Immunology: an introduction/ Ian Tizard

Contents
CHAPTER 1
GeneralPrinciples ofImmunology 1
Historical Background 2
Antibody-Mediated Immune Responses 5
CellrMediated Immune Responses 7
Tolerance 9
ImmuneResponse Mechanisms 10
Current Problems in Immunology 10
CHAPTER 2
IrtfecHans and Diseases 14
Organisms That CauseDisease 15
Bacteria 17
Classification 17
..How Bacteria Cause Disease 19
The Normal Flora 21
Fungi 9
Viruses 9
Virus Multiplication 23
Virus Diseases 24
Protozoa 25
Helminths 25
TheImportance of theImmuneSystem 25
CHAPTER 3
Key BiochemicalProcesses 28
Basic Genetic Mechanisms 29
' bNA Transcription 29
RNA Translation 31.
Introns and Exons 32 . -
Protein Structure 32
. Protein Shape 32
Folding Patterns 34
Protein Assemblies 36
Glycoproteins 36
Isoforms and Glycoforms 37
CHAPTER 4
Antigens and Ant^enicity 39
Essential Features ofAntig^ ^
FactorsThat Influence Antigenidty 40
Epitopes 41
Haptens 42
Protein Epitopes 44
Examples of Hapten-CarrierConjugation 44
Cross-Recu:tivity 44
Some Specific Anti^ns 46
Cell Surface Antigens 47
Autoandgens 48
CHAPTER 5
Destruction ofForeignMaterial—
The MyeloidSystem 50
TheMyeloid System 51
Neutrophils 51
Structure of Neutrophils 52
Functions of Neutrophils 52
Neutrophil Surface Proteins 56
Fate of Neutrophils 57
Eosinophils 57
Basophils 58
Platelets 58
XI
xii Contents
CHAPTER 6
The Morumudear-Phagpcytic System 61
TheMononuclear-Phagocytic System 62
The Structure ofMacrophages 62
The Life History of Macrophages 63
The Functions ofMacrophages 65
Macrophage Surface Receptors 67
Macrophages and Wound Healing 67
Macrophages as Sectetory Cells 67
Interleukin-1 68
Interleukin-1 Receptor Antagonist 69
Interleukin-6 69
Interleukin-12 69
Tumor Necrosis Factor-a 70
Fate ofForeign Material Within theBody 71
Particles Given Intravenously 71
Soluble Antigens Given Intravenously 72
Fate of Antigen Given by Other Routes 72
CHAPTER 7
CeUidar Interactions 75
CellSurfaceProteins 76
Cell SurfaceDyrwmics 76
The Endocytic Pathway 76
The Exocytic Pathway 78
The Cell Cycle 78
Cell Surface Receptors and Signal Transduction 79
B^protein Phosphorylation 81
Transcription Factors 82
Oncogenes 82
Cell Adhesion Molecules (CAMs) 83
' The Immunoglobulin Super&unily 83
The Cadherin Family 84
The Integrin Family 84
The Selectin Family 86
CHAPTER 8
/antigen Processing and
HistocompatibILity Antigens 88
Processing of Exogenous Antigen 89
Ant^Processing Cells S9
Macrophages 89 -
Dendritic Cells 89
B Cells 91 . „ oi
Other Antigen-Presenting s
The Major HUtocampotOnlilyComP'^
MHC Class n Proteins 92
Structure 92
Gene Arrangement 92
Polymorphism 94
Function 97
Processing ofEndogenous Antigen 99
MHC Class la Proteins 99
Structure 99
Gene Arrangement 99
Polymorphism 99
Fimction 100
Evolutionary S^ificance ofMHCBinding 103
MHC Class lb Proteins 104
Structure and Gene Arrangement 104
Function 104
MHC Class III Proteins 105
CHAPTER 9
The Lymphoid Organs 108
Sources Lymphoid Cells 109
Bone Marrow 109
Primary Lymphoid Organs 110
Thymus 110
Skin 113
Bur^ of Fabricius 113
Peyer's Patches 115
Secondary Lyrnphoid Organs 116
Lymph Nodes 116 "
Spleen 121 ' . ^
Lymphocyte Trapping 122
Bone Marrow * 122
Other Secondary Lyrnphoid Organs 122
CHAPTER 10
Lymphocytes 125
T and B Lymphocytes 126
Lymphocyte Surface Molecules 128
Changes in Surface Protein Expression 129
Lymphocyte Surface RecepTors 129
Antigen Receptors 129
Lymphokine Receptors 129
Antibody Receptors 129
Complement Receptors 132
OtherLymphocyte Receptors 132
Lymphocyte Enzymes 132
Other Lymphocyte Surface Proteins 133
Lymphocyte Mitogens 134
The Flaw Cytometer 134
CHAPTER 11
The Helper T-CeU Responses 139
Antigen Presentation 140
Antigen-Presenting Cells 140
The T-Cell Antigen Receptors 140
Antigen Recognition 140
. TheAccessory Molecules 143
CDS 143
^ and Ti Chains 144
Fc€Rl7 Chain 144
CD4andCD8 144
Costimulators 145
Soluble Factors 145 .
