1 Properties and Overview of Immune Responses
INNATE AND ADAPTIVE IMMUNITY, 2
INNATE IMMUNITY: THE EARLY DEFENSE, 3
ADAPTIVE IMMUNITY, 4
- Cardinal Features of Adaptive Immune Responses, 4
- Overview of Humoral and Cell-Mediated Immunity, 5
- Initiation and Development of Adaptive Immune Responses, 8
- Humoral Immunity, 10
- Cell-Mediated Immunity, 10
SUMMARY, 11
2 Cells and Tissues of the Immune System
CELLS OF THE IMMUNE SYSTEM, 13
- Phagocytes, 14
- Mast Cells, Basophils, and Eosinophils, 17
- Lymphocytes, 21
- Natural Killer Cells and Cytokine-Secreting Innate Lymphoid Cells, 27
ANATOMY AND FUNCTIONS OF LYMPHOID TISSUES, 27
- Bone Marrow, 28
- Thymus, 28
- The Lymphatic System, 30
- Lymph Nodes, 32
- Spleen, 35
- Cutaneous and Mucosal Immune Systems, 36
SUMMARY, 36
3 Leukocyte Circulation and Migration into Tissues
OVERVIEW OF LEUKOCYTE MIGRATION, 39
ADHESION MOLECULES ON LEUKOCYTES AND ENDOTHELIAL CELLS INVOLVED IN LEUKOCYTE RECRUITMENT, 41
- Selectins and Selectin Ligands, 41
- Integrins and Integrin Ligands, 42
CHEMOKINES AND CHEMOKINE RECEPTORS, 43
- Chemokine Structure, Production, and Receptors, 43
- Biologic Actions of Chemokines, 44
LEUKOCYTE-ENDOTHELIAL INTERACTIONS AND LEUKOCYTE RECRUITMENT INTO TISSUES, 45
MIGRATION OF NEUTROPHILS AND MONOCYTES TO SITES OF INFECTION OR TISSUE INJURY, 46
MIGRATION AND RECIRCULATION OF T LYMPHOCYTES, 47
- Recirculation of Naive T Lymphocytes Between Blood and Secondary Lymphoid Organs, 47
- Recirculation of T Cells Through Other Lymphoid Tissues, 52
- Migration of Effector T Lymphocytes to Sites of Infection, 52
- Memory T Cell Migration, 53
MIGRATION OF B LYMPHOCYTES, 53
SUMMARY, 55
4 Innate Immunity
OVERVIEW OF INNATE IMMUNITY, 57
- Functions and Reactions of Innate Immune Responses, 57
- Comparative Features of Innate and Adaptive Immunity, 58
- Evolution of Innate Immunity, 58
RECOGNITION OF MICROBES AND DAMAGED SELF BY THE INNATE IMMUNE SYSTEM, 59
CELL-ASSOCIATED PATTERN RECOGNITION RECEPTORS AND SENSORS OF INNATE IMMUNITY, 62
- Toll-Like Receptors, 63
- Cytosolic Receptors for Pathogen-Associated Molecular Patterns and Damage-Associated Molecular Patterns, 66
- Other Cell-Associated Pattern Recognition Receptors, 71
CELLULAR COMPONENTS OF THE INNATE IMMUNE SYSTEM, 72
- Epithelial Barriers, 72
- Phagocytes, 73
- Dendritic Cells, 74
- Cytokine-Producing Innate Lymphoid Cells, 74
- T and B Lymphocytes With Limited Antigen Receptor Diversity, 78
- Mast Cells, 79
SOLUBLE EFFECTOR MOLECULES OF INNATE IMMUNITY, 79
- The Complement System, 79
- Pentraxins, 80
- Collectins and Ficolins, 81
THE INFLAMMATORY RESPONSE, 82
- The Major Proinflammatory Cytokines of Innate Immunity, 82
- Recruitment of Leukocytes to Sites of Infection, 86
- Ingestion and Killing of Microbes by Activated Phagocytes, 87
- Systemic and Pathologic Consequences of Inflammation, 88
- THE ANTIVIRAL RESPONSE, 90
STIMULATION OF ADAPTIVE IMMUNITY, 92
MECHANISMS THAT LIMIT INNATE IMMUNE RESPONSES, 93
SUMMARY, 93
5 Antibodies and Antigens
ANTIBODY STRUCTURE, 98
- General Features of Antibody Structure, 98
