Preface and Acknowledgments Preface and Acknowledgments to the Third Edition Preface to the Second Edition Preface to the First Edition

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1 Preface and Acknowledgments p. xxi Preface and Acknowledgments to the Third Edition p. xxiii Preface to the Second Edition p. xxv Preface to the First Edition p. xxvii Acknowledgments to the First and Second Editions p. xxix Introduction and Overview p. 1 Innate and Acquired Immunity p. 2 Active, Passive, and Adoptive Immunization p. 3 Characteristics of the Immune Response p. 4 Cells Involved in the Acquired Immune Response p. 4 Clonal Selection Theory p. 5 Humoral and Cellular Immunity p. 7 Generation of Diversity in the Immune Response p. 11 Benefits of Immunology p. 11 Damaging Effects of the Immune Response p. 12 Regulation of the Immune Response p. 13 The Future of Immunology p. 13 Elements of Innate and Acquired Immunity p. 17 Innate (Nonspecific) Immunity p. 17 Physiologic and Chemical Barriers (Skin and Mucous Membranes) p. 18 Cellular Defenses p. 18 Phagocytosis and Extracellular Killing p. 18 Inflammation p. 24 Fever p. 26 Biologically Active Substances p. 26 Acquired Immunity p. 26 Cells Involved in the Immune Response p. 27 Lymphatic Organs p. 27 Lymphocyte Recirculation p. 33 The Fate of Antigen After Penetration p. 34 Interrelationship Between Innate and Acquired Immunity p. 36 Immunogens and Antigens p. 41 Requirements for Immunogenicity p. 42 Foreignness p. 42 High Molecular Weight p. 42 Chemical Complexity p. 42 Degradability p. 43 Haptens p. 43 Further Requirements for Immunogenicity p. 45 Primary and Secondary Responses p. 46 Antigenicity and Antigen-Binding Site p. 46

2 Epitopes Recognized by B Cells and T Cells p. 47 Major Classes of Antigens p. 49 Binding of Antigen with Antigen-Specific Antibodies or T Cells p. 51 Cross-Reactivity p. 51 Immunologic Adjuvants p. 52 Antibody Structure and Function p. 57 Isolation and Characterization p. 58 Structure of Light and Heavy Chains p. 59 Domains p. 62 Hinge Region p. 63 Variable Region p. 63 Immunoglobulin Variants p. 65 Isotypes of Immunoglobulins p. 65 Allotypes p. 66 Idiotypes p. 66 Structural Features of IgG p. 69 Biologic Properties of IgG p. 69 Agglutination and Formation of Precipitate p. 71 Passage Through the Placenta and Absorption in Neonates p. 72 Opsonization p. 72 Antibody-Dependent, Cell-Mediated Cytotoxicity p. 72 Activation of Complement p. 73 Neutralization of Toxin p. 73 Immobilization of Bacteria p. 73 Neutralization of Viruses p. 74 Structural Features of IgM p. 74 Biological Properties of IgM p. 74 Agglutination p. 75 Isohemagglutinins p. 75 Activation of Complement p. 76 Structural and Biologic Properties of IgA p. 76 Role in Mucosal Infections p. 77 Bactericidal Activity p. 78 Antiviral Activity p. 78 Structural and Biologic Properties of IgD p. 78 Structural and Biologic Properties of IgE p. 79 Importance of IgE in Parasitic Infections and Hypersensitivity Reactions p. 79 Kinetics of the Antibody Response Following Immunization p. 79 Primary Response p. 79 Secondary Response p. 80 The Immunoglobulin Superfamily p. 81

3 Antigen-Antibody Interactions, Immune Assays, and Experimental Systems p. 87 Primary Interactions Between Antibody and Antigen p. 89 Association Constant p. 90 Affinity and Avidity p. 91 Secondary Interactions Between Antibody and Antigen p. 91 Agglutination Reactions p. 91 Precipitation Reaction p. 94 Immunoassays p. 98 Direct Binding Immunoassays p. 98 Solid-Phase Immunoassays p. 101 Immunofluorescence p. 102 Direct Immunofluorescence p. 102 Indirect Immunofluorescence p. 103 Fluorescence-Activated Cell-Sorting Analysis p. 103 Immunoabsorption and Immunoadsorption p. 104 Assays to Assess Lymphocyte Function p. 105 B-Cell and T-Cell Proliferation Assays p. 105 Antibody Production by B Cells p. 106 Effector Cell Assays for T Cells and NK Cells p. 106 Cell Culture Systems p. 106 Primary Cell Cultures and Cloned Lymphoid Cell Lines p. 106 Monoclonal and Genetically Engineered Antibodies p. 107 Monoclonal Antibodies p. 107 T-Cell Hybridomas p. 108 Genetically Engineered Molecules and Receptors p. 108 Experimental Animal Models p. 110 Inbred Strains p. 110 Adoptive Transfer p. 110 SCID Mice p. 111 Thymectomized and Congenically Athymic (Nude) Mice p. 111 Transgenic Mice and Gene Targeting p. 111 Transgenic Mice p. 111 Knockout Mice p. 112 The Genetic Basis of Antibody Structure p. 117 A Brief Review of Nonimmunoglobulin Gene Structure and Gene Expression p. 118 Genetic Events in the Synthesis of Immunoglobulin Chains p. 120 Organization and Rearrangement of Light-Chain Genes p. 120 Organization and Rearrangement of Heavy-Chain Genes p. 122 Regulation of Immunoglobulin Gene Expression p. 124 Class or Isotype Switching p. 125 Generation of Antibody Diversity p. 126

