoid arthritis  119

K

Kabat and Wu plot  31 Kappa (κ) chains  30 Kell blood group system  130 Killer immunoglobulin-like receptors (KIRs)  48 Kinins  89 KIRs (killer immunoglobulin-like receptors)  48 c-Kit (CD117)  19 Kupffer cells  14

L

L-selectin (CD62L)  11, 93 Lactoferrin  81

xvi Lad-1, Lad-2 (leukocyte adhesion deficiency)  114 Lambda (λ) chains  30 Lambert-Eaton syndrome  131 Langerhans cells  12 Large granular lymphocytes (LGLs)  4 Late-phase reactions  129 Lateral flow test (Immunochromatography)  139 LCA (leukocyte common antigen, CD45)  10, 68 lck  63 Lectin-like receptors  48, 51 Lectin pathway, complement  96 Leprosy  133 Leukocyte chemokine receptors  95 development  18 migration  90–93 Leukocyte adhesion deficiency (Lad-1, Lad-2)  114 Leukocyte common antigen (LCA, CD45)  10, 68 Leukocyte immunoglobulin-like receptor (LILRB1)  48 Leukosialin (CD43)  10, 92 Leukotriene B4 (LTB4)  88 Leukotriene D4 (LTD4)  88 Leukotrienes (LT)  89 Lewisx/sialyl Lex (CD15)  10 LFA-1 (CD11a/CD18)  64, 93 LFA-2 (CD2)  10, 65 LFA-3 (CD58)  11, 65 Light chains  28 LILRB1 (leukocyte immunoglobulin-like receptor)  48 Linkage  118 Linkage disequilibrium  118 Lipopolysaccharide (LPS)  53, 110 LMP-2  47 LMP-7  47 Low-zone tolerance  105 LPAM  93 LPS (lipopolysaccharide)  53 LPS-binding protein  52 LT (leukotrienes)  89 LT (lymphotoxin, TNF)  75 LTB4 (leukotriene B4)  88 LTD4 (leukotriene D4)  88 LTIs (lymphoid tissue inducers)  8 Lutheran blood group system  130 Lymph nodes  22–23 Lymphatic system  17 Lymphatics, afferent and efferent  23 Lymphocyte(s)  2, 4–7 development  7 migration  90

proliferation  147 separation  148 traffic  16 Lymphocyte functional antigen see LFA Lymphoid follicles  23 Lymphoid system  16–17 Lymphoid tissue inducers (LTIs)  8 Lymphoid tissue/organs  16 Lymphotoxin (LT, TNF)  75 Lysosomes  77 Lysozyme  81 Lytic pathway, complement  96

M

MAC (membrane attack complex)  96 Macrophage-inducible C-type lectin (MINCLE)  51 Macrophages  3, 14 activation  53, 81–82 antigen-presenting cells  12, 13 functions in Biozzi mice  107 intracellular receptors for pathogens  83 marginal zone  13 phagocytosis  77 Macrosialin (CD68)  11 MadCAM  92, 93 Major basic protein (MBP)  86 Major histocompatibility complex see MHC Malaria  106, 133 MALT (mucosa-associated lymphoid tissue)  17 Mannan-binding lectin (MBL)  98, 99 Mannose receptor (CD206)  11, 50 Marginal sinus  22 Marginal zone  24 Marginal zone macrophages  13 Markers, cell surface  9–11 MASP-1  99 MASP-2  99 Mast cells  3, 15 triggering  129 Matrix metalloproteases (MMP)  82 MBL (mannan-binding lectin)  98, 99 MBP (major basic protein)  86 MCP (membrane cofactor protein, CD46)  10, 98 MCP-1 (CCL2)  88 MDP (muramyl dipeptide)  110 Mediators of inflammation  88, 89 Medulla lymph node  22 thymic  20 Membrane attack complex (MAC)  96 Membrane cofactor protein (MCP, CD46)  10, 98