- Structural Features of Antibody Variable Regions, 101
- Structural Features of Antibody Constant Regions, 103
- Monoclonal Antibodies, 106
SYNTHESIS, ASSEMBLY, AND EXPRESSION OF IMMUNOGLOBULIN MOLECULES, 107
- Half-Life of Antibodies, 109
ANTIBODY BINDING OF ANTIGENS, 110
- Features of Biologic Antigens, 110
- Structural and Chemical Basis of Antigen Binding, 111
STRUCTURE-FUNCTION RELATIONSHIPS IN ANTIBODY MOLECULES, 113
- Features Related to Antigen Recognition, 113
- Features Related to Effector Functions, 114
SUMMARY, 115
6 Antigen Presentation to T Lymphocytes and the Functions of MHC Molecules
PROPERTIES OF ANTIGENS RECOGNIZED BY T LYMPHOCYTES, 118
ANTIGEN CAPTURE AND THE FUNCTIONS OF ANTIGEN-PRESENTING CELLS, 119
- General Properties of Antigen-Presenting Cells, 119
- Role of Dendritic Cells in Antigen Capture and Display, 121
- Functions of Other Antigen-Presenting Cells, 123
THE MAJOR HISTOCOMPATIBILITY COMPLEX, 123
- Discovery of the Major Histocompatibility Complex, 123
- MHC Genes, 124
- Structure of MHC Molecules, 128
- Binding of Peptides to MHC Molecules, 131
PROCESSING OF PROTEIN ANTIGENS, 133
- The Class I MHC Pathway for Processing and Presentation of Cytosolic Proteins, 134
- The Class II MHC Pathway for Presentation of Proteins Degraded in Lysosomes, 136
- Cross-Presentation, 139
- Physiologic Significance of MHC-Associated Antigen Presentation, 139
PRESENTATION OF NONPROTEIN ANTIGENS TO T CELLS, 141
SUMMARY, 142
7 Immune Receptors and Signal Transduction
OVERVIEW OF SIGNAL TRANSDUCTION, 146
- Modular Signaling Proteins and Adaptors, 148
- Prion-Like Polymerization and Signaling, 149
THE IMMUNE RECEPTOR FAMILY, 149
- General Features of Antigen Receptor Signaling, 150
THE T CELL RECEPTOR COMPLEX AND T CELL SIGNALING, 151
- The Structure of the T Cell Receptor for Antigen, 151
- Signal Initiation by the T Cell Receptor, 153
- The Role of the CD4 and CD8 Coreceptors in T Cell Activation, 154
- Activation of Tyrosine Kinases and a Lipid Kinase During T Cell Activation, 156
- Recruitment and Modification of Adaptor Proteins, 156
- Formation of the Immune Synapse, 158
- Mitogen-Activated Protein Kinase Signaling Pathways in T Lymphocytes, 158
- Calcium- and Protein Kinase C-Mediated Signaling Pathways in T Lymphocytes, 161
- Activation of Transcription Factors That Regulate T Cell Gene Expression, 161
- Modulation of T Cell Signaling by Protein Tyrosine Phosphatases, 164
- Costimulatory Receptor Signaling in T Cells, 164
- Metabolic Changes During T Cell Activation, 165
THE B LYMPHOCYTE ANTIGEN RECEPTOR COMPLEX, 165
- Structure of the B Cell Receptor for Antigen, 165
- Signal Initiation by the B Cell Receptor, 165
- Role of the CR2/CD21 Complement Receptor as a Coreceptor for B Cells, 166
- Signaling Pathways Downstream of the B Cell Receptor, 168
THE ATTENUATION OF IMMUNE RECEPTOR SIGNALING, 169
- Inhibitory Receptors of Natural Killer Cells, B Cells, and T Cells, 169
- Ubiquitin-Dependent Degradation of Signaling Proteins, 170
CYTOKINE RECEPTORS AND SIGNALING, 170
- Classes of Cytokine Receptors, 170
