IMMUNOLOGY · v 1 overview of the immune system, 1 2 innate immunity, 11 3 adaptive immunity, 26 4 immunogens and antigens, 35 5 antibody structure and function, 47

IMMUNOLOGYA Short Course

ToLisa, Jonathan, and Jennifer

R.C.

ToIlene, Caroline, Alex, and Pearl

G.S.

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IMMUNOLOGYA Short Course

SEVENTH EDITION

Richard CoicoSUNY Downstate College of Medicine, Brooklyn, New York

Geoffrey SunshineHeath Effects Institute, and Tufts University School of Medicine, Boston, Massachusetts

This edition first published 2015 © 2015 by John Wiley & Sons Ltd

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Coico, Richard, author. Immunology : a short course / Richard Coico, Geoffrey Sunshine. – Seventh edition. p. ; cm. Includes bibliographical references and index. ISBN 978-1-118-39691-9 (pbk.) I. Sunshine, Geoffrey, author. II. Title. [DNLM: 1. Allergy and Immunology. 2. Immune System Diseases. 3. Immune System Processes. 4. Immunity. QW 504] QR181 616.07′9–dc23 2014023101

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v

1 OVERVIEW OF THE IMMUNE SYSTEM, 1

2 INNATE IMMUNITY, 11

3 ADAPTIVE IMMUNITY, 26

4 IMMUNOGENS AND ANTIGENS, 35

5 ANTIBODY STRUCTURE AND FUNCTION, 47

6 ANTIGEN–ANTIBODY INTERACTIONS, IMMUNE ASSAYS, AND EXPERIMENTAL SYSTEMS, 67

7 THE GENETIC BASIS OF ANTIBODY STRUCTURE, 88

8 BIOLOGY OF THE B LYMPHOCYTE, 100

9 HOW T CELLS RECOGNIZE ANTIGEN: THE ROLE OF THE MAJOR HISTOCOMPATIBILITY COMPLEX, 117

10 BIOLOGY OF THE T LYMPHOCYTE, 137

CONTENTS IN BRIEF

11 ACTIVATION AND FUNCTION OF T CELLS, 153

12 CYTOKINES, 176

13 TOLERANCE AND AUTOIMMUNITY, 194

14 COMPLEMENT, 217

15 HYPERSENSITIVITY: TYPE I, 233

16 HYPERSENSITIVITY: TYPES II AND III, 249

17 HYPERSENSITIVITY: TYPE IV, 259

18 IMMUNODEFICIENCY DISORDERS AND NEOPLASIAS OF THE LYMPHOID SYSTEM, 268

19 TRANSPLANTATION, 298

20 TUMOR IMMUNOLOGY, 312

21 RESISTANCE AND IMMUNIZATION TO INFECTIOUS DISEASES, 328

vii

About the Authors, xv

Contributors, xvi

Preface and Acknowledgments, xvii

How to Use Your Textbook, xix

About the Companion Website, xxiii

1 OVERVIEW OF THE IMMUNE SYSTEM, 1Introduction, 1

Innate and Adaptive Immunity, 2

Innate Immunity, 2

Adaptive Immunity, 2

Clonal Selection Theory, 3

Active, Passive, and Adoptive Immunization, 5

Major Characteristics of the Adaptive Immune Response, 5

Cells Involved in the Adaptive Immune Response, 5

Humoral and Cellular Immunity, 6

Humoral Immunity, 6

Cell-Mediated Immunity, 7

Generation of Diversity in the Immune Response, 8

Benefits of Immunology, 8

Damaging Effects of the Immune Response, 9

The Future of Immunology, 9

The Short Course Begins Here, 10

References and Bibliography 10

2 INNATE IMMUNITY, 11Introduction, 11

Physical and Chemical Barriers of Innate Immunity, 11

Origin, Differentiation, and Characterization of Cells of the Innate Immune System, 12