4 Presence of Multiple V Genes in the Germ Line p. 126 VJ and VDJ Combinatorial Association p. 126 Random Assortment of H and L Chains p. 127 Junctional and Insertional Diversity p. 127 Somatic Hypermutation p. 127 Somatic Gene Conversion p. 128 Receptor Editing p. 129 Biology of the B Lymphocyte p. 135 Sites of Early B-Cell Differentiation p. 135 Ontogeny of the B Lymphocyte p. 136 Early Phases of B-Cell Differentiation: Pro-B and Pre-B Cells p. 136 Immature B Cells p. 138 Mature B Cells p. 139 Anatomical Distribution of B-Cell Populations p. 140 B-1 or CD5[superscript +] B Cells p. 140 B-Cell Membrane Proteins p. 141 Antigen-Binding Molecules: Membrane Immunoglobulin p. 141 Signal Transduction Molecules Associated with Membrane Immunoglobulin p. 142 Molecules Involved in Antigen Presentation p. 142 Fc Receptor, CD32 p. 143 CD21 p. 143 The Role of The Major Histocompatibility Complex in the Immune Response p. 147 Variability of MHC Genes and Products p. 148 Genetic Polymorphism p. 150 Pattern of Expression p. 150 Codominant Expression p. 151 Structure of MHC Molecules p. 151 Structure of MHC Class I Moleules p. 151 Structure of MHC Class II Molecules p. 153 Function of MHC Molecules p. 154 Antigen Processing and Presentation p. 156 MHC Molecules Bind Peptides Derived from Self-Molecules p. 161 Inability to Respond to an Antigen p. 161 One Antigen can Trigger MHC Class I- or Class II-Restricted Responses p. 161 Diversity of MHC Molecules: MHC Association with Resistance and Susceptibility to Disease p. 162 Other Genes Within the MHC Region p. 164 Biology of the T Lymphocyte p. 169 Nature of the Antigen-Specific T-Cell Receptor p. 169 Molecules That Interact with Antigen p. 169 The T-Cell Receptor Complex p. 170 CD4 and CD8 p. 171

5 Interaction of the TCR with MHC Molecules p. 172 [gamma delta] T Cells p. 173 Genes Coding for T-Cell Receptors p. 174 Generation of T-Cell Receptor Diversity p. 174 T-Cell Differentiation in the Thymus p. 175 Introduction p. 175 Thymocytes Interact with Thymic Nonlymphoid Cells p. 175 T-Cell Receptor Gene Rearrangement p. 177 Thymic Selection p. 178 Lymphocyte Trafficking to Tissues p. 180 Specialized Cells Present Antigen to T Cells p. 181 Activation and Function of T and B Cells p. 187 Activation of CD4[superscript +] T Cells p. 187 Paired Interactions Between the APC and the CD4[superscript +] T Cell p. 188 Intracellular Events in CD4[superscript +] T-cell Activation p. 190 Functions of Costimulatory Pairs p. 192 Subsets of CD4[superscript +] Cells Defined by Cytokine Production p. 192 CD4[superscript +] T Memory Cells p. 195 Function of CD8[superscript +] T Cells p. 195 Killing of Target Cells by Cytotoxic T Cells p. 196 T-Cell Recognition of Lipids p. 198 Other Ways to Activate Unprimed T Cells p. 200 Superantigens p. 200 Plant Proteins and Antibodies to T-Cell Surface Molecules p. 200 B-Cell Activation and Function p. 201 T-B Cooperation p. 201 The Carrier Effect p. 203 T-Independent Responses p. 204 B-Cell Activation in the Absence of T-Cell Help p. 204 Intracellular Pathways in B-Cell Activation p. 205 Control Mechanisms in the Immune Response p. 211 Tolerance p. 211 Induction of Tolerance in Immature T and B Lymphocytes p. 212 Regulation of Cell Death in Immature and Mature Lymphocytes p. 214 Induction of Tolerance in Mature T and B Lymphocytes p. 215 Fas-FasL Interactions p. 215 Mechanisms That Inhibit T- and B-Cell Activation p. 216 Other Potential Mechanisms of Regulating the Function of Lymphocytes p. 217 Active Suppression via T Cells p. 217 Idiotype Network p. 218 Regulation of the Response in the Individual p. 218

