Immunology:a short course/ Richard Coico

O 1 OVERVIEW OF THE IMMUNE SYSTEM, 1
Introduction, 1
Innate and Acquired Immunity, 2
Innate Immunity, 2
Acquired Immunity, 2
Active, Passive, and Adoptive Immunization, 3
Clonal Selection Theory, 4
Humoral and Cellular 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, 10
O 2 ELEMENTS OF INNATE AND ACQUIRED
IMMUNITY, 11
Introduction, II
Innate Immunity, 11
Physical and Chemical Barriers ofInnate Immunity, 11
Intracellular and Extracellular Killing
of Microorganisms, 12
Cells Involved in the Innate Immune System, 14
Inflammation, 16
Fever, 17
Biologically Active Substances, 18
Receptors Involved in the Innate Immune System, 18
Pattern Recognition Receptors, 18
Acquired Immunity, 19
Cells and Organs Involved in Acquired Immunity, 20
The Lymphatic Organs, 20
Lymphocyte Migration and Recirculation, 23
CONTENTS
Fate of Antigen After Penetration, 24
Frequency ofAntigen-Specific Naive Lymphocytes, 25
Interrelationship Between Innate and Acquired
Immunity, 25
Summaiy, 26
References, 26
Review Questions, 26
Answers to Review Questions, 27
O 3 IMMUNOGENS AND ANTIGENS, 29
Introduction, 29
Requirements for Immunogenicity, 29
Foreignness, 29
High Molecular Weight, 30
Chemical Complexity, 30
Degradability, 30
Haptens, 30
Further Requirements for Immunogenicity, 31
Primary and Secondary Immune Responses, 32
Antigenicity and Antigen-Binding Site, 32
Epitopes Recognized by B and T Cells, 33
Major Classes of Antigens, 34
Binding of Antigen to Antigen-Specific Antibodies
or T Cell Receptors, 35
Cross-Reactivity, 35
Adjuvants, 36
Summary, 37
References, 38
Review Questions, 38
Answers to Review Questions, 39
O 4 ANTIBODY STRUCTURE AND FUNCTION, 41
Introduction, 41
Isolation and Characterization of Immunoglobulins, 42
Structure of Light and Heavy Chains, 42
Immunoglobulin Domains, 44
Immunoglobulin Hinge Region, 45
Immunoglobulin Variable Region, 45
IX
Immunoglobulin Variants, 47
Isotypes, 47
Allotypes, 47
Idiotypes, 47
Structural Features of IgG, 49
Biologic Properties of IgG, 49
Agglutination and Formation of Precipitate, 50
Passage of Ig Through the Placenta and Absorption
in Neonates, 51
Opsonization, 51
Antibody-Dependent, Cell-Mediated Cytotoxicity, 52
Activation of Complement, 52
Neutralization of Toxins, 52
Immobilization of Bacteria, 52
Neutralization of Viruses, 52
Structural Features of IgM, 52
Biologic Properties of IgM, 53
Complement Fixation, 53
First Line of Humoral Defense, 53
Agglutination, 54
Isohemagglutinins, 54
Structural and Biologic Properties of IgA, 54
Biologic Properties of IgA, 54
Role in Mucosal Infections, 54
Bactericidal Activity, 55
Antiviral Activity, 55
Structural and Biologic Properties of IgD, 55
Structural and Biologic Properties of IgE, 55
Importance of IgE in Parasitic Infections
and Hypersensitivity Reactions, 56
Kinetics of Antibody Responses Following
Immunization, 56
Primary Response, 56
Secondary Response, 56
The Immunoglobulin Superfamily, 57
Summary, 58
References, 58
Review Questions, 59
Answers to Review Questions, 60
O 5 ANTIGEN-ANTIBODY INTERACTIONS,
IMMUNE ASSAYS, AND EXPERIMENTAL
SYSTEMS, 61
Introduction, 61
Antigen-Antibody Interactions, 61
Primary Interactions Between Antibody and Antigen, 62
Association Constant, 63
Affinity and Avidity, 63
Secondary Interactions Between Antibody and Antigen, 63
Agglutination Reactions, 63
Precipitation Reactions, 65
Immunoassays, 67
Direct-Binding Immunoassays, 67
Solid-Phase Immunoassays, 68
Immunofluorescence, 70
Direct Immunofluorescence, 70
Indirect Immunofluorescence, 70
Fluorescence-Activated Cell-Sorting Analysis, 70
Immunoabsorption and Immunoadsorption, 71
Cellular Assays, 71