Pattern Recognition: The Hallmark of Innate Immune Responses, 15

Pattern Recognition Receptors, 15

Complement, 18

Intracellular and Extracellular Killing of Microorganisms, 19

CONTENTS

Inflammation, 20

Hallmark Signs of Inflammation, 20

Localized Inflammatory Responses, 21

Chronic Inflammation, 23

Fever, 23

References and Bibliography, 24

Review Questions, 24

Answers to Review Questions, 25

3 ADAPTIVE IMMUNITY, 26Cells and Organs Involved in Adaptive Immunity, 26

The Lymphatic Organs, 27

Lymphocyte Migration and Recirculation, 29

The Fate of Antigen after Penetration, 31

Frequency of Antigen-Specific Naïve Lymphocytes, 32

Interrelationship between Innate and Adaptive Immunity, 33



4 IMMUNOGENS AND ANTIGENS, 35Introduction, 35

Requirements for Immunogenicity, 35

Foreignness, 35

High Molecular Weight, 36

Chemical Complexity, 36

Degradability, 36

Haptens, 36

Further Requirements for Immunogenicity, 37

Primary and Secondary Responses, 38

Antigenicity and Antigen-Binding Site, 38

Epitopes Recognized by B Cells and T Cells, 39

Major Classes of Antigens, 40

Binding of Antigen with Antigen-Specific Antibodies or T Cells, 41

Cross-Reactivity, 41

Adjuvants, 42




viii CONTENTS

5 ANTIBODY STRUCTURE AND FUNCTION, 47Introduction, 47

Isolation and Characterization of Immunoglobulins, 48

Structure of Light and Heavy Chains, 48

Domains, 51

Hinge Region, 51

Variable Region, 51

Immunoglobulin Variants, 53

Isotypes, 53

Allotypes, 54

Idiotypes, 54

Structural Features of IgG, 55

Biologic Properties of IgG, 55

Agglutination and Formation of Precipitate, 56

Passage through the Placenta and Absorption in Neonates, 56

Opsonization, 57

Antibody-Dependent Cell-Mediated Cytotoxicity, 58

Activation of Complement, 58

Neutralization of Toxins, 58

Immobilization of Bacteria, 58

Neutralization of Viruses, 58

Structural Features of IgM, 59

Biologic Properties of IgM, 59

Complement Fixation, 59

Neonatal Immunity and First Line of Humoral Defense, 59

Agglutination, 60

Isohemagglutinins, 60

Structural and Biologic Properties of IgA, 60

Biologic Properties of IgA, 60

Role in Mucosal Infections, 60

Bactericidal Activity, 61

Antiviral Activity, 61

Structural and Biologic Properties of IgD, 61

Structural and Biologic Properties of IgE, 62

Importance of IgE in Parasitic Infections and Hypersensitivity Reactions, 62

Kinetics of the Antibody Response Following Immunization, 62

Primary Response, 62

Secondary Response, 62

The Immunoglobulin Superfamily, 63




6 ANTIGEN–ANTIBODY INTERACTIONS, IMMUNE ASSAYS, AND EXPERIMENTAL SYSTEMS, 67Introduction, 67

Antigen–Antibody Interactions, 67

Primary Interactions between Antibody and Antigen, 68

Association Constant, 68

Affinity and Avidity, 70

Secondary Interactions between Antibody and Antigen, 70

Agglutination Reactions, 70

Precipitation Reactions, 72

Immunoassays, 74

Direct-Binding Immunoassays, 74

Solid-Phase Immunoassays, 75

Immunofluorescence, 76

Direct Immunofluorescence, 76

Indirect Immunofluorescence, 76

Flow Cytometry, 76

Immunoabsorption and Immunoadsorption, 78

Cellular Assays, 78

Assays of Lymphocyte Function, 78

B-Cell and T-Cell Proliferation Assays, 78

Antibody Production by B Cells, 78

Effector Cell Assays for T Cells and Natural Killer Cells, 79

Cell Culture, 79

Primary Cell Cultures and Cloned Lymphoid Cell Lines, 79

B-Cell Hybridomas and Monoclonal Antibodies, 80

T-Cell Hybridomas, 80

Genetically Engineered Molecules and Receptors, 80

Experimental Animal Models, 81

Inbred Strains, 81

Adoptive Transfer, 82

SCID Mice, 82

Thymectomized and Congenitally Athymic (Nude) Mice, 82

Transgenic Mice and Gene Targeting, 82

Transgenic Mice, 82

Knockout and Knock-in Mice, 83

Analysis of Gene Expression, 83

Microarrays to Assess Gene Expression, 83




7 THE GENETIC BASIS OF ANTIBODY STRUCTURE, 88Introduction, 88

A Brief Review of Nonimmunoglobulin Gene Structure and Gene Expression, 88

Genetic Events in Synthesis of Ig Chains, 90

Organization and Rearrangement of Light-Chain Genes, 90

Contents ix

κ-Chain Synthesis, 91

λ-Chain Synthesis, 92

Organization and Rearrangement of Heavy-Chain Genes, 92

Allelic Exclusion and the Regulation of Ig Gene Expression, 93

Class or Isotype Switching, 94

Generation of Antibody Diversity, 95

Presence of Multiple V Genes in the Germline, 95

VJ and VDJ Combinatorial Association, 95

Random Assortment of H and L Chains, 95

Junctional Diversity, 95

Somatic Hypermutation, 95

Somatic Gene Conversion, 96

Role of Activation-Induced Cytidine Deaminase in Generating Antibody Diversity, 96




8 BIOLOGY OF THE B LYMPHOCYTE, 100Introduction, 100

Development of B Lymphocytes, 100

Overview, 100

Sites of Early B-Cell Differentiation, 101

Pro-B and Pre-B Cells: First Ig Rearrangements, 101

Immature B Cells, 103

Transitional B cells, 104

Mature B Cells, 104

Plasma Cells, 104

Memory B Cells, 105

Sites of Antibody Synthesis, 105

Interaction of Antigen, B Cells, and Helper T Cells in the Lymph Node, 105

Events in the Germinal Center, 105

Antibody Synthesis in Mucosal Tissue, 107

Thymus-Independent Antibody Responses, 109

B-Cell Membrane Proteins, 110

Stage-Specific Markers, 110

Antigen-Binding Molecules: Membrane Immunoglobulin, 111

Signal Transduction Molecules Associated with Membrane Immunoglobulin, 111

Molecules Involved in T–B Cell Interactions, 111

Homing, 112

Intracellular Signaling in B Cells, 112




9 HOW T CELLS RECOGNIZE ANTIGEN: THE ROLE OF THE MAJOR HISTOCOMPATIBILITY COMPLEX, 117Introduction, 117

How the MHC Got Its Name, 117

MHC Role in Antigen Presentation, 118

Different MHC Molecules Are Expressed by Distinct Host Cells and Interact with Different Sets of T Cells, 119

MHC Class I, 119

MHC Class II, 119

Variability of MHC Class I and MHC Class II Molecules, 119

Structure of MHC Class I and Class II Molecules, 120

MHC Class I, 120

Structure of MHC Class II Molecules, 122

Antigen Processing and Presentation: How MHC Molecules Bind Peptides and Create Ligands That Interact with T Cells, 124

Exogenous Antigens and Generation of MHC Class II–Peptide Complexes, 124

Endogenous Antigens: Generation of MHC Class I–Peptide Complexes, 126

Cross-Presentation: Exogenous Antigens Presented in the MHC Class I Pathway, 127

Which Antigens Trigger Which T-Cell Responses?, 128

MHC Molecules Bind Peptides Derived from Self-Molecules, 128

Inability to Respond to an Antigen, 129

Other Types of Antigen That Activate T-Cell Responses, 129

Superantigens, 129

Lipids and Glycolipids, 129

Multiple Antigens Activate γδ T Cells, 130

Genes of the HLA Region, 130

Nomenclature of Polymorphic MHC Molecules, 131

Regulation of Expression of MHC Genes, 131

Codominant Expression, 131

Coordinate Regulation, 131

Inheritance of MHC Genes, 131

MHC in Other Species, 132

Diversity of MHC Molecules: MHC Association with Resistance and Susceptibility to Disease, 132




10 BIOLOGY OF THE T LYMPHOCYTE, 137Introduction, 137

The Antigen-Specific T-Cell Receptor, 137

Molecules That Interact with Antigen, 137

x CONTENTS

The T-Cell Receptor Complex, 139

Co-Receptors, 140

Other Important Molecules Expressed on the T-Cell Surface, 141

γδ T Cells, 142

Genes Coding for T-Cell Receptors, 143

Generation of T-Cell Receptor Diversity, 144

T-Cell Differentiation in the Thymus, 144

The Thymus as Primary Organ for T-Cell Differentiation, 144

Key Steps in Thymic Differentiation, 145

Early T-Cell Receptor Gene Rearrangements: Double-Negative Cells and Splitting Off of γδ T Cells, 145