Cell Adiierence Molecules 146
Costimulatory Signals 146
Signal Transduction 147
Biological Consequences 149
Activation Antigens 149
Helper T-CeU Subpopulations 149
AlternativePathways 151
TheDevelopment of T Cells 151
CHAPTER 12
Lymphokines and Cytokines 155
TheMain Classes of Cytokine 156
Cytokines Produced Mainlyhy Macrophc^ 157
Interleukin-l 157
Interleukin-6 157
Interleukin-l2 157
Tumor Necrosis Factor-a 157
Lymphokines Produced Mainly by T Cells 159
Lymphokines Produced Mainly by Thl Cells 159
Interleukin-2 159
Interferon-7 160
Lymphotoxin (Tumor Necrosis Factor-P) 161
Lymphokines Produced Mainly by Th2 Cells 162
^ Interleukin-4 162
Interleukin-5 162
Interleukin-9 163
Interleukin-l0 163
Interleukin-l3 164
Lymphocyte-Derived Growth Factors 164
Interleukin-3 164
Interleukin-7 164
Interleukin-H. 164
Interleukin-l4 164
Interleukin-15 164
Granulocyte Colony-Stimulating Factor (G-CSF) 165
Contents xiii
Macrophage Colony^timulating Factor (M-CSF) 165
Granulocyte-Macrophage Colony-Stimulating
Factor (GM-CSF) 165
Transforming Growth Factor-p (TGF-p) 165
Cytokine Receptors 166
CHAPTER 13
TheNature ofAnHhodies 170
Properties ofAntibodies 171
Electrophoretic Mobility 171
Overall Structure 171
Structure ofImmuno^obulins' 172
Immunoglobulin G 172
PrimaryStructureofImmuno^obuUns 175
Light-Chain Sequences 175
Heavy-Chain Sequences 175
Variable Regions 175
Constant Regions 176
Hinge Region 177
The Immunoglobulin Supeifamily 178
Immuno^obulin Classes 179
Immunoglobulin G 179
Immunoglobulin M 180
Immunoglobulin A 181
Immunoglobulin D 182 ^
Immunoglobulin E. 183
Secondary Structure of Immurw^jobulins 183
Immuno^buUn VaricUions 184
Antigen-Antibody Binding
18.5
Strength of Binding 185
Biological Significance
ofAndbody Affinity 186
Biological Consequences ofAntigen-Antibody
Interaction 188
CHAPTER 14
The Response ofB CeUs to Antigen 192
CUmal Selection 193
B CeUs 193
The B Cell Antigen Receptor 193
The CD19 Complex 194
HelperT CeUs and B CeUs 196
TheResponse ofB CeUs to Antigen 196
StageOne—CeW-CeU Interactions 196
Helper T-Cell-BCell Interaction 196
Antigen Processing by B Cells 197
Stage Two—Activation by Cytokines 198
Helper Cell Subpopulations 198
XIV Ck)ntents
Interleukins That Stimulate B Cells 198
Stage Three—The BCell Respmse 199
Thymus-Independent Antigens 201
Plasma Cells 203
Memory Cells 205
Germinal Centers 205
B Cell Ontogeny 207
The Role ofIgp 208
Myelomas 208
Hybridomas 210
CHAPTER 15
The Genetic Basis ofAnt^mRecognttUm 215
Immuno^bulin Diversity 216
Immunoglobulin Gene Structure 217
Generation ofVRegion Diversity 218
.y
Potential Immunoglobulin Diversity 222
Constant Region Diversity 222
TCR Diversity 227
TCR Gene Structure 227
Generation of TCR VRegion Diversity 228
Where Does This Happen? 229
Potential TCR Diversity 230
CHAPTER 16
The Onnplement System 233
Complement 234
Complement Components 235
Classical Complement Pathway 235
Third Component of Complement 238