Assays to Assess Lymphocyte Function, 71
B- and T-Cell Proliferation Assays, 72
Assays that Assess Antibody Production by B Cells, 72
Effector Cell Assays for T and NK Cells, 72
Cell Culture, 72
Primary Cell Cultures and Cloned Lymphoid
Cell Lines, 73
B-Cell Hybridomas and Monoclonal Antibodies, 73
T-Cell Hybridomas, 74
Genetically Engineered Molecules and Receptors, 74
Experimental Animal Models, 75
Inbred Strains, 75
Adoptive Transfer, 75
SCID Mice, 75
Thymectomized and Congenically Athymic (Nude)
Mice, 76
Transgenic Mice and Gene Targeting, 76
Transgenic Mice, 76
Knockout Mice, 76
Analysis of Gene Expression: Microarrays, 77
Summary, 78
References, 79
Review Questions, 79
Answers to Review Questions, 80
O 6 THE GENETIC BASIS OF ANTIBODY
STRUCTURE, 81
Introduction, 81
A Brief Review of Nonimmunoglobulin Gene Structure
and Gene Expression, 81
Genetic Events in Synthesis of Ig Chains, 83
Organization and Rearrangement of Light-Chain
Genes, 83
Organization and Rearrangement of Heavy-Chain
Genes, 84
Regulation of Ig Gene Expression, 85
Class or Isotype Switching, 86
Generation of Antibody Diversity, 87
Presence of Multiple V Genes in the Germline, 87
VJ and VDJ Combinatorial Association, 87
CONTENTS
CONTENTS
Random Assortment of H and L Chains, 87
Junctional Diversity, 87
Somatic Hypermutation, 87
Somatic Gene Conversion, 88
Receptor Editing, 88
Role of Activation-Induced Cytidine Deaminase
in Generating Antibody Diversity, 88
Summary, 89
References, 89
Review Questions, 90
Case Study, 91
Answers to Review Questions, 91
Answer to Case Study, 91
O 7 BIOLOGY OF THE BLYMPHOCYTE, 93
Introduction, 93
Development of B Lymphocytes, 93
Overview, 93
Sites of Early B-Cell Differentiation, 94
Early Stages of B-Cell Differentiation: Pro-B
and Pre-B Cells, 94
Immature B Cells, 95
Mature B Cells, 96
B-Lymphocyte Traffic: Anatomical Distribution
of B-Cell Populations, 97
Sites of Antibody Synthesis, 98
Thymus-Dependent Antibody Synthesis in the
Germinal Center, 98
Antibody Synthesis in Mucosal Tissue, 100
Thymus-Independent Antibody Responses at Different
Sites, 101
B-Cell Membrane Proteins, 102
Stage-Specific Markers, 103
Antigen-Binding Molecules: Membrane
Immunoglobulin, 103
Signal Transduction Molecules Associated
with Membrane Immunoglobulin, 103
Molecules Involved in T Cell-B Cell Interactions, 104
Summary, 104
References, 105
Review Questions, 105
Answers to Review Questions, 106
O 8 ROLE OF THE MAJOR HISTOCOMPATIBILITY
COMPLEX IN THE IMMUNE RESPONSE, 107
Introduction, 107
How the MHC Got Its Name, 107
Different MHC Molecules Interact with Different Sets
of T Cells, 108
Variability of MHC Class I and MHC Class II
Molecules, 109
Structure of MHC Class I Molecules, 109
Selectivity of Peptide Binding to MHC Class I
Molecules, 111
CD8 Binding to Invariant Region of MHC Class I
Molecules, 111
Structure of MHC Class II Molecule, 111
Antigen Processing and Presentation: How MHC
Molecules Bind Peptides and Create Ligands that
Interact with T Cells, 111
Exogenous Antigens and Generation of MHC Class
n-Peptide Complexes, 112
Endogenous Antigens: Generation of MHC Class
I-Peptide Complexes, 114
Decreased MHC Class I Expression in Virus-Infected
and Tumor Cells, 115
Cross-Presentation: Exogenous Antigens Presented
in the MHC Class I Pathway, 116
Which Antigens Trigger Which T-Cell
Responses?, 116
Binding of Peptides Derived from Self-Molecules
by MHC Molecules, 116
Inability to Respond to an Antigen, 117
Other Types of Antigen that Activate T-Cell
Responses, 117
Lipids and Glycolipids Presented by CDl to NKT
Cells, 118
Genes of the HLA Region, 118
Polymorphic MHC Class I and II Genes, 118
Nomenclature of Polymorphic MHC Molecules, 118