Pre-T Cells, 146

Double-Positive Cells, 146

Thymic Selection, 146

Leaving the Thymus, 148

Generation of the T-Cell Repertoire, 148

Characteristics of αβ T Cells Emerging from the Thymus, 148

Further Differentiation of CD4+ and CD8+ T Cells Outside the Thymus, 149

Differentiation of Other Cell Types in the Thymus, 149




11 ACTIVATION AND FUNCTION OF T CELLS, 153Introduction, 153

A Two-Signal Model for the Activation of T Cells, 153

Dendritic Cells Are the Key APC for Naïve T Cells, 153

Activation of CD4+ T Cells, 155

Paired Interactions at the Surface of the APC and CD4+ T Cell, 155

Intracellular Events in CD4+ T-Cell Activation, 156

Differentiation to Effector Cells and Migration Out of the Lymph Node, 159

Termination of the Response, 159

Other Ways to Activate CD4+ T Cells, 160

CD4+ T-Cell Function, 160

Cytokine Synthesis, 161

Major Subsets of Cytokine-Producing CD4+ T Cells, 161

Cross-Inhibition of CD4+ T-Cell Subsets, 164

Other Sets of Cytokine-Producing CD4+ T Cells, 165

Further Points on Cytokine Synthesis, 165

Help for B Cell in the Response to TD Antigens, 165

Events in the Germinal Center, 166

Linked Recognition, 167

Activation and Function of CD8+ T Cells, 168

Generation of Effector CD8+ T Cells, 168

CD8+ T-Cell Killing of Target Cells, 169

MHC Restriction and CD8+ T Cell Killer Function, 170

Memory T Cells, 171

Function of Other Subsets of T Cells, 171

NKT Cells, 171

γδ T Cells, 172

Innate Lymphoid Cells, 172




12 CYTOKINES, 176Introduction, 176

The History of Cytokines, 176

Pleiotropic and Redundant Properties of Cytokines, 177

General Properties of Cytokines, 177

Common Functional Properties, 177

Common Systemic Activities, 178

Common Cell Sources and Cascading Events, 179

Functional Categories of Cytokines, 179

Cytokines That Facilitate Innate Immune Responses, 179

Cytokines That Regulate Adaptive Immune Responses, 181

Cytokines That Induce Differentiation of Distinct T-Cell Lineages, 181

Cytokines That Inhibit Lineage-Specific T-Cell Differentiation, 182

Cytokines That Promote Inflammatory Responses, 183

Cytokines That Affect Leukocyte Movement, 183

Cytokines That Stimulate Hematopoiesis, 184

Cytokine Receptors, 185

Cytokine Receptor Families, 185

Common Cytokine Receptor Chains, 186

Cytokine Receptor-Mediated Signal Transduction, 186

Role of Cytokines and Cytokine Receptors in Disease, 188

Toxic Shock Syndrome, 188

Bacterial Septic Shock, 188

Cancers, 189

Autoimmunity and Other Immune-Based Diseases, 189

Therapeutic Exploitation of Cytokines and Cytokine Receptors, 189

Cytokine Inhibitors/Antagonists, 189

Reversing Cellular Deficiencies, 190

Contents xi

Treatment of Immunodeficiencies, 190

Treatment of Patients with Cancer, Transplanted Organs, and Tissues, and Viral Infections, 190

Treatment of Allergies and Asthma, 191




13 TOLERANCE AND AUTOIMMUNITY, 194Introduction, 194

Central Tolerance, 195

Mechanisms of Central Tolerance: T and B Cells, 195

Mechanisms of Central Tolerance: B Cells, 196

Peripheral Tolerance, 197

Anergy, 198

Regulatory T Cells, 198

Fas–FasL Interactions, 200

Oral Tolerance, 200

Immune Privilege, 201

Autoimmunity and Disease, 201

Genetic Susceptibility, 202

Environmental Susceptibility, 203

Drug and Hormonal Triggers of Autoimmunity, 205

Autoimmune Diseases, 205

Autoimmune Diseases in Which Antibodies Play a Predominant Role in Mediating Organ Damage, 205

Autoimmune Diseases in Which T Cells Play a Predominant Role in Organ Damage, 210

Therapeutic Strategies, 212




14 COMPLEMENT, 217Introduction, 217

Overview of Complement Activation, 217

Classical Pathway, 218

Lectin Pathway, 219

Alternative Pathway, 220

Steps Shared by All Pathways: Activation of C3 and C5, 221

Terminal Pathway, 222

Regulation of Complement Activity, 222

Biologic Activities of Complement, 224

Production of Opsonins, 224

Production of Anaphylatoxins, 225

Lysis, 225

Other Important Complement Functions, 225

Complement Deficiencies, 228




15 HYPERSENSITIVITY: TYPE I, 233Introduction, 233

Hypersensitivity, 233

Coombs–Gell Hypersensitivity Designations, 233

General Characteristics of Allergic Reactions, 234

Sensitization Phase, 234

TH2 Cell Dependency of IgE Antibody Production, 234

Activation Phase, 235

Effector Phase, 237

Preformed Mediators, 237

Newly Synthesized Mediators, 238

Late-Phase Reaction, 238

Clinical Aspects of Allergic Reactions, 240

Allergic Rhinitis, 240

Food Allergies, 241

Atopic Dermatitis, 241

Asthma, 241

Clinical Tests for Allergies and Clinical Intervention, 242

Detection, 242

Intervention, 242

The Protective Role of IgE, 244




16 HYPERSENSITIVITY: TYPES II AND III, 249Introduction, 249

Type II Hypersensitivity, 249

Complement-Mediated Reactions, 249


Antibody-Mediated Cellular Dysfunction, 250

Examples of Type II Hypersensitivity Reactions, 251

Transfusion Reactions, 251

Drug-Induced Reactions, 251

Rhesus Incompatibility Reactions, 251

Reactions Involving Cell Membrane Receptors, 252

Reactions Involving Other Cell Membrane Determinants, 252

Type III Hypersensitivity, 252

Systemic Immune Complex Disease, 253

Localized Immune Complex Disease, 255



Answers to Review Questions 258

xii CONTENTS

17 HYPERSENSITIVITY: TYPE IV, 259Introduction, 259

General Characteristics and Pathophysiology of DTH, 259

Mechanisms Involved in DTH, 260

Examples of DTH, 261

Contact Sensitivity, 261

Granulomatous Hypersensitivity, 262

Tuberculin-Type Hypersensitivity, 263

Allograft Rejection, 264

Additional Examples of DTH, 264

Treatment of DTH, 264




18 IMMUNODEFICIENCY DISORDERS AND NEOPLASIAS OF THE LYMPHOID SYSTEM, 268Introduction, 268

Immunodeficiency Syndromes, 269

Primary Immunodeficiency Syndromes, 270

Immunodeficiency Disorders Associated with T Cells and Cell-Mediated Immunity, 274