xvii Membrane immunoglobulins  28 Memory cells  7 6-Mercaptopurine  108 Mesangial phagocytes  15 Metalloproteases  82 Methotrexate  108 mev mouse  125 MG (myasthenia gravis)  119, 131 MHC  44 disease associations 118–119, 119 genes  46–47 genetic polymorphism  106 molecules  44–45 nomenclature  120 restriction  63 typing  120 see also HLA MHC class I-like (nonclassical, Ib) molecules  44 MHC class I molecules  44 MHC class I pathway  62 MHC class II deficiency  113 MHC class II molecules  45 MHC class II pathway  61 Microglial cells  15 β2-Microglobulin (β2m)  44 MIF (migration inhibition factor)  71 Migration, cell  90–93 Migration inhibition factor (MIF)  71 MIIC compartment  61 MINCLE (macrophage-inducible C-type lectin)  51 Minor histocompatibility loci  116 MIP-1α (CCL3)  88 Mixed lymphocyte culture/reaction (MLC/MLR)  120 MLR.lpr mouse  125 MMCs (mucosal mast cells)  15 MMP (matrix metalloproteases)  82 MN blood group system  130 Monoclonal antibodies  38 production  147 therapeutic  109 Monocytes  2, 14 Mononuclear phagocyte system  14 Motheaten mouse  125 MTT assay  151 Mucosa-associated lymphoid tissue (MALT)  17 Mucosal mast cells (MMCs)  15 Mucosal tolerance  105 Multiple sclerosis  119 Muramyl dipeptide (MDP)  110 Mutant strains  124–125 Myasthenia gravis (MG)  119, 131 Mycophenolate  108 Myeloid cells  19 Myeloperoxidase  80

N

N-region diversity  35 Naive lymphocytes  6 Nanobodies  30 Narcolepsy  119 Natural cytotoxicity receptors (NCRs)  49 Natural (innate) immunity  54–55 Natural killer cells (NK cells)  8 immune recognition by  48–49 Natural resistance associated macrophage protein (nRAMP)  82 NBT (nitroblue tetrazolium)  151 NCAM (CD56)  11 NCRs (natural cytotoxicity receptors)  49 Negative selection  21 Neonatal tolerance  104 Nephelometry  138 Neuroendocrine regulation of immune responses  103 Neuropeptide regulation, of immune response  103 Neutrophils  3, 15 Nezelof syndrome  113 NFκB  75 Nijmegen breakage syndrome  113 Nitroblue tetrazolium (NBT)  151 NK cell-mediated cytotoxicity  85 NK cells (natural killer cells)  8, 48–49 NKG2  49 NKG2A (CD94)  11, 49 NKp30  49 NKp44  49 NKp46  49 NLRs (NOD-like receptors)  83 NOD-like receptors (NLRs)  83 Nod (non-obese diabetic) mouse  125 nRAMP (natural resistance associated macrophage protein)  82 Nude mouse  125 Nude rat  125 NZB mouse  125 (NZB x NZW)F1 mouse  125

O

Obese chicken  125 Opsonins  76 Opsonization  76 Optical biosensors  143 Oral tolerance  105 Organ nonspecific autoimmune diseases  121 Organ-specific autoimmune diseases  121, 121 Oxygen-dependent killing  80

xviii P

P (properdin)  99 P-selectin (CD62P)  11, 93 p150/95 (CR4, CD11c/CD18) 78, 93 PAF (platelet-activating factor)  88 PALS (periarteriolar lymphatic sheath)  24 PAMPs (pathogen-associated molecular patterns)  50 Panning  148 Paracortex, lymph node  22 Paratopes  40 Paroxysmal nocturnal hemoglobinuria (PNH)  98 Passenger cells  116 Passive immunization  57 Patch testing  135 Pathogen-associated molecular patterns (PAMPs)  50 Pathogens, intracellular receptors for  83 Pattern recognition receptors (PRRs)  50 PD1 (programmed death-1, CD279)  66 PECAM (CD31)  10, 92, 93 Pemphigus  131 Pemphigus vulgaris  119 Pentraxins  53 Peptide:MHC complexes  147 Percoll gradients  149 Perforin  84 Periarteriolar lymphatic sheath (PALS)  24 Peripheral tolerance  104 Peroxidase, eosinophil  86 Peyer’s patches  25 PFCs (plaque-forming cells)  150 PG (prostaglandins)  89 PGE2 (prostaglandin E2)  88 Phage display antibodies  38 Phagocytes  2, 14–15 mesangial  15 microbicidal systems  80 Phagocytosis  76–77 frustrated  77 Phagolysosomes  77 Phagosomes  77 Photobleaching recovery  151 Pituitary/adrenal axis  103 Plaque-forming cells (PFCs)  150 Plasma cells  6 Plasma enzyme systems  89 Plasmodium falciparum malaria  106 Platelet-activating factor (PAF)  88 PLT (primed lymphocyte typing test)  120 PNAd  93