Regulation of Expression of MHC Genes, 119
Codominant Expression, 119
Coordinate Regulation, 119
Inheritance of MHC Genes, 119
Other Genes Within HLA, 120
MHC in Other Species, 120
Diversity of MHC Molecules: MHC Association
with Resistance and Susceptibility to Disease, 121
Summary, 122
References, 123
Review Questions, 123
Answers to Review Questions, 124
O 9 BIOLOGY OF THE TLYMPHOCYTE, 125
Introduction, 125
The Antigen-Specific T-Cell Receptor, 125
Molecules that Interact with Antigen, 125
T-Cell Receptor Complex, 127
Coreceptor Molecules, 127
Other Important Molecules Expressed on the T-Cell
Surface, 128
XI
Xll
Genes Coding for T-Cell Receptors, 130
Generation of T-Cell Receptor Diversity, 130
T-Cell Differentiation in Thymus, 131
Interactions of Developing T Cells with Nonlymphoid
Cells of Thymus, 131
Early T-Cell Receptor Gene Rearrangements:
Double-Negative Cells and Splitting Off
of yST Cells, 132
Pre-T Cells, 133
Double-Positive Cells, 133
Thymic Selection, 134
Role of AIRE Gene Product in Negative Selection, 134
Single-Positive Cells, 135
Generation of the T-Cell Repertoire, 135
Characteristics of ap T Cells Emerging
from Thymus, 135
Further Differentiation of CD4+ and CDS"^ T Cells
Outside Thymus, 136
Differentiation of Other Sets of Cells in Thymus, 136
Summary, 136
References, 137
Review Questions, 138
Answers to Review Questions, 138
O 10 ACTIVATION AND FUNCTION
OF T AND B CELLS, 141
Introduction, 141
Activation of CD4+ T Cells, 141
Specialized Cells Present Antigen to Naifve CD4''"
T Cells, 141
Paired Interactions at the Surface of APC and CD4+
T Cells, 143
Intracellular Events in CD4+ T-Cell Activation, 144
Clonal Expansion, Differentiation to Effector Cells,
and Migration Out of the Lymph Node, 147
Other Ways to Activate CD4"'" T Cells, 147
Superantigens, 148
Plant Proteins and Antibodies to T-Cell Surface
Molecules, 148
T-Cell Function, 148
Subsets of CD4+ T Cells Defined by Cytokine
Production and Effector Function, 148
CD4+ T Cells, 148
T-Helper-Cell Function: Interaction of CD4"'' T Cells
with B Cells to Synthesize Antibody, 151
Activation and Function of
CDS"^ T Cells, 153
Generation of Effector CD8+ T Cells, 154
CD8'^ T-Cell Killing of Target Cells, 154
MHC Restriction and CDS"^ T Cell Killer
Function, 156
Tentiination of the Response: Induction of Memory
Cells, 156
Function of NKT Cells and T Cells. 157
NKT Cells. 157
yh T Cells, 157
B-Cell Function: Antibody Synthesis in the
Absence of
T-Cell Help, 157
Conjugate Vaccines, 158
Intracellular Pathways in B-Cell Activation, 159
Modulation of BCR Signal, 160
Summary, 161
References, 162
Review Questions, 162
Answers to Review Questions, 163
O 11 CYTOKINES, 165
Introduction, 165
The History of Cytokines, 165
Pleiotropic and Redundant Properties of Cytokines, 166
General Properties of Cytokines, 166
Common Functional Properties, 166
Common Systemic Activities, 167
Common Cell Sources and Cascading Events, 168
Functional Categories of Cytokines, 168
Cytokines that Facilitate Innate Immune
Responses, 168
Cytokines that Regulate Adaptive Immune
Responses, 170
Cytokines that Induce Differentiation of Distinct
T-Cell Lineages, 170
Cytokines that Inhibit Lineage-Specific T-Cell
Differentiation, 171
Cytokines that Promote Inflammatory Responses, 171
, Cytokines that Affect Leukocyte Movement, 172
Cytokines that Stimulate Hematopoiesis, 173
Cytokine Receptors, 174
Cytokine Receptor Families, 174
Common Cytokine Receptor Chains, 175
Cytokine Receptor-Mediated Signal Transduction, 176
Role of Cytokines and Cytokine Receptors in Disease, 176
Toxic-Shock Syndrome, 176
Bacterial Septic Shock, 177
Cancers, 177
Autoimmunity and Other Immune-Based Diseases, 177