B-Cell–Associated or Immunoglobulin-Associated Immunodeficiency Disorders, 276

Disorders of T–B Interactions, 277

Phagocytic Dysfunctions, 278

Natural Killer Cell Deficiency, 280

Diseases Caused by Abnormalities in the Complement System, 280

Secondary Immunodeficiency Diseases, 281

Acquired Immunodeficiency Syndrome, 282

Initial Description and Epidemiology, 282

Human Immunodeficiency Virus, 282

Clinical Course, 284

Prevention, Control, Diagnosis, and Therapy of HIV Infection, 286

Neoplasms of Lymphoid System, 287

B-Cell Neoplasms, 288

Mature B-Cell Neoplasms, 288

Plasma Cell Neoplasms, 291

T-Cell Neoplasms, 291

Mature T-Cell Neoplasms, 292

Immunotherapy, 293




19 TRANSPLANTATION, 298Introduction, 298

Relationship between Donor and Recipient, 298

Immune Mechanisms Are Responsible for Allograft Rejection, 300

Categories of Allograft Rejection, 300

Hyperacute Rejection, 300

Acute Rejection, 300

Chronic Rejection, 301

Role of MHC Molecules in Allograft Rejection, 301

Mechanisms of Alloantigen Recognition by T Cells, 301

Role of T Cell Lineages and Cytokines in Allograft Rejection, 302

Laboratory Tests Used in Tissue Typing, 303

Prolongation of Allograft Survival: Immunosuppresive Therapy, 304

Anti-Inflammatory Agents, 305

Cytotoxic Drugs, 305

Agents That Interfere with Cytokine Production and Signaling, 306

Immunosuppressive Antibody Therapy, 306

New Immunosuppressive Strategies and Frontiers, 306

Hematopoietic Stem Cell Transplantation, 307

Graft-versus-Host Disease, 308

Xenogeneic Transplantation, 308

The Fetus: A Tolerated Allograft, 309




20 TUMOR IMMUNOLOGY, 312Introduction, 312

Tumor Antigens, 312

Categories of Tumor Antigens, 313

Normal Cellular Gene Products, 313

Mutant Cellular Gene Products, 314

Tumor Antigens Encoded by Oncogenes, 315

Immunologic Factors Influencing the Incidence of Cancer, 315

Effector Mechanisms in Tumor Immunity, 316

B-Cell Responses to Tumors, 317

Destruction of Tumor Cells by Opsonization and Phagocytosis, 318

Antibody-Mediated Loss of Adhesive Properties of Tumor Cells, 318

Cell-Mediated Responses to Tumor Cells, 318

Destruction of Tumor Cells by T Lymphocytes, 318


Destruction of Tumor by NK Cells, NK/T Cells, and Cytokine-Activated Killer Cells, 318

Destruction of Tumor Cells by Activated Macrophages and Neutrophils, 318

Cytokines, 319

Contents xiii

Limitations of the Effectiveness of the Immune Response against Tumors, 320

Immunodiagnosis, 320

Detection of Myeloma Proteins Produced by Plasma Cell Tumors, 321

Detection of α-Fetoprotein, 321

Carcinoembryonic Antigen, 321

Detection of Prostate-Specific Antigen, 321

Cancer Antigen-125, 321

Tumor Immunoprophylaxis, 321

Immunotherapy, 322

Other Immunotherapeutic Strategies in Cancer, 323




21 RESISTANCE AND IMMUNIZATION TO INFECTIOUS DISEASES, 328Introduction, 328

Host Defense against the Various Classes of Microbial Pathogens, 330

Immunity to Viruses, 330

Immunity to Bacteria, 331

Immunity to Parasites, 332

Immunity to Fungi, 333

Mechanisms by Which Pathogens Evade the Immune Response, 334

Encapsulated Bacteria, 334

Toxins, 334

Superantigens, 335

Antigenic Variation, 335

Intracellular Survival, 335

Suppression of the Immune System, 336

Extracellular Enzymes, 336

Expression of Antibody-Binding Proteins, 336

Principles of Immunization, 336

Objectives of Immunization, 337

Active Immunizations, 337

Recommended Immunizations, 337

Use of Vaccines in Selected Populations, 337

Basic Mechanisms of Protection, 339

Significance of the Primary and Secondary Responses, 339

Age and Timing of Immunizations, 339

Vaccine Precautions, 341

Site of Administration of Antigen, 341

Hazards, 341

Recent Approaches to Production of Vaccines, 342

Vaccines Produced by Recombinant DNA, 342

Conjugated Polysaccharides, 342

Synthetic Peptide Vaccines, 343

Virus-Carrier Vaccine, 343

Bacterium-Carrier Vaccine, 343

DNA Vaccines, 343

Toxoids, 343

Passive Immunization, 344

Passive Immunization through Placental Antibody Transfer, 344

Passive Immunization via Colostrum, 344

Passive Antibody Therapy and Serum Therapy, 344

Monoclonal and Polyclonal Preparations, 345

Preparation and Properties of Human Immune Serum Globulin, 346

Indications for the Use of Immune Globulin, 346

Precautions on the Uses of Human Immune Serum Globulin Therapy, 347

Colony-Stimulating Factors, 347




Glossary, 351

Appendix: Partial List of CD Antigens, 378

Index, 381

xv

Richard Coico is Professor of Cell Biology and Medicine and Vice Dean for Scientific Affairs at SUNY Downstate College of Medicine in New York. His major research interest concerns the study of the physiologic role of IgD—a B-cell membrane immunoglobulin co-expressed with IgM. Another area of research concerns computational approaches to the identification of candidate vaccines for several hemorrhagic viruses, including Ebola and Lassa Fever viruses. He serves on several editorial boards includ-ing Current Protocols in Immunology.

ABOUT THE AUTHORS

Geoffrey Sunshine is a Senior Scientist at the Health Effects Institute in Boston, Massachusetts, which funds research worldwide on the health effects of air pollution. He is also a lecturer in the Tufts School of Medicine immunol-ogy course. For several years, he has directed a course in immunology for graduate dental students at Tufts University School of Dental Medicine and previously directed a course for veterinary students at Tufts University School of Veteri-nary Medicine. He was also a member of the Sackler School of Graduate Biomedical Sciences at Tufts University, doing research on antigen presentation and teaching immunology to medical graduate and undergraduate students.

xvixvi

Philip L. CohenTemple University School of MedicinePhiladelphia, Pennsylvania

CONTRIBUTORS

Susan R.S. GottesmanDepartment of PathologySUNY Downstate College of MedicineBrooklyn, New York

xvii

As with our previous editions, the seventh edition of Immu-nology: A Short Course is intended to provide the reader with a clear and concise overview of our current understand-ing of the physiology of the immune system as well as the pathophysiology associated with various immune-mediated diseases. Although our knowledge of how the immune system develops and functions and the ways in which these physiological phenomena can fail or be compromised and thereby cause disease has significantly expanded since the previous edition, we have preserved our commitment to the motto less is more, the guiding light of this series. We are still committed to teaching our students and presenting to our readers only the information that we consider absolutely essential. To reflect this new knowledge, we have updated and rewritten every chapter in the sixth edition to incorpo-rate new findings or to remove information that no longer reflects current thinking. We have also provided new multi-ple choice questions and answers at the end of each chapter so that the reader can evaluate his or her understanding. We have also made one other pivotal change as compared with earlier editions: At its most basic level, and since the first edition of the book, we have introduced the subject of immune response by highlighting the fact that it can be split into two arms: the innate response and the adaptive immune response. The past decade has witnessed the delineation of innate immunity in ways that have revolutionized our under-standing of host–pathogen interactions and their impact on defense mechanisms in infectious diseases. Because of this growth in knowledge, we have added a new chapter on the subject of innate immunity (Chapter 2).