Alternative Complement Pathway 239
Terminal Complement Pathway 240
Mannose-Binding Proteins 241
Regulation ofthe Complement System 242
Complement Receptors 243
Consequences of Complement Activation 244
Complement-Mediated Opsonization 244
Removal ofImmime Complexes 244
Complement-Mediated Immune Regulation 244
Complement-Mediated Cytolysis 245
Complement-Mediated Chemotaxis 245
Complement-Mediated Inflammation 245
Complefn&fit Genetics 246
CmplmmtDefictencks 246
Complement Fixatioti Test 247
Cytotoxicity Tests -^248
CHAPTER 17
The Measurement ofAntigen and
Antibody Combination 251
Reagents Employed in Serological Tests 252
Primary Binding Tests 252
Radioimmunoassays 252
Immunofluorescence Assays 254
Immunoenzyme Assays 255
Other Labels Used in Primary Binding Tests 258
Secondary BindingTests 258
Precipitation 258
Titration ofAntibodies 262
Agglutination 262
Diagnostic Applications ofImmunoh^al Tests 265
CHAPTER 18
Effector T-CeU Function 268
Antig^ That Provoke Cytotoxic T-CeU Responses 269
Endogenous Antigens 269
Superantigens 269
Apoptosis 270
Apoptosis in Inflammation 272
Apoptosis in Immunity 272
Cytotoxic T-Cell Responses 27^ .
The Adhesion Phase 273
T^get Cell Perforation 275
Cytotoxic Factors 275
TargetCell Apoptosis 277
Regulation of Cytotoxicity 277
Macrophage Cytotoxicity 278
Other Mechanisms ofQytotoxxdVy 258
Other CeUrMediated Immune Reactions 279
Immunity to Intracellular Bacteria 279
Cell-Mediated Resistance toViruses 280
Delayed Hypersensitivity Reactions 282
Tuberculin Reaction 282
T-Cell Memory 284
Measurement of CeU-Mediated Immunity 284
CHAPTER 19
Organ Transplantation 288
AUografts Are Rejected 289
Allograft R^ection 290
Pathology of Allograft Rejection 290
Mechanisms of Allograft Rejection 291
Grajt-Versus-H6$]t Disease 294
Orajis That Are Not Ejected 295
Privileged Sites 295
Sperm 295
Pregnancy 295
Cultured or Stored Organs 296
Immunologically Favored Organs 297
Suppression ofthe Allograft Response 297
Radiation 297
Corticosterbids 298
Cytotoxic Drugs 299
Cyclosporine 300
Depletion of Lymphocytes 301
Blood Transfusions 302
The Ethics ofOrgan Ordfiing 302
CHAPTER 20
Resistance to Tumors 306
Tumors as AUografts 307
Tumor Antigens 307
Immune Responses to Tumor Anti^ns 309
Natural Killer CeUs 309
Basic Features 309
Surfiace Markers 310
Functions 311
Control ofNKActivity 311
Other Cellular Defenses 312
T-Cell-Mediated Immunity 312
Macrophage-Mediated Immunity 312
Antibody^Mediated Immunity 313
Failure ofImmunity to Tumor Cells 313
Immunosuppression 313
Tumor-Cell Selection 314
TumorImmunotherapy 314
Immune Stimulation 314
Active Immunization 315
Cytokine Therapy 315
LAKand TIL Cell Therapy 316
AntibodyTherapy 316
Successfiil Antitumor Vaccines 317
Lymphoid Tumors 317 '
Biu'kitt's Lymphoma 317
CHAPTER 21
Tolerance 321
Tolerance 322
T-CeU Tolerance 324
Selection of the TCR 324
Clonal Anergy 327
T Suppression 329-
B-CeU Tolerance 329
Clonal Abortion and Anergy 330