6 Age p. 218 Neurologic and Endocrine Factors p. 219 Expression of MHC Molecules p. 219 Effects of Cytokines p. 220 Effects of Antigen p. 221 Immunologically Privileged Sites p. 223 Immunosuppression by Drugs or Radiation p. 224 Cytokines p. 229 The History of Cytokines p. 229 General Properties of Cytokines p. 231 Functional Categories of Cytokines p. 233 Cytokines That Regulate Specific Immune Responses p. 233 Cytokines Produced by T[subscript H]1 and T[subscript H]2 Cells p. 235 Cytokines That Facilitate Innate Immune Responses and Activate Inflammatory Responses p. 236 Chemokines: Cytokines That Affect Leukocyte Movement p. 238 Cytokines That Stimulate Hematopoiesis p. 238 Cytokine Receptors p. 240 Cytokine Receptor-Mediated Signal Transduction p. 243 Role of Cytokines and Cytokine Receptors in Disease p. 243 Toxic Shock Syndrome p. 244 Bacterial Septic Shock p. 244 Cancers p. 245 Autoimmunity p. 245 Cytokine Antagonists and Inhibitors p. 245 Therapeutic Uses of Cytokines and Cytokine Receptors p. 246 Reversing Cellular Deficiences p. 246 Treatment of Immunodeficiences p. 246 Treatment of Cancer p. 246 Treatment of Chronic Inflammatory Diseases p. 247 Treatment of Transplant Patients p. 247 Treatment of Allergies p. 247 Complement p. 253 Historical Background p. 253 The Activation Pathways and Their Proteins p. 254 The Classical Pathway p. 256 The Lectin Pathway p. 257 The Alternative Pathway p. 259 The Terminal Pathway p. 264 Complement Control Proteins p. 267 Other Complement Receptors p. 268 Biological Activities of Complement p. 269

7 Complement and Disease p. 273 Hypersensitivity Reactions: Antibody-Mediated (Type I) Reactions p. 279 Historical Background p. 280 General Characteristics of Type I Hypersensitivity p. 280 Sensitization Phase p. 281 IgE Antibody Production is T Cell-Dependent p. 281 Activation Phase p. 283 Effector Phase p. 285 Preformed Mediators p. 286 Newly Synthesized Mediators p. 287 Late-Phase Reaction p. 288 Clinical Aspects of Type I Hypersensitivity p. 291 Allergic Rhinitis p. 291 Food Allergies p. 291 Atopic Dermatitis p. 291 Asthma p. 291 Detection p. 292 Intervention p. 293 The Protective Role of IgE p. 295 Hypersensitivity Reactions: Antibody-Mediated (Type II) Cytotoxic Reactions and Immune Complex (Type III) Reactions p. 301 Type II Cytotoxic Reactions p. 301 Introduction p. 301 Transfusion Reactions p. 303 Rh Incompatibility Reaction p. 304 Autoimmune Reactions p. 304 Drug-Induced Reactions p. 305 Type III Immune Complex Reactions p. 305 Introduction p. 305 Systemic Immune Complex Disease p. 306 Localized Immune Complex Disease p. 307 Infection-Associated Immune Complex Disease p. 307 Occupational Diseases (Hypersensitivity Pneumonitis) p. 310 Hypersensitivity Reactions: T-Cell-Mediated, Type IV--Delayed-Type Hypersensitivity p. 317 General Characteristics p. 318 Gross Appearance and Histology of the Reaction p. 318 Mechanism of DTH p. 318 Consequences of DTH p. 320 Variants of DTH p. 322 Treatment of Cell-Mediated Immunity p. 324 Autoimmunity p. 329