Other advances since the sixth edition include an explo-sion of targeted therapies for diseases ranging from cancer to Crohn’s disease. For many years the path toward this goal was principally pharmacologic in nature. Now, with the advent of hybridoma technology to generate monoclonal antibodies and their use in translational studies in humans, we have entered an era in which we are witnessing the potential for these antibodies to treat many different diseases including inflammatory and autoinflammatory disorders and cancer. Indeed, many antibody therapies are now approved for clinical use by the U.S. Food and Drug Administration. Similarly, the growth in our knowledge of cytokines, together with the successful development of soluble cytokine

PREFACE AND ACKNOWLEDGMENTS

receptors (antagonists), cytokine analogs, and anti-cytokine or anti-cytokine receptor antibodies has yielded many opportunities for therapeutic exploitation of this knowledge. The seventh edition highlights some of these important therapeutic successes and possibilities for success. We have also woven discussion of these therapies into chapters that deal with basic immune mechanisms. Our goal is to inspire the reader to consider how advances in the field of immunol-ogy have generated clinical and translational fruits that have improved health both through the prevention of infectious diseases using vaccines and by treating diseases with a variety of immune-based biological magic bullets, a term first coined by Paul Ehrlich more than 100 years ago.

Our goal is to provide a basic understanding of the immune system. For the reader who would like a more in-depth knowledge of clinical conditions, we refer in the text at several places to clinical cases in a companion book Immunology: Clinical Case Studies and Disease Pathophys-iology, edited by Warren Strober (NIAID/NIH) and Susan Gottesman (SUNY-Downstate) (ISBN: 9780471326595, see http://bit.ly/ICCSDPsg). We are confident that the synergy created by the material in the seventh edition of Immunology: A Short Course and the linked clinical cases will be a true asset to students of medicine and other health professions.

We are very grateful to Dr. Philip Cohen (Temple University School of Medicine), who updated Chapter 13 on the subject of “Tolerance and Autoimmunity.” We would also like to thank Dr. Susan Gottesman (SUNY-Downstate), who updated Chapter 18, “Immunodeficiency Disorders and Neoplasias of the Lymphoid System.” We also offer our profuse thanks to Dr. Gottesman for reviewing and provid-ing comments on drafts of every chapter, as well as writing many of the multiple choice questions and answers that are found on the accompanying website.

Richard Coico would like acknowledge the loving, enduring support of his wife, Lisa, during the writing of this book. “Her encouragement and inspiration is second to none with two possible exceptions, namely, our children, Jonathan and Jennifer. Jonathan, a talented writer himself, and Jen-nifer, an emerging public health advocate, are each blessed with patience and bright inquisitive minds”—the ideal mix of attributes for children and students alike. Finally, once

http://bit.ly/ICCSDPsg

xviii Preface and acknowledgments

again, he would like to thank his mentor, Dr. G. Jeanette Thorbecke, who greatly influenced his commitment and passion to the field of immunology. Special thanks also go to co-workers, including secretaries, office assistants, and other staff members who helped with the preparation of the manuscript.

Geoffrey Sunshine would like to thank his companion lecturers in the Tufts University School of Medicine immu-nology course, Peter Brodeur and Arthur Rabson. They pro-vided enormous help in addressing the key questions of what is important to teach students who know little or no immunology and how best to present this information. Peter also gave many constructive suggestions during the prepara-

tion of the current edition. In addition, Geoffrey would like to thank his wife, Ilene, for her continued support and under-standing during the writing, and his daughter, Caroline, for her help in revising the Glossary.

The authors also wish to express their appreciation to our copyeditor, William Krol; Stephanie Sakson, at Toppan Best-set Premedia; and to Martin Davies, Karen Moore, Elizabeth Norton, and Sam French of John Wiley and Sons, who helped to publish the seventh edition.

Richard CoicoGeoffrey Sunshine

xix

FEATURES CONTAINED WITHIN YOUR TEXTBOOK

Standard icons are used throughout this book to denote different immunological molecules

HOW TO USE YOUR TEXTBOOK

Tcell

antibody production

DNA RNA protein

protein

activatedT cell

Bcell

dendriticcell

deadcell

antigen-presentingcell (APC)

plasma cell antibody

G protein

Cytoplasmic proteintyrosine kinase

cytokine

cell membrane

cytokinereceptor

chemokinereceptorCD40

peptide

virus

bacterium

mastcell

natural killer (NK) cell

Icons used in this book

neutrophil macrophage erythrocyteeosinophil basophil

CD8CD28CD4

MHCclass II

processedpeptides

CD154

T cellreceptor

peptide

T cell receptor

MHCclass I

B7(CD80/CD86)

ZAP 70/Syktyrosine kinase

Src familytyrosine kinase

cell

Fcreceptor

antibody

membrane-attack complex

C1 complex

Complementcomponents

xx HOW TO USE YOUR TEXTBOOK

The case icon indicates that you can find a correlated clinical case in Immunology: Clinical Case Studies and Disease Pathophysiology, edited by Warren Strober (NIAID/NIH) and Susan Gottesman (SUNY-Downstate) (ISBN: 9780471326595; see http://bit.ly/ICCSDPsg).

Your textbook is full of photographs, illustrations, and tables.

arms of the immune system beginning with elements of the innate immune system followed by the adaptive immune system. But it is important to underscore the interrelation-ship of these two arms of our immune system. Clearly, they are interrelated developmentally due to their common hematopoietic precursor, the pluripotential stem cell. A classic example of their functional interrelationship is illus-trated by the roles played by innate immune cells involved in antigen presentation. These so-called antigen-presenting cells (APCs) do just what their name implies: they present antigens (e.g., pieces of phagocytized bacteria) to T cells within the adaptive immune system. As will be discussed in great detail in subsequent chapters, T cells must interact with APCs that display antigens for which they are speci�c in order for the T cells to be activated to generate antigen-speci�c responses. Thus, while the title of this section implies that the cells described below are principally involved in innate immune responses, it is important to recognize their important role in adaptive immune responses (Chapter 3) at this early stage of study of the immune system.

Figure 2.2. A PMN (surrounded by erythrocytes) with trilobed nucleus and cytoplasmic granules (×950). (Reproduced with permission from Olana and Walker, Infect Med 19: 318 [2007].)

Figure 2.3. Scanning electron micrograph of macrophage withruf�ed membrane and surface covered with microvilli (×5200).(Reproduced with permission from J Clin Invest 117 [2007].)