PNH (paroxysmal nocturnal hemoglobinuria)  98 Poly-Ig receptor  33 Polyarteritis  133 Polyclonal antibodies  38 Polymorphism, genetic  106–107 Polymorphs  15 Polymyositis  133 Positive selection  21 Post-Salmonella arthritis  119 Post-Shigella arthritis  119 Pre-B-cell receptor  28 Precipitin reactions  142 Prick test  129 Primary antibody response  56 Primary lymphoid tissue  16 Primed lymphocyte typing test (PLT)  120 Private specificities  120 Privileged tissues and sites  117 Programmed death-1 (PD1, CD279)  66 Proliferation assay  147 Properdin (P)  99 Properdin pathway  96 Prostaglandin E2 (PGE2)  88 Prostaglandins (PG)  89 Proteasomes  62 Protectin (CD59)  11, 98 Protein A  138 Protein families, cell-surface  9 Protein G  138 PRRs (pattern recognition receptors)  50 PSGL-1 (CD162)  11, 93 Psoriasis vulgaris  119 PTx (Bordetella pertussis toxin/ toxoid)  110 Public specificities  120 Pyropoptosis  83

Q

Qa loci  47

R

Radioallergosorbent test (RAST)  137 Radioimmunoassay (RIA)  136 Radioimmunosorbent test (RIST)  137 RAG-1 (recombination-activating gene-1)  36 RAG-2 (recombination-activating gene-2)  36 RANTES (CCL5)  88 Rapamycin  108 RAST (radioallergosorbent test)  137 Reactive nitrogen intermediates (RNIs)  81

xix Reactive oxygen intermediates (ROIs)  80 Recombinant inbred strains  124 Recombinant strains  124 Recombination-activating genes (RAG-1, RAG-2)  36 Recombination signal sequences (RSSs)  34 Recurrent idiotypes  30 Red pulp  24 Regulatory T cells (Treg)  6 Reiter’s disease  119 Rejection reactions  116 Relative risk (RR)  118 Repertoire  107 Respiratory burst  80 Rhesus blood group system  130 Rhesus prophylaxis  131 Rheumatoid arthritis  119, 133 RIA (radioimmunoassay)  136 RIG-like receptors (RLRs)  83 Right lymphatic duct  17 Rilonacept  39 RIST (radioimmunosorbent test)  137 RLRs (RIG-like receptors)  83 RNIs (reactive nitrogen intermediates)  81 ROIs (reactive oxygen intermediates)  80 Rosetting  149 RR (relative risk)  118 RSSs (recombination signal sequences)  34

S

S-protein  99 Sandwich immunoassays  137 SAP (serum amyloid-P)  53 Scavenger receptors  50 SCF (stem cell factor)  19 SCID (severe combined immunodeficiency)  112 SCID mouse  125 Second-set rejection  116 Secondary antibody response  56 Secondary lymphoid tissue  16 Secreted immunoglobulins  28 Secretory immune system  25 Secretory piece  33 Selectins (CD62)  11, 92, 93 Self-tolerance  104 mechanisms for breakdown  123 Sensitization  128 Serotonin  88 Serum amyloid-P (SAP)  53 Serum sickness  133 Severe combined immunodeficiency (SCID)  112 Shared epitope hypothesis  118

sIgA  33 Sickness behavior  71 Siglecs  51 Single-chain antibodies  30, 38 Single-domain antibodies  30, 38 SLE (systemic lupus erythematosus)  133 Soluble cytokine inhibitors  75 Soluble cytokine receptors  75 Somatic hypermutation  36 Spleen  24 STATs  70 Steel factor  19 Stem cell factor (SCF)  19 Steroids  108 Streptavidin reagents  138 Subclasses, antibody  30, 33 Subunit vaccines  111 Superantigens  104 Supratypic specificities  120 Surface plasmon resonance  143 Synapse, immunological  65 Synovial A cells  15 Systemic lupus erythematosus (SLE)  133