- Signaling by Janus Kinases and Signal Transducers and Activators of Transcription, 173
- Pathways of NF-κB Activation, 175
SUMMARY, 177
8 Lymphocyte Development and Antigen Receptor Gene Rearrangement
OVERVIEW OF LYMPHOCYTE DEVELOPMENT, 179
- Commitment to the B and T Cell Lineages and Proliferation of Progenitors, 180
- Role of Epigenetic Changes and MicroRNAs in Lymphocyte Development, 181
- Antigen Receptor Gene Rearrangement and Expression, 182
- Selection Processes That Shape the B and T Lymphocyte Repertoires, 182
REARRANGEMENT OF ANTIGEN RECEPTOR GENES IN B AND T LYMPHOCYTES, 183
- Germline Organization of Immunoglobulin and T Cell Receptor Genes, 184
- V(D)J Recombination, 186
- Generation of Diversity in B and T Cells, 191
B LYMPHOCYTE DEVELOPMENT, 192
- Stages of B Lymphocyte Development, 193
- Selection of the Mature B Cell Repertoire, 198
T LYMPHOCYTE DEVELOPMENT, 199
- Role of the Thymus in T Cell Maturation, 200
- Stages of T Cell Maturation, 200
- Selection Processes in the Maturation of MHC-Restricted αβ T Cells, 203
- γδ T Lymphocytes, 205
SUMMARY, 205
9 Activation of T Lymphocytes
OVERVIEW OF T LYMPHOCYTE ACTIVATION, 209
SIGNALS FOR T LYMPHOCYTE ACTIVATION, 211
- Recognition of Antigen, 211
- Role of Costimulation in T Cell Activation, 212
FUNCTIONAL RESPONSES OF T LYMPHOCYTES, 216
- Changes in Surface Molecules During T Cell Activation, 216
- Cytokines in Adaptive Immune Responses, 217
- Clonal Expansion of T Cells, 220
- Differentiation of Activated T Cells Into Effector Cells, 220
- Development and Properties of Memory T Cells, 220
DECLINE OF T CELL RESPONSES, 222
SUMMARY, 222
10 Differentiation and Functions of CD4+ Effector T Cells
OVERVIEW OF CD4+ T CELL–MEDIATED IMMUNE RESPONSES, 225
SUBSETS OF CD4+ EFFECTOR T CELLS, 228
- Properties of Th1, Th2, and Th17 Subsets, 228
- Development of Th1, Th2, and Th17 Subsets, 230
THE Th1 SUBSET, 231
- Development of Th1 Cells, 231
- Functions of Th1 Cells, 232
THE Th2 SUBSET, 234
- Development of Th2 Cells, 234
- Functions of Th2 Cells, 235
THE Th17 SUBSET, 237
- Development of Th17 Cells, 237
- Functions of Th17 Cells, 238
FUNCTIONS OF OTHER T CELL SUBSETS, 240
- γδ T Cells, 240
- Natural Killer T Cells, 240
- Mucosa-Associated Invariant T (MAIT) Cells, 241
SUMMARY, 241
11 Differentiation and Functions of CD8+ Effector T Cells
DIFFERENTIATION OF CD8+ T CELLS INTO CYTOTOXIC T LYMPHOCYTES, 243
- Nature of Antigen and Antigen-Presenting Cells for Activation of CD8+ T Lymphocytes, 244
- Role of Helper T Cells, 245
- Role of Cytokines, 245
- Inhibition of CD8+ T Cell Responses: T Cell Exhaustion, 246
EFFECTOR FUNCTIONS OF CD8+ CYTOTOXIC T LYMPHOCYTES, 246
- Mechanisms of CTL-Mediated Cytotoxicity, 246
- Cytokine Production by CD8+ Effector T Cells, 249
ROLES OF CD8+ CTLs IN HOST DEFENSE, 249
SUMMARY, 250
12 B Cell Activation and Antibody Production
OVERVIEW OF HUMORAL IMMUNE RESPONSES, 251
ANTIGEN RECOGNITION AND ANTIGEN-INDUCED B CELL ACTIVATION, 254
- Antigen Capture and Delivery to B Cells, 254
- Activation of B Cells by Antigens and Other Signals, 255