TABLE 2.2. Acute Phase Proteins

Protein Immune System Function

C-reactive protein • Binds to phosphocholine expressed on the surface of dead or dying cells and some types of bacteria

• Opsonin

Serum amyloid P component Opsonin

Serum amyloid A • Recruitment of immune cells to in�ammatory sites• Induction of enzymes that degrade extracellular matrix

Complement factors • Opsonization, lysis, and clumping of target cells• Chemotaxis

Mannan-binding lectin Mannan-binding lectin pathway of complement activation

Fibrinogen (α β globulin), prothrombin, factor VIII, von Willebrand factor

• Coagulation factors• Trapping invading microbes in blood clots.• Some cause chemotaxis

Plasminogen Degradation of blood clots

Alpha 2-macroglobulin• Inhibitor of coagulation by inhibiting thrombin.• Inhibitor of �brinolysis by inhibiting plasmin

Ferritin Binding iron, inhibiting microbe iron uptake

Hepcidin Stimulates the internalization of ferroportin, preventing release of iron bound by ferritin within intestinal enterocytes and macrophages

Ceruloplasmin Oxidizes iron, facilitating for ferritin, inhibiting microbe iron uptake

Haptoglobin Binds hemoglobin, inhibiting microbe iron uptake

Orosomucoid (Alpha-1-acid glycoprotein, AGP) Steroid carrier

Alpha 1-antitrypsin, Alpha alpha 1-antichymotrypsin Serpin, downregulates in�ammation

Figure 2.11. Leukocyte adhesion to endothelium leads to their adhesion, activation, and extrava-sation from the blood to tissue where they are needed to help destroy (e.g., phagocytize) path-ogens such as bacteria that initiate this response.

Chemokines(IL-1, IL-8,TNF-α)

Bacteria

RollingTethering Activation Adherenceand crawling

Blood flowLumen of blood vessel

Endothelium

Transendothelialmigration

Self-assessment review questions help you test yourself after each chapter.

REVIEW QUESTIONS

For each question, choose the ONE BEST answer or completion.

1. Which of the following applies uniquely with respect to B cells found in secondary lymphoid organs?A) present as precursor B cellsB) express only IgMC) terminally differentiate into plasma cellsD) undergo proliferation

2. The germinal centers found in the cortical region of lymph nodes and the peripheral region of splenic peri-arteriolar lymphatic tissueA) support the development of immature B and T cellsB) function in the removal of damaged erythrocytes

from the circulationC) act as the major source of stem cells and thus help

maintain hematopoiesisD) provide an infrastructure that on antigenic stimulation

contains large populations of B lymphocytes and plasma cells

E) are the sites of natural killer T (NKT)-cell differentiation

3. Which of the following sequence correctly describes lymphocyte migration from lymph nodes to blood?A) postcapillary venules, efferent lymphatic vessels, tho-

racic duct, vena cava, heartB) postcapillary venules, afferent lymphatic vessels, tho-

racic duct, vena cava, heartC) postcapillary venules, efferent lymphatic vessels,

vena cava, thoracic duct, heartD) postcapillary venules, afferent lymphatic vessels,

vena cava, thoracic duct, heart

4. Clonal expansion of which of the following cells occurs following their direct interaction with the antigen for which they are speci�c?A) macrophagesB) basophilsC) BcellsD) T cellsE) mast cells

http://bit.ly/ICCSDPsg

HOW TO USE YOUR TEXTBOOK xxi

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cells are, however, capable of responding to haemo-poietic growth factors with increased production of one or other cell line when the need arises.

e development of the mature cells ,sllec der( granulocytes, monocytes, megakaryocytes and lym-phocytes) is considered further in other sections of

.koob siht

e bone marrow forms a suitable environment for fo noitamrof dna lawener - fles ,lavivrus llec mets

erentiated progenitor cells. It is composed of .) 4.1 .giF( krowten ralucsavorcim a dna sllec lamorts

tseilrae eht si elpmaxe nA .aidem dilos - imes nidetectable mixed myeloid precursor which gives rise to granulocytes, erythrocytes, monocytes and meg-

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the primary site of origin of lymphocytes (see erentiate from a common

.rosrucerp diohpmyl e stem cell has the capability for self - renewal

-noc sniamer ytiralullec worram taht os ) 3.1 .giF( ere is con-

cation in the system: one stem cell is capable of producing about 10 6 doolb erutam

e precursor

Pluripotentstem cell

Erythroidprogenitors

CFUGEMMCommon myeloidprogenitor cell

BFUE

CFUE

CFUMegMegakary-ocyteprogenitor

CFUGMGranulocytemonocyteprogenitor

CFUEoEosinophilprogenitor

CFUGMEo

CFUbaso

Thymus

CFU-M CFU-G

Common lymphoidprogenitor cell

Redcells

Platelets Mono-cytes

Neutro-phils

Eosino-phils

Baso-phils

Lymphocytes NK cell

B T NK

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There you will find valuable material designed to enhance your learning, including:

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1

1

OVERVIEW OF THE IMMUNE SYSTEM

INTRODUCTION

Anyone who has had the good fortune to hear an orchestra brilliantly perform a symphony composed by one of the great masters knows that each of the carefully tuned musical instruments contributes to the collective, harmonious sound produced by the musicians. In many ways, the normally tuned immune system continuously plays an orchestrated symphony to maintain homeostasis in the context of host defenses. However, as William Shakespeare noted, “Untune that string, and, hark, what discord follows!” (Troilus and Cressida). Similarly, an untuned immune system can cause discord, which manifests as autoimmunity, cancer, or chronic inflammation. Fortunately for most of us, our immune system is steadfastly vigilant in regard to tuning (regulating) itself to ensure that its cellular components behave and interact symbiotically to generate protective immune responses that ensure good health. In many ways the immune system can be described in anthropomorphic terms: Its memory allows it to remember and recognize pathogens years or decades after initial exposure; it can distinguish between the body’s own cells and those of another organism; and it makes decisions about how to respond to particular pathogens—including whether or not to respond at all, as will be discussed in Chapters 2 and 3.

In his penetrating essays, scientist–author Lewis Thomas, discussing symbiosis and parasitism, described the forces that would drive all living matter into one huge ball of protoplasm were it not for regulatory and recognition mechanisms that allow us to distinguish self from nonself.

The origins of these mechanisms go far back in evolutionary history, and many, in fact, originated as markers for allowing cells to recognize and interact with each other to set up symbiotic households. Genetically related sponge colonies that are placed close to each other, for example, will tend to grow toward each other and fuse into one large colony. Unrelated colonies, however, will react in a different way, destroying cells that come in contact with each other and leaving a zone of rejection between the colonies.