T

T cell(s)  4 autoreactivity  122 development  20–21 education  21 immune recognition  63 separation  149 T-cell activation  64–66 T-cell antigen receptor (TCR)  27, 42 T-cell bypass  122 T-cell development  21–21 T-cell help  59 T-cell lines  147 T-cell-mediated cytotoxicity  84 T-cell receptor genes  43 T-cell tolerance  104 T-dependent antigens  67 T-independent antigens  67 Tacrolimus  108 TAP-1  47, 62 TAP-2  47, 62 TAPA (CD81)  11, 68–69 TC cells (cytotoxic T cells)  4 TCR (T-cell antigen receptor)  27, 42 TCRαβ (TCR2)  42 TCRγδ (TCR1)  42 Tdt (terminal deoxynucleotidyl transferase)  36 Terminal deoxynucleotidyl transferase (Tdt)  36 TGFβ (transforming growth factor-β)  71 Th cells (helper T cells)  4

xx Th1 cells  5 Th1-type responses  100, 101 Th2 cells  5 Th2-type responses  100, 101 Th17 cells  5, 101, 102 Thoracic duct  17 Thromboxanes (Tx)  89 Thy-1 (CD90)  11 Thymic cortex  20 Thymic epithelial cells  20 Thymic medulla  20 Thymocytes  20 Thymus  20–21, 21 Ti  42 Tissue-dependent regulation  102 Tissue typing  120 Tla loci  47 TLR (Toll-like receptors)  52 TLR2  52 TLR4  52 TNF (tumor necrosis factor)  75 TNFα (tumor necrosis factor-α)  75 TNFβ (lymphotoxin)  75 TNF receptor superfamily  75 Tolerance  104 mechanisms  105 Toll-like receptors (TLR)  52 Tonsils  17 Toxoids  111 Transferrin receptor (CD71)  11 Transforming growth factor-β (TGFβ)  71 Transfusion reactions  130 Transplantation  116–117 Transudate  87 Treg (regulatory T cells)  6 Tregs, immunoregulation by  102, 102 Trypan blue  151 Trypanosomiasis  133 Tuberculin-type hypersensitivity  134 Tuberculosis  106 Tumor necrosis factor (TNF)  75 Tumor necrosis factor-α (TNFα)  75 Tumor necrosis factor-β (TNFβ, lymphotoxin)  75 Tx (thromboxanes)  89

U

Urokinase plasminogen activator receptor (CD87)  11

V

V genes  34 V (variable) regions  29 Vaccination  57 Vaccines  111 Valency, antibody  41 VAP-1  93 Variable (V) regions  29 Vasodilation  87 VCAM-1 (CD106)  11, 92, 93 VDJ recombination  35 VE-cadherin (CD144)  11 Vector vaccines  111 Veiled cells  12 Very late antigens (VLA)  92 VH domain  29 Virgin lymphocytes  6 Vitronectin  99 VL domain  29 VLA (very late antigens)  92 VLA-1 (CD49a)  10 VLA-2 (CD49b)  10 VLA-3 (CD49c)  10 VLA-4 (CD49d)  10,  93 VLA-5 (CD49e)  10 VLA-6 (CD49f)  10

W

Waldeyer’s ring  17 WAS (Wiskott-Aldrich syndrome)  113 Western blotting  141 White pulp  24 Wiskott-Aldrich syndrome (WAS)  113

X

X-linked agammaglobulinemia  114 X-linked hyper-IgM (HIGM)  114 X-linked proliferative syndrome (XLP)  114 XCR1  95 XLP (X-linked proliferative syndrome)  114

