TY - BOOK AU - Coico,Richard TI - Immunology:a short course U1 - 616.079 PY - 2009/// CY - New York PB - Wiley-blakwell N1 - 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 ER -