HELPER T CELL-DEPENDENT ANTIBODY RESPONSES TO PROTEIN ANTIGENS, 256
- The Sequence of Events During T Cell-Dependent Antibody Responses, 256
- Initial Activation and Migration of Helper B Cells and T Cells, 256
- Antigen Presentation by B Cells and the Hapten-Carrier Effect, 257
- Role of CD40L:CD40 Interaction in T-Dependent B Cell Activation, 259
- Extrafollicular B Cell Activation, 260
- The Germinal Center Reaction, 260
- The Induction and Functions of Follicular Helper T Cells, 261
- Heavy Chain Isotype (Class) Switching, 263
- Affinity Maturation: Somatic Mutation of Ig Genes and Selection of High-Affinity B Cells, 266
- B Cell Differentiation Into Antibody-Secreting Plasma Cells, 269
- Generation of Memory B Cells, 270
- Role of Transcriptional Regulators in Determining the Fate of Activated B Cells, 270
ANTIBODY RESPONSES TO T-INDEPENDENT ANTIGENS, 271
- Subsets of B Cells That Respond to T-Independent Antigens, 271
- Mechanisms of T-Independent Antibody Responses, 271
- Protection Mediated by T-Independent Antibodies, 272
ANTIBODY FEEDBACK: REGULATION OF HUMORAL IMMUNE RESPONSES By Fc RECEPTORS, 272
SUMMARY, 273
13 Effector Mechanisms of Humoral Immunity
OVERVIEW OF HUMORAL IMMUNITY, 275
NEUTRALIZATION OF MICROBES AND MICROBIAL TOXINS, 277
ANTIBODY-MEDIATED OPSONIZATION AND PHAGOCYTOSIS, 277
- Leukocyte Fc Receptors, 278
- Antibody-Dependent Cell-Mediated Cytotoxicity, 281
- Antibody-Mediated Clearance of Helminths, 281
THE COMPLEMENT SYSTEM, 281
- Pathways of Complement Activation, 282
- Receptors for Complement Proteins, 288
- Regulation of Complement Activation, 290
- Functions of Complement, 293
- Complement Deficiencies, 296
- Pathologic Effects of the Complement System, 296
- Evasion of Complement by Microbes, 297
NEONATAL IMMUNITY, 297
SUMMARY, 298
14 Specialized Immunity at Epithelial Barriers and in Immune Privileged Tissues
GENERAL FEATURES OF IMMUNITY AT EPITHELIAL BARRIERS, 299
IMMUNITY IN THE GASTROINTESTINAL SYSTEM, 301
- Innate Immunity in the Gastrointestinal Tract, 301
- Adaptive Immunity in the Gastrointestinal Tract, 304
- Regulation of Immunity in the Gastrointestinal Tract by Regulatory T Cells and Cytokines, 312
- Oral Tolerance and Oral Vaccines, 312
- The Role of the Commensal Microbiome in Immune Regulation, 313
- Diseases Related to Immune Responses in the Gut, 313
IMMUNITY IN OTHER MUCOSAL TISSUES, 315
- Immunity in the Respiratory System, 315
- Immunity in the Genitourinary System, 316
THE CUTANEOUS IMMUNE SYSTEM, 316
- Innate and Adaptive Immune Responses in the Skin, 316
- Diseases Related to Immune Responses in the Skin, 318
- IMMUNE PRIVILEGED TISSUES, 320
- Immune Privilege in the Eye, Brain, and Testis, 320
- Immune Privilege of the Mammalian Fetus, 321
SUMMARY, 322
15 Immunologic Tolerance and Autoimmunity
OVERVIEW OF IMMUNOLOGIC TOLERANCE, 325
- Central T Cell Tolerance, 327
- Peripheral T Cell Tolerance, 328
- Factors That Determine the Tolerogenicity of Self Antigens, 338
TOLERANCE TO COMMENSAL MICROBES AND OTHER FOREIGN ANTIGENS, 340
MECHANISMS OF AUTOIMMUNITY, 340