Therapeutic Exploitation of Cytokines and Cytokine
Receptors, 178
Cytokine Inhibitors/Antagonists, 178
Reversing Cellular Deficiencies, 179
Treatment of Immunodeficiencies, 179
Treatment of Cancer and Transplant Patients, 179
Treatment of Allergies and Asthma, 180
Summary, 180
CONTEHTS
CONTENTS
References, 181
Review Questions, 181
Answers to Review Questions, 182
O 12 TOLERANCE AND AUTOIMMUNITY, 183
Introduction, 183
Central Tolerance, 184
Anergy, Receptor Editing, Deletion, and Clonal
Ignorance, 184
Peripheral Tolerance, 186
Anergy, 186
Fas-FasL Interactions, 187
Regulatory/Suppressor T Cells, 188
Oral Tolerance, 189
Immune Privilege, 190
Autoimmunity and Disease, 190
Genetic Susceptibility, 190
Environmental Susceptibility, 192
Drug and Hormonal Triggers of Autoimmunity, 193
Autoinmiune Diseases, 193
Autoimmune Diseases in Which Antibodies Play a
Predominant Role in Mediating Organ Damage, 194
Autoimmune Diseases in Which T Cells Play a
Predominant Role in Organ Damage, 198
Therapeutic Strategies, 201
Summary, 201
References, 202
Review Questions, 203
Answers to Review Questions, 204
O 13 COMPLEMENT, 205
Introduction, 205
Overview of Complement Activation, 205
Classical Pathway, 206
Lectin Pathway, 207
Alternative Pathway, 207
Steps Shared by All Pathways: Activation of C3
and C5, 209
Terminal Pathway, 209
Regulation of Complement Activity, 210
Biologic Activities of Complement, 212
Production of Opsonins, 212
Production of Anaphylatoxins, 213
Lysis, 214
Other Important Complement Functions, 214
Complement Deficiencies, 216
Summary, 217
References, 218
Review Questions, 218
Answers to Review Questions, 219
O 14 HYPERSENSITIVITY: TYPE I. 221
Introduction, 221
Coombs-Gell Hypersensitivity Designations, 221
General Characteristics of Allergic Reactions, 222
Sensitization Phase, 222
Activation Phase, 223
Effector Phase, 224
Late-Phase Reaction, 226
Clinical Aspects of Allergic Reactions, 228
Allergic Rhinitis, 228
Food Allergies, 228
Atopic Dermatitis, 229
Asthma, 229
Clinical Tests for Allergies and Clinical Intervention, 229
Detection, 229
Intervention, 229
Protective Role of IgE, 231
Summary, 233
References, 233
Review Questions, 234
Answers to Review Questions, 235
O 15 HYPERSENSITIVITY: TYPES II AND III, 237
Introduction, 237 .
TVpe II Hypersensitivity, 237
Complement-Mediated Reactions, 237
Antibody-Dependent, Cell-Mediated Cytotoxicity, 237
Antibody-Mediated Cellular Dysfunction, 238
Examples of l^pe II Hypersensitivity Reactions, 239
Transfusion Reactions, 239
Drug-Induced Reactions, 239
Rh Incompatibility Reactions, 239
Reactions Involving Cell Membrane Receptors, 240
Reactions Involving Other Cell Membrane
Determinants, 240
Type III Hypersensitivity, 240
Systemic Immune Complex Disease, 241
Localized Immune Complex Disease, 243
Summary, 244
References, 245
Review Questions, 245
Answers to Review Questions, 246
O 16 HYPERSENSITIVITY: TYPE IV, 247
Introduction, 247
General Characteristics and Pathophysiology of DTH, 247
Mechanisms Involved in DTH, 248
Examples of DTH, 249
XIII
XIV
Contact Sensitivity, 249
Granulomatous Hypersensitivity, 250
Tuberculin-Type Hypersensitivity, 251
Allograft Rejection, 252
Additional Examples of DTH, 252
Treatment of DTH, 252
Summary, 252
References, 253
Review Questions, 253
Answers to Review Questions, 254
O 17 IMMUNODEFICIENCY DISORDERS
AND NEOPLASIAS OF THE LYMPHOID SYSTEM, 255
Introduction, 255
Immunodeficiency Syndromes, 256
Primary Immunodeficiency Syndromes, 256
Secondary Immunodeficiency Diseases, 268
Acquired Immunodeficiency Syndrome, 268
Initial Description and Epidemiology, 268
Human Immunodeficiency Virus, 269
Clinical Course, 270
Prevention, Control, Diagnosis, and Therapy of HIV