In the plant kingdom, similar types of recognition occur. In self-pollinating species, a pollen grain landing on the stigma of a genetically related flower will send a pollen tubule down the style to the ovary for fertilization. A pollen grain from a genetically distinct plant either will not germi-nate or the pollen tubule, once formed, will disintegrate in the style. The opposite occurs in cross-pollinating species: self-marked pollen grains disintegrate, whereas nonself grains germinate and fertilize.

The nature of these primitive recognition mechanisms has not been completely worked out, but almost certainly it involves cell-surface molecules that are able to specifically bind and adhere to other molecules on opposing cell sur-faces. This simple method of molecular recognition has evolved over time into the very complex immune system that retains, as its essential feature, the ability of a protein molecule to recognize and bind specifically to a particular shaped structure on another molecule. Such molecular rec-ognition is the underlying principle involved in the discrimi-nation between self and nonself during an immune response. It is the purpose of this book to describe how the fully

Immunology: A Short Course, Seventh Edition. Richard Coico and Geoffrey Sunshine.© 2015 John Wiley & Sons, Ltd. Published 2015 by John Wiley & Sons, Ltd.Companion Website: www.wileyimmunology.com/coico

2 CHAPTER 1 OvERvIEw Of THE ImmUNE SySTEm

mature immune system—which has evolved from this simple beginning—makes use of this principle of recogni-tion in increasingly complex and sophisticated ways.

Perhaps the greatest catalyst for progress in this and many other biomedical areas has been the advent of molecular biologic techniques. It is important to acknowledge, however, that certain technological advances in the field of molecular biology were made possible by earlier progress in the field of immunology. For example, the importance of immunologic methods (Chapter 6) used to purify proteins as well as identify specific cDNA clones cannot be understated. These advances were greatly facilitated by the pioneering studies of Köhler and Milstein (1975), who developed a method for producing monoclonal antibodies. Their achievement was rewarded with the Nobel Prize in Medicine. It revolutionized research efforts in virtually all areas of biomedical science. Some monoclonal antibodies produced against so-called tumor-specific antigens have now been approved by the US Food and Drug Admin-istration for use in patients to treat certain malignancies. Monoclonal antibody technology is, perhaps, an excellent example of how the science of immunology has transformed not only the field of medicine but also fields ranging from agriculture to the food science industry.

Given the rapid advances occurring in immunology and the many other biomedical sciences and, perhaps most important, the sequencing of the human genome, every con-temporary biomedical science textbook runs a considerable risk of being outdated before it appears in print. Neverthe-less, we take solace from the observation that new formula-tions generally build on and expand the old rather than replacing or negating them completely. Let’s begin, there-fore, with an overview of innate and adaptive immunity (also called acquired immunity) which continue to serve as a conceptual compass that orients our fundamental under-standing of host defense mechanisms.

INNATE AND ADAPTIvE ImmUNITy

The Latin term immunis, meaning “exempt,” gave rise to the English word immunity, which refers to all the mecha-nisms used by the body as protection against environmental agents that are foreign to the body. These agents may be microorganisms or their products, foods, chemicals, drugs, pollen, or animal hair and dander.

Innate Immunity

Innate immunity is conferred by all those elements with which an individual is born and that are always present and available at very short notice to protect the individual from challenges by foreign invaders. The major properties of the innate immune system are discussed in Chapter 2. Table 1.1 summarizes and compares some of the features of the innate and adaptive immune systems. Elements of the innate system

TABLE 1.1. Major Properties of the Innate and Adaptive Immune Systems

Property Innate Adaptive

Characteristics Antigen nonspecific Antigen specificRapid response

(minutes to hours)Slow response (days)

No memory Memory

Immune components

Natural barriers (e.g., skin, mucous membranes)

Lymphocytes

Phagocytes and natural killer cells

Antigen recognition molecules (B and T cell receptors)

Soluble mediators (e.g., complement)

Secreted molecules (e.g., antibody)

Pattern recognition molecules

include body surfaces and internal components, such as the skin, the mucous membranes, and the cough reflex, which present effective barriers to environmental agents. Chemical influences, such as pH and secreted fatty acids, constitute effective barriers against invasion by many microorganisms. Another noncellular element of the innate immune system is the complement system. As in the previous editions of this book, we cover the subject of complement in Chapter 14.

Numerous other components are also features of innate immunity: fever, interferons (Chapter 12), other substances released by leukocytes, and pattern-recognition molecules (innate receptors), which can bind to various microorgan-isms (e.g., Toll-like receptors or TLRs; Chapter 2), as well as serum proteins such as β-lysin, the enzyme lysozyme, polyamines, and the kinins, among others. All of these ele-ments either affect pathogenic invaders directly or enhance the effectiveness of host reactions to them. Other internal elements of innate immunity include phagocytic cells such as granulocytes, macrophages, and microglial cells of the central nervous system, which participate in the destruction and elimination of foreign material that has penetrated the physical and chemical barriers.

Adaptive Immunity

We introduce the subject of adaptive immunity in Chapter 3. Later chapters provide more details about the cellular and molecular features of this arm of the immune system. Adap-tive immunity came into play relatively late, in evolutionary terms, and is present only in vertebrates. Although an indi-vidual is born with the capacity to mount immune responses to foreign substances, the number of B and T cells available for mounting such responses must be expanded before one is said to be immune to that substance. This is achieved by activation of lymphocytes bearing antigen-specific receptors

Clonal SeleCtion theory 3

CLONAL SELECTION THEORy

A turning point in immunology came in the 1950s with the introduction of a Darwinian view of the cellular basis of specificity in the immune response. This was the now univer-sally accepted clonal selection theory proposed and devel-oped by Jerne and Burnet (both Nobel Prize winners) and by Talmage. The clonal selection theory had a truly revolutionary effect on the field of immunology. It dramatically changed our approach to studying the immune system and stimulated research carried out during the last half of the twentieth century. This work ultimately provided us with knowledge regarding the molecular machinery associated with activation and regulation of cellular elements of the immune system. The essential postulates of this theory are summarized below.