8 Autoimmunity and Disease p. 329 Criteria for Autoimmune Disease p. 330 Direct Proof p. 330 Indirect Evidence p. 330 Circumstantial Evidence p. 331 Etiology of Autoimmune Disease p. 331 Genetic Factors in Autoimmune Disease p. 331 Environmental Factors p. 332 Examples of Autoimmune Disease p. 335 Antibody-Mediated Autoimmune Disease p. 335 Immune Complex-Mediated Autoimmune Disease p. 337 T-Cell-Mediated Autoimmune Diseases p. 339 Autoimmune Diseases Arising From Deficiency in Components of Complement p. 342 Immunodeficiency and Other Disorders of the Immune System p. 347 Immune Deficiency Syndromes p. 347 Primary Immunodeficiency Syndromes p. 348 Secondary Immunodeficiency Syndromes p. 361 Acquired Immunodeficiency Syndrome (AIDS) p. 361 Initial Description and Epidemiology p. 361 Human Immunodeficiency Virus p. 362 Clinical Course p. 364 Prevention, Control, and Therapy of HIV Infection p. 367 Neoplasms of the Immune System p. 368 B-Cell Neoplasms p. 370 T-Cell Neoplasms p. 372 Hodgkin's Disease p. 373 Transplantation Immunology p. 379 Relationship Between Donor and Recipient p. 379 The Role of the Immune Response in Allograft Rejection p. 381 Clinical Characteristics of Allograft Rejection p. 382 Hyperacute Rejection p. 382 Acute Rejection p. 382 Chronic Rejection p. 383 Histocompatibility Antigens p. 383 MHC Class I and Class II Molecules as Targets in Allograft Rejection p. 384 Xenogeneic Transplantation p. 385 Tests for Histocompatibility Antigens p. 386 Serologic Detection of Transplantation Antigens p. 386 Genotyping of Transplantation Epitopes p. 387 Detection of Transplantation Antigens by Mixed Leukocyte Reaction p. 387 Prolongation of Allograft Survival p. 388

9 Antiinflammatory Agents p. 389 Cytotoxic Drugs p. 390 Cyclosporine, FK-506 (Tacrolimus), and Rapamycin (Sirolimus) p. 390 Antibody Therapy and Blocking of Costimulatory Molecules p. 391 Bone Marrow Transplantation p. 392 Graft-Versus-Host Reactions p. 393 Fetal--Maternal Relationship p. 393 Heart Transplantation: A Personal Story p. 394 Tumor Immunology p. 401 Tumor Antigens p. 401 Categories of Tumor Antigens p. 403 Normal Cellular Gene Products p. 403 Mutant Cellular Gene Products p. 404 Tumor Antigens Encoded by Viral Genes p. 404 Immunologic Factors Influencing the Incidence of Cancer p. 405 Effector Mechanisms in Tumor Immunity p. 405 B-Cell Responses p. 406 Cell-Mediated Responses p. 407 Cytokines p. 410 Limitations of the Effectiveness of the Immune Response Against Tumors p. 410 Immunodiagnosis p. 412 Detection Of Myeloma Proteins Produced By Plasma Cell Tumors p. 412 Detection of [alpha]-fetoprotein p. 412 Carcinoembryonic Antigen p. 413 Detection of Prostate-Specific Antigen p. 414 Tumor Immunoprophylaxis p. 415 Immunotherapy p. 415 Resistance and Immunization to Infectious Diseases p. 421 Innate and Adaptive Immune Defenses p. 422 Host Defense Against the Various Classes of Microbial Pathogens p. 423 Immunity to Viruses p. 423 Immunity to Bacteria p. 425 Immunity to Parasites p. 426 Immunity to Fungi p. 427 Mechanisms by Which Pathogens Evade the Immune Response p. 427 Encapsulated Bacteria p. 428 Toxins p. 428 Antigenic Variation p. 429 Intracellular Survival p. 430 Suppression of the Immune System p. 430 Extracellular Enzymes p. 431

10 Expression of Antibody Binding Properties p. 431 Principles of Immunization p. 431 Objectives of Immunization p. 431 Historical Aspects of Immunization p. 432 Active Immunizations p. 433 Recommended Immunizations p. 433 Use of Vaccines in Selective Populations p. 434 Basic Mechanisms of Protection p. 435 Anatomic Location of Host Immune Response p. 435 Significance of the Primary and Secondary Responses p. 436 Protective Effect of the Immune Response p. 437 Age and Timing of Immunizations p. 437 Use of Mixed, Multiple Antigens p. 439 Precautions p. 439 Site of Administration of Antigen p. 439 Hazards p. 440 Recent Approaches to Production of Vaccines p. 441 Vaccines Produced by Recombinant DNA p. 441 Conjugated Polysaccharides p. 441 Synthetic Peptide Vaccines p. 442 Blocking of Specific Receptors p. 442 Anti-Idiotype Vaccines p. 442 Virus-Carrier Vaccine p. 443 Bacterium-Carrier Vaccine p. 443 DNA Vaccines p. 443 Toxoids p. 444 Passive Immunization p. 444 Passive Immunization Through Placental Antibody Transfer p. 444 Passive Immunization via Colostrum p. 444 Passive Antibody Therapy and Serum Therapy p. 445 Monoclonal and Polyclonal Preparations p. 447 Preparation and Properties of Human Immune Serum Globulin p. 447 Indications for the Use of Immune Globulin p. 448 Precautions on the Use of Immune Therapy p. 449 Immunotherapy p. 449 Antibody Therapies p. 450 Colony Stimulating Factors p. 450 Glossary p. 455 Partial List of CD Antigens p. 477 Index p. 481 Table of Contents provided by Blackwell's Book Services and R.R. Bowker. Used with permission.