- General Features of Autoimmune Disorders, 341
- Immunologic Abnormalities Leading to Autoimmunity, 342
- Genetic Basis of Autoimmunity, 342
- Role of Infections in Autoimmunity, 346
- Other Factors in Autoimmunity, 348
SUMMARY, 348
16 Immunity to Microbes
OVERVIEW OF IMMUNE RESPONSES TO MICROBES, 351
IMMUNITY TO EXTRACELLULAR BACTERIA, 354
- Innate Immunity to Extracellular Bacteria, 354
- Adaptive Immunity to Extracellular Bacteria, 355
- Injurious Effects of Immune Responses to Extracellular Bacteria, 356
- Immune Evasion by Extracellular Bacteria, 356
IMMUNITY TO INTRACELLULAR BACTERIA, 357
- Innate Immunity to Intracellular Bacteria, 357
- Adaptive Immunity to Intracellular Bacteria, 358
- Immune Evasion by Intracellular Bacteria, 360
IMMUNITY TO FUNGI, 360
- Innate and Adaptive Immunity to Fungi, 361
IMMUNITY TO VIRUSES, 362
- Innate Immunity to Viruses, 362
- Adaptive Immunity to Viruses, 363
- Immune Evasion by Viruses, 364
IMMUNITY TO PARASITES, 366
- Innate Immunity to Parasites, 366
- Adaptive Immunity to Parasites, 366
- Immune Evasion by Parasites, 368
STRATEGIES FOR VACCINE DEVELOPMENT, 368
- Attenuated and Inactivated Bacterial and Viral Vaccines, 369
- Purified Antigen (Subunit) Vaccines, 369
- Synthetic Antigen Vaccines, 370
- Live Viral Vaccines Involving Recombinant Viruses, 370
- DNA Vaccines, 370
- Adjuvants and Immunomodulators, 370
- Passive Immunization, 370
SUMMARY, 371
17 Transplantation Immunology
GENERAL PRINCIPLES OF TRANSPLANTATION IMMUNOLOGY, 373
ADAPTIVE IMMUNE RESPONSES TO ALLOGRAFTS, 374
- The Nature of Alloantigens, 374
- Recognition of Alloantigens by T Cells, 377
- Activation and Effector Functions of Alloreactive T Lymphocytes, 379
- Activation of Alloreactive B Cells and Production and Functions of Alloantibodies, 381
PATTERNS AND MECHANISMS OF ALLOGRAFT REJECTION, 381
- Hyperacute Rejection, 381
- Acute Rejection, 382
- Chronic Rejection and Graft Vasculopathy, 384
PREVENTION AND TREATMENT OF ALLOGRAFT REJECTION, 384
- Methods to Reduce the Immunogenicity of Allografts, 385
- Immunosuppression to Prevent or to Treat Allograft Rejection, 387
- Methods to Induce Donor-Specific Tolerance, 390
XENOGENEIC TRANSPLANTATION, 391
BLOOD TRANSFUSION AND THE ABO AND RH BLOOD GROUP ANTIGENS, 391
- ABO Blood Group Antigens, 391
- Other Blood Group Antigens, 393
HEMATOPOIETIC STEM CELL (HSC) TRANSPLANTATION, 393
- Indications, Methods, and Immune Barriers in Hematopoietic Stem Cell Transplantation, 393
- Immunologic Complication of Hematopoietic Stem Cell Transplantation, 394
SUMMARY, 395
18 Immunity to Tumors
OVERVIEW OF TUMOR IMMUNITY, 397
TUMOR ANTIGENS, 399
- Neoantigens: Antigens Encoded by Mutated Genes, 399
- Antigens of Oncogenic Viruses, 399
- Over-Expressed Cellular Proteins, 399
- Other Antigens of Tumors, 401
IMMUNE RESPONSES TO TUMORS, 402
- T Lymphocytes, 402
- Antibodies, 404
- Natural Killer Cells, 404
- Macrophages, 404
- The Role of Innate and Adaptive Immunity in Promoting Tumor Growth, 404
EVASION OF IMMUNE RESPONSES BY TUMORS, 405
- Immune Checkpoints: Inhibition of Immune Responses, 406