Immunology An Illustrated Outline

1

The Immune System

INTRODUCTION The immune system has evolved to protect the body from damage caused by microorganisms—bacteria, fungi, viruses, and parasites. This defensive function is performed by leukocytes (white blood cells) and a number of accessory cells, which are distributed throughout the body but are found particularly in lymphoid organs, including the bone marrow, thymus, spleen, and mucosa-associated lymphoid tissues (MALT). Lymphoid organs are strategically placed to protect different areas of the body from infection. Cells migrate between these tissues via the bloodstream and lymphatic system. As they do so they interact with each other to generate coordinated immune responses, aimed at eliminating pathogens or minimizing the damage they cause. Lymphocytes are key cells controlling the immune response. They do so by recognizing molecules produced by pathogens. They can also recognize molecules on the cells of the body, although they do not normally react against the body’s own tissues. Molecules recognized by lymphocytes are referred to as “antigens.” Lymphocytes are of two main types: B cells, which produce antibodies, and T cells, which have a number of functions, including (1) helping B cells to make antibodies; (2) recognizing and destroying cells that have become infected with intracellular pathogens; (3) activating phagocytes to destroy pathogens that they have taken up, and (4) regulating the level and quality of the immune response. Lymphocytes recognize foreign material by specific cell-surface antigen receptors. To recognize the enormous variety of different molecules, the antigen receptors must be equally diverse. Each lymphocyte makes only one type of antigen receptor and thus can only recognize a very limited number of antigens, but as the receptors differ on each clone of cells, the lymphocyte population, as a whole, can recognize a vast range of different antigens. A third population of lymphocytes, the innate lymphoid cells (ILCs) do not have specific antigen receptors but generate a variety of immune defense functions. Phagocytes include blood monocytes, macrophages, and neutrophils. They can internalize (phagocytose) pathogens, antigens, and cell debris and break them down. Antibodies and various other immune recognition molecules bound to the pathogens facilitate this process. Macrophages can also process and present antigens, so that they can be recognized by T cells.

3 Accessory cells include eosinophil and basophil granulocytes, mast cells, platelets, and antigen-presenting cells (APCs). Eosinophils have a role in protection against some parasites. Basophils, mast cells, and platelets contain a variety of molecules that mediate inflammation. APCs are a functionally defined group of cells; both B cells and macrophages can present antigen, but leukocyte dendritic cells are particularly important in presenting antigen to naive T cells, which have not previously encountered their specific antigen. small lymphocyte

large granular lymphocyte

monocyte

macrophage

neutrophil

eosinophil

basophil

mast cell

Fig. 1.1  Cells involved in the immune response. Macrophage courtesy of A. V. Hoffbrand.

4

LYMPHOCYTES Lymphocytes constitute about 20% of the total blood leukocytes. The two major populations of lymphocytes, T cells and B cells, are small lymphocytes responsible for recognizing antigens or antigen fragments. Innate lymphoid cells (ILCs) are a heterogenous group, which can carry out many of the functions of T cells—the group includes natural killer (NK) cells. Large granular lymphocytes (LGLs) are morphologically defined cells containing large amounts of cytoplasm, with azurophilic granules, which constitute 5–15% of the blood T cells. Both NK cells and γδ T cells have this morphology. T cells are lymphocytes that develop in the thymus. This organ is seeded by lymphocytic stem cells from the bone marrow during embryonic development. The cells then develop their T-cell antigen receptors (TCR) and differentiate into the two major peripheral T-cell subsets; the helper T cells express CD4, and the cytotoxic T cells express CD8. T cells can also be differentiated into two populations according to whether they use an aβ (TCR2) or a γδ (TCR1) antigen receptor. The essential role of T cells is to recognize antigens associated with cells of the host. γδ T cells express the γδ form of the T-cell receptor. They constitute 70%). They spend less than 48 hours in the circulation before migrating into the tissues under the influence of chemotactic stimuli, where they phagocytose material and eventually die. They have receptors for antibody and complement to facilitate the uptake of opsonized particles. Eosinophils—comprising 2–5% of blood leukocytes. Their granules contain a crystalloid core of basic protein, which can be released by exocytosis, causing damage to a number of pathogens, particularly parasitic worms. The granules also contain histaminase and aryl sulfatase, which downregulate inflammatory reactions. Basophils—constituting 1 indicates that the haplotype is more prevalent in patients than the general population, whereas a relative risk