Clonal Exhaustion 331
Blockage of B-Cell Receptors 331
Incomplete Tolerance 331
Duration of Tolerance 331
CHAPTER 22
Regulation ofthe Immune Response 334
Ant^en Regulates Irnmune Responses 335
Contents XV
Antigen Processing andImmune Regulation 336
Regulation byEpitopes 336
Antibody Regulates Immune Responses 336
Idiotype Networks 338
Immune Response Genes 339
Non-MHC Immune ResponseGenes 340
Regulatory Cell Function 340
Suppressor T Cells 340
IJ Antigens 340
Macrophage-Mediated Suppression 341
Natural Suppressor Cells 341
WhenDo Suppressor Cells Work? 341
CellularRegulatory Networks 341
Contrasuppressor Cells, 341
DoSuppressor T Cells Exist? ,342
Neural Regulation ofImmunity ^342
Conclusion 343
CHAPTER 23
Immunity at Body Surfaces 347
Nmimmunohgkal Surface-Protective Mechanisms 348
Immunologjical Surface-Protective Mechanisms 350
Immimoglobulins Aand E 350
Control of IgAProduction 354
Immunity in the Gastrointestinal Tract 354
Immunity in the Mammary Gland 355
Immunity in the Urogenital Tract 356
Immunity iii the Respiratory Tract 356
Immunityin the Skin 357
CHAPTER 24
Vaccine and Vaccination 359'
Types ofImmunization Procedures 361
Passive Immunization 362
Active Immunization 364
XVI Contents
S(m£ New Approaches to Vaccine Production 366
Genetically Modified Organisms 366
Recombinant Vaccines 367
Synthetic Peptides 368
Naked DNA 368
Anti-Idiotype Vaccines 368
Use of Vaccines 368
Route of^Administration 368
Vaccinatiqn Schedules 370
Failuresin Vaccination 371
Adverse Consequences ofVaccination 372
The Benefits of Vaccination 373
CHAPTER 25
Immunity to IttfectUm 377
Factors Influencing Resistance 378
Immunity toBacteria 378
Nonspecific Immunity 378
Specific Immunity 380
Immunity to Exotoxigenic Bacteria 380
Immunity toSystemically Invasive Bacteria 380
Modification ofBacterial Disease by the
Immune Response 381
Evasion ofthe Immune Response by Bacteria 382
Immunity to Viruses 383
Nonspecific Immunity 383
Interferons 383
Specific Immunity 386
Destruction by Antibody 386
Cell-Mediated Immunity 387
Modification ofViral-Disease by the
Immune Response 387
Evasion ofthe Immune Response by Viruses 387
Immunity toProtozoa 389
Nonspecific Immunity 389
Specific Immunity 390
Evasion ofthe Immune Response by Protozoa 390
Immunity toHelminths' 392
Nonspecific Inmiunity 392
Specific Immunity 393 ^
Evasion ofdie Immune Response by Helminths 395
CHAPTER 26
Drfects in fheImmune System 399
Defects in Phagocytosis and Antigen Processing 400
Neutrophil Deficiencies 400
Neutrophil Dysfunction 400
Primary Immunod^ciencies 403
Stem-Cell Deficiency Diseases 403
Deficiencies ofthe T-Cell System 406
Deficiencies ofthe B-Cell System 406
Complex Immunodeficiency Syndromes 406
The DiGeorge Anomaly 407
Immunod^cient Mouse Strains 407
Nude Mice (nu) 407
Severe Combined Immunodeficiency
Mice (scid) 408
Motheaten Mice (me) 408
X-Linked Immunodeficiency Mice (xid) 408
Beige Mice (bg) 408.