As we have discussed earlier, the specificity of the immune response is based on the ability of B and T lym-phocytes to recognize particular foreign molecules (anti-gens) and respond to them in order to eliminate them. The process of clonal expansion of these cells is highly efficient, but there is always the rare chance that errors or mutations will occur, resulting in the generation of cells bearing recep-tors that bind poorly or not at all to the antigen, or, in a worse-case scenario, cells that have autoreactivity. Under normal conditions, nonfunctional cells may survive or be aborted with no deleterious consequences to the individual. In contrast, the rare self-reactive cells are clonally deleted or suppressed by other regulatory cells of the immune system charged with this role among others. If such a mech-anism were absent, autoimmune responses might occur rou-tinely. It is noteworthy that during the early stages of development, lymphocytes with receptors that bind to self-antigens are also produced, but fortunately they are also eliminated or functionally inactivated. This process gives rise to the initial repertoire of mature lymphocytes that are programmed to generate antigen-specific responses with a relatively minute population functionally benign, albeit potentially autoreactive cells (Figure 1.1). The circum-stances and predisposing genetic conditions that may lead to the latter phenomenon are discussed in Chapter 13.As we have already stated, the immune system is capable of recognizing innumerable foreign substance serving as anti-gens. How is a response to any one antigen accomplished? In addition to the now-proven postulate that self-reactive clones of lymphocytes are functionally inactivated or aborted, the clonal selection theory proposed the following:

• T and B lymphocytes of a myriad of specificities exist before there is any contact with the foreign antigen.

• Lymphocytes participating in an immune response express antigen-specific receptors on their surface membranes. As a consequence of antigen binding to the lymphocyte, the cell is activated and releases various products. In the case of B lymphocytes, these receptors, so-called B-cell receptors (BCRs), are the

following their contact with the antigen. Antigenic stimulation of B cells and T cells together with antigen-presenting cells (APCs) initiates a chain of events that leads to proliferation of activated cells together with a program of differentiation events that generate the B- or T-effector cells responsible for the humoral or cell-mediated responses, respectively. These events take time to unfold (days to weeks). Fortunately, the cellular and noncellular components of the innate system are rapidly mobilized (minutes to hours) to eliminate or neutralize the foreign substance. One way to think about this host defense strategy is to consider this as a one-two punch launched ini-tially by innate cells and noncellular elements of the immune system that are always available to quickly remove or cordon off the invader, followed by a round of defense that calls into play cells of the adaptive immune system (B and T cells) that are programmed to react with the foreign substance by virtue of their antigen-specific receptors. Moreover, the clonal expansion of these cells—a process first explained by the clonal selection theory discussed in the section below—gives rise to an arsenal of antigen-specific cells available for rapid responses to the same antigen in the future, a phenomenon referred to as memory responses. By this process, the indi-vidual acquires the immunity to withstand and resist a subse-quent attack by, or exposure to, the same offending agent.

The discovery of adaptive immunity predates many of the concepts of modern medicine. It has been recognized for centuries that people who did not die from such life-threatening diseases as bubonic plague and smallpox were subsequently more resistant to the disease than were people who had never been exposed to it. The rediscovery of adap-tive immunity is credited to the English physician Edward Jenner, who, in the late eighteenth century, experimentally induced immunity to smallpox. If Jenner performed his experiment today, his medical license would be revoked, and he would be the defendant in a sensational malpractice lawsuit: He inoculated a young boy with pus from a lesion of a dairy maid who had cowpox, a relatively benign disease that is related to smallpox. He then deliberately exposed the boy to smallpox. This exposure failed to cause disease! Because of the protective effect of inoculation with cowpox (vaccinia, from the Latin word vacca, meaning “cow”), the process of inducing adaptive immunity has been termed vaccination.

The concept of vaccination or immunization was expanded by Louis Pasteur and Paul Ehrlich almost 100 years after Jenner’s experiment. By 1900, it had become apparent that immunity could be induced against not only microorgan-isms but also their products. We now know that immunity can be induced against innumerable natural and synthetic com-pounds, including metals, chemicals of relatively low molec-ular weight, carbohydrates, proteins, and nucleotides.

The compound to which the adaptive immune response is induced is termed an antigen, a term initially coined due to the ability of these compounds to cause antibody responses to be generated. Of course, we now know that antigens can generate antibody-mediated and T-cell–mediated responses.

4 CHAPTER 1 OvERvIEw Of THE ImmUNE SySTEm

tors. They are stimulated under appropriate conditions to proliferate and differentiate into clones of cells with the corresponding epitope-specific receptors.

• With B-cell clones, this will lead to the synthesis of antibodies having the same specificity. In most cases, the antigen stimulating the response is complex and contains many different epitopes, each capable of activating a clone of epitope-specific B cells. Hence, collectively, the clonally secreted antibodies constitute what is often referred to as polyclonal antiserum, which is capable of interacting with the multiple epitopes expressed by the antigen.

• T cells are similarly selected by appropriate epitopes or portions thereof. Each selected T cell will be activated to divide and produce clones of the same specificity. Thus the clonal response to the antigen will be ampli-fied, the cells will release various cytokines, and sub-sequent exposure to the same antigen will now result in the activation of many cells or clones of that specificity. Instead of synthesizing and releasing antibodies like the B cells, the T cells synthesize and release cytokines. These cytokines, which are soluble mediators, exert their effect on other cells to grow or become activated facilitating elimination of the antigen. Several distinct regions of an antigen (epitopes) can be recognized: Several different clones of B cells will be stimulated to produce antibody, whose sum total is an antigen-specific antiserum that is made up of antibodies of differing specificity (Figure 1.1); all the T-cell clones that recog-

very molecules that subsequently get secreted as anti-bodies following B-cell activation.

• T cells have receptors denoted as T-cell receptors (TCRs). Unlike the B-cell products, the T-cell products are not the same as their surface receptors but are other protein molecules, called cytokines, that participate in elimination of the antigen by regulating the many cells needed to mount an effective immune response.

• Each lymphocyte carries on its surface receptor mol-ecules of only a single specificity as demonstrated in Figure 1.1 for B cells and also holds true for T cells.

These postulates describe the existence of a large rep-ertoire of possible specificities formed by cellular multipli-cation and differentiation before there is any contact with the foreign substance to which the response is to be made. The introduction of the foreign antigen then selects from among all the available specificities those with specificity for the antigen, enabling binding to occur. The scheme shown in Figure 1.1 for B cells also applies to T cells; however, T cells have receptors that are not antibodies and secrete molecules other than antibodies.

The remaining postulates of the clonal selection theory account for this process of selection by the antigen from among all the available cells in the repertoire.

• Immunocompetent lymphocytes combine with the foreign antigen, or a portion of it termed the epitope or antigenic determinant, by virtue of their surface recep-

Figure 1.1. Clonal selection theory of B cells leading to antibody formation.

Stem cell

Uncommitted cells

Early differentiation oflymphoid precursor cells

Removal of self-reactiveimmature lymphocytes

Pool of non-self-reactivemature lymphocytes

Antigen stimulation oflymphocyte clones

Anti-7 IgAnti-4 Ig

Antiserum to antigen

Anti-3 Ig

1

1

2 3 4

4

5

5

6 7

3 7

7 7

7 7

44

33

34

34

8

fleSfleSfleS

Antigen

IMMUNOLOGY · v 1 overview of the immune system, 1 2 innate immunity, 11 3 adaptive immunity, 26 4 immunogens and antigens, 35 5 antibody structure and function, 47

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