Infection, 272
Neoplasms of Lymphoid System, 273
B-Cell Neoplasms, 274
T-Cell Neoplasms, 278
Hodgkin Lymphoma, 279
Immunotherapy, 279
Summary, 280
References, 280
Review Questions, 281
Answers to Review Questions, 282
O 18 TRANSPLANTATION, 285
Introduction, 285
Relationship Between Donor and Recipient, 285
Immune Mechanisms Responsible for Allograft
Rejection, 287
Categories of Allograft Rejection, 287
Hyperacute Rejection, 287
Acute Rejection, 287
Chronic Rejection, 288
Role of MHC Molecules in Allograft Rejection, 288
Mechanisms of Alloantigen Recognition
by T Cells, 288
Role of T-Cell Lineages and Cytokines in Allograft
Rejection, 289
Laboratory Tests Used in Tissue Typing, 290
Prolongation of Allograft Survival: Immunosuppresive
Therapy, 291
Anti-Inflammatory Agents, 291
Cytotoxic Drugs, 292
Agents that Interfere with Cytokine Production
and Signaling, 292
Immunosuppressive Antibody Therapy, 293
New Immunosuppressive Strategies and Frontiers, 293
Hematopoietic Stem Cell Transplantation, 293
Graft-Versus-Host Disease, 294
Xenogeneic Transplantation, 295
The Fetus: A Tolerated Allograft, 295
Summary, 295
References, 296
Review Questions, 296
Answers to Review Questions, 297
O 19 TUMOR IMMUNOLOGY, 299
Introduction, 299
Tumor Antigens, 299
Categories of Tumor Antigens, 300
Normal Cellular Gene Products, 300
Mutant Cellular Gene Products, 301
Tumor Antigens Encoded by Oncogenes, 302
Immunologic Factors Influencing the Incidence of
Cancer, 302
Effector Mechanisms in Tumor Immunity, 303
B-Cell Responses to Tumors, 305
Cell-Mediated Responses to Tumor Cells, 305
Cytokines, 306
Limitations of the Effectiveness of Immune Responses
Against Tumors, 307
Immunodiagnosis, 307
Detection of Myeloma Proteins Produced by Plasma
Cell Tumors, 308
Detection of a-Fetoprotein, 308
Carcinoembryonic Antigen, 308
Detection of Prostate-Specific Antigen, 308
Cancer Antigen-125, 308
Radiolabeled Monoclonal Antibody B72.3, 308
Tumor Immunoprophylaxis, 308
Immunotherapy, 309
Summary, 311
References, 311
Review Questions, 312
Answers to Review Questions, 312
O 20
RESISTANCE AND IMMUNIZATION
TO INFECTIOUS DISEASES, 313
Introduction, 313
CONTENTS
CONTENTS
Host Defense Against Various Classes of Microbial
Pathogens, 315
Immunity to Viruses, 315
Immunity to Bacteria, 316
Immunity to Parasites, 317
Immunity to Fungi, 318
Mechanisms by Which Pathogens Evade Immune
Responses, 318
Encapsulated Bacteria, 318
Toxins, 319
Superantigens, 319
Antigenic Variation, 319
Intracellular Survival, 320
Suppression of the Immune System, 320
Extracellular Enzymes, 321
Expression of Antibody-Binding Proteins, 321
Principles of Immunization, 321
Objectives
of Immunization, 321
Active Immunizations, 322
Recommended Immunizations, 322
Use of Vaccines in Selected Populations, 322
Basic Mechanisms of Protection, 324
Significance of Primary and Secondary
Immune Responses, 324
Age and Timing of Immunizations, 324
Vaccine Precautions, 326
Site of Administration of Antigen, 326
Hazards, 326
Recent Approaches to Production of Vaccines, 327
Vaccines Produced by Recombinant DNA, 327
Conjugated Polysaccharides, 327
Synthetic Peptide Vaccines, 327
Anti-Idiotype Vaccines, 327
Virus-Carrier Vaccine, 328
Bacterium-Carrier Vaccine. 328
DNA Vaccines, 328
Toxoids, 328
Passive Immunization, 328
Passive Immunization Through Placental Antibody
Transfer, 329
Passive Immunization via Colostrum, 329
Passive Antibody Therapy and Serum
Therapy, 329
Monoclonal and Polyclonal Antibodies, 330
Preparation and Properties of Human Immune Serum
Globulin, 331
Indications for Use of Immune Globulin, 331
Precautions About Uses of Human Immune Serum
Globulin Therapy, 332
Colony-Stimulating Factors, 332