- Loss of Tumor Antigen Expression, 407
IMMUNOTHERAPY FOR TUMORS, 407
- Checkpoint Blockade: Blocking T Cell Inhibitory Pathways, 408
- Vaccination With Tumor Antigens, 409
- Adoptive Cellular Therapy With Antitumor T Cells, 410
- Passive Immunotherapy With Antibodies, 413
- Other Approaches for Stimulating Antitumor Immunity, 414
SUMMARY, 415
19 Hypersensitivity Disorders
CAUSES OF HYPERSENSITIVITY DISEASES, 417
MECHANISMS AND CLASSIFICATION OF HYPERSENSITIVITY REACTIONS, 418
DISEASES CAUSED BY ANTIBODIES, 419
- Diseases Caused by Antibodies Against Fixed Cell and Tissue Antigens, 419
- Immune Complex–Mediated Diseases, 421
DISEASES CAUSED BY T LYMPHOCYTES, 424
- Diseases Caused by Cytokine-Mediated Inflammation, 425
- Diseases Caused by Cytotoxic T Lymphocytes, 427
THERAPEUTIC APPROACHES FOR IMMUNOLOGIC DISEASES, 428
SELECTED IMMUNOLOGIC DISEASES: PATHOGENESIS AND THERAPEUTIC STRATEGIES, 430
- Systemic Lupus Erythematosus (SLE): The Prototypic Immune Complex–Mediated Disease, 430
- Rheumatoid Arthritis (RA), 430
- Multiple Sclerosis (MS), 432
- Type 1 Diabetes, 433
- Inflammatory Bowel Disease, 434
- SUMMARY, 434
20 Allergy
OVERVIEW OF IgE-DEPENDENT ALLERGIC REACTIONS, 438
PRODUCTION OF IgE, 439
- The Nature of Allergens, 439
- Activation of Type 2 Cytokine-Producing Helper T Cells, 440
- Activation of B Cells and Switching to IgE, 440
CELLS INVOLVED IN ALLERGIC REACTIONS, 440
- Role of Th2 Cells and Innate Lymphoid Cells in Allergic Disease, 440
- Properties of Mast Cells and Basophils, 440
- Properties of Eosinophils, 448
IgE- AND MAST CELL–DEPENDENT REACTIONS, 448
- The Immediate Reaction, 448
- The Late-Phase Reaction, 449
GENETIC SUSCEPTIBILITY TO ALLERGIC DISEASE, 450
- Environmental Factors in Allergy, 451
ALLERGIC DISEASES IN HUMANS: PATHOGENESIS AND THERAPY, 452
- Systemic Anaphylaxis, 452
- Bronchial Asthma, 452
- Immediate Hypersensitivity Reactions in the Upper Respiratory Tract, Gastrointestinal Tract, and Skin, 453
- Specific Immunotherapy (“Desensitization”) for Allergic Diseases, 455
THE PROTECTIVE ROLES OF IgE- AND MAST CELL–MEDIATED IMMUNE REACTIONS, 455
SUMMARY, 456
21 Congenital and Acquired Immunodeficiencies
OVERVIEW OF IMMUNODEFICIENCY DISEASES, 459
PRIMARY (CONGENITAL) IMMUNODEFICIENCIES, 460
- Defects in Innate Immunity, 460
- Severe Combined Immunodeficiencies, 463
- Antibody Deficiencies: Defects in B Cell Development and Activation, 468
- Defects in T Lymphocyte Activation and Function, 471
- Multisystem Disorders With Immunodeficiency, 473
- Therapeutic Approaches for Congenital Immunodeficiencies, 474
SECONDARY (ACQUIRED) IMMUNODEFICIENCIES, 474
HUMAN IMMUNODEFICIENCY VIRUS AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME, 475
- Molecular and Biologic Features of HIV, 475
- Pathogenesis of HIV Infection and AIDS, 479
- Clinical Features of HIV Disease, 482
- Immune Responses to HIV, 484
- Elite Controllers and Long-Term Nonprogressors: A Possible Role for Host Genes, 485
- Treatment and Prevention of AIDS and Vaccine Development, 485
SUMMARY, 486