Lipopolysaccharide Response (Ips) 408
Secondary Immunod^dendes 409
Malnutrition and the Immune Response 409
Exercise and the Immune Response 409
Trauma and the Immune Response 409
Age and the Immune Response 410
Toxins and the Immune Response 410
Other Secondary ImmuneDeficiencies 410
CHAPTER 27
Acquired Immune Deficiency
Syndrome (AIDS) 413 •
The Current State ofAIDS 414
United States 414
Worldwide 415
The AIDS Viruses 416
HIV-1 416
HIV-2 418
•Genetic Viability of HIV-1 418
Immunohgical Lesions in AIDS 419
T-Cell Abnormalities 421
B-Cell Abnormalities 421
NK-Cell Abnormalities 422
Mach^rophage Abnormalities 422
HIV in Other Cells 422
AIDS—TheDisease 423
Secondary Infections 423
Neurologic Lesions 425
Kaposi's Sarcoma 425
Diagnosis of HIVInfection 426
Treatment of HIV Infection 426
An AIDS Vaccine? 427
AIDS in Animals 427
Other Human Viruses Effecting the Immune System 427
AIDS Prevention andits Social Implications 428
CHAPTER 28
Inflammation 432
AcuteInflammation 433
Changes in Vascular Permeability 433
Cellular Emigration 433
Chemokines , 436
The Coagulation System in Inflammation 438
Vasoactive Factors 439
Factors Derived from Mast Cells 439
Factors Derived from Arachidonic Acid 439
Vasoactive Peptides 439
Factors Derived froni Neutrophils 440
Factors Derived from Platelets 441
Control ofAcuteInflammation 441
Inflammation as a Result ofImmuneReactions 441
Type I (Immediate) Hypersensitivity 441
Eosinophils 441
Type II (Cytotoxic) Hypersensitivity 444
Type ni (Immune Complex) Hypersensitivity 444
Type IV (Delayed) Hypersensitivity 444
Chronic Inflammation 444
Cytokines and Inflammation 446
Amyloidosis 449
CHAPTER 29
AUer^es: TypeI Hypersensitiznty 454
Type I Hypersensitivity 455
Induction of
Type I Hypersensitivity 455
Immunoglobulin E 456
Mast Cells and Basophils 456
IgE Receptors 457
Response ofMast Cells to Antigen 458
BiologicallyActive Molecules Released by Mast
Cells 460
Controlof Type I Hypersensitivity 462
Regulation of the IgE Response 462
Regulation of Mast-Cell Degranulation 462
Regulation of the Response to Mediators 462
Function
of Eosinophils in Type I
Hypersensitivity 462
Clinical Manifestations of Type I Hypersensitivity 463
Acute Anaphylaxis 463
Respiratory Allergy 464
Food Allergy 464
The Late-Phase Reaction 465
Diagnosis of Type I Hypersensitivity
Prevention of Type I Hypersensitivity 465
CHAPTER 30
Other Hypersensitivities 468
Type II Hypersensitivity 469
Blood Groups 469
Blood Transfusions 469
Blood Groups of Humans 470
Blood Groups
and Disease 472
Hemolytic Disease of the Newborn 474
Diagnosis 474
Prevention 474
Contents XVll
Blood Groups and Hemolytic Disease ofAnimals 475
Type III Hypersensitivity 476
Classification of Type III Hypersensitivity 476
Local Type III Hypersensitivity Reactions 476
Arthus Reaction 476
H)^ersensitivity Pneumonitis 478
Generalized Type III Hypersensitivity Reactions 479
Acute Serum Sickness 479
Chronic Serum Sickness 480
Immune Complex-Mediated Diseases 481
Type TV Hypersensitivity 482
Allergic Contact Dermatitis 483
CHAPTER 31
AuUnmmunily: Breakdown in Se^-
Tolerance 488
Physiologic Autoimmunity 489
Recognition ofSelf-Idiotypes 489
Removal of Aged Cells 489 ^
Induction of Autoimmunity 489
Exposure bf Hidden Antigens 490
Formation of New Epitopes 490
Cross-Reactivity with Microorganisms 490
Loss of Control of Lymphocyte Responses 491
Viruses as Inducers ofAutoimmunity 492
Genetic Factors and Autoimmune Disease 492
Hormonal iFactors 493
Clinical Associations Between Autoimmune
Diseases 493
Mechanisms of TissueDamagein Autoimmunity 494
Type I Hypersensitivity 494
. Type II Hypersensitivity 494
Type III Hypersensitivity 494
Type IV Hypersensitivity 494
Some Selected Autoimmune Diseases 495
Autoimmune Thyroiditis 495
Multiple Sclerosis 495
xviii Contents
Myasthenia Gravis 497
Systemic LupusErythematosus 497
j^rheumatoid Arthritis 499
Treatment For Autoimmune Diseases 501
CHAPTER 32
The Phylogeny of the Immune System 504
Immunity in Invertebrates 505
Phagocytosis 505
Humoral Immunity 505
The Prophenoloxidase System 506
Cell-Mediated Immunity 506
The Evolution of Vertdrraies 507
The Evolution of Lymphoid Organs 508
Lymphocytes 510
The Evolution of Humoral Immunity 510
Immunoglobulins 510
The Evolution of Complement 512
The Antibody Response 513
The Evolution of car Mediated Immunity 513
Temperature and the Immune Response 514
Inflammation in Fish 514
Hypersensitivity 515