Immunology: an introduction Ian Tizard,

GeneralPrinciples ofImmunology 1
historical background 2
Antibody-MediatedImmune Responses 5
CeVrMediatedImmuneResponses 7
Tolerance 9
Immune Response M^hanisms 10
current problems in Immunology 10
CHAPTER 2
Infections and Diseases 14
Organisms Thai cause disease 15
Bacteria 17
Classification 17
-How Bacteria Cause Disease 19
The Normal Flora 21
Fun^ 9
Viruses 9
"N^rus Multiplication 23
WusDiseases 24
Protozoa 25
Helminths 25
TheImportance oftheImmune System 25
CHAPTER 3
Key BiochenncalProcesses 28
Basic Genetic Mechanisms 29 ^
~ DNA 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 antigenicity 39
essential features of antigens 40
Factors that influence Antigenicity 40
Epitopes 41
Haptens 42
Protein Epitope^ 44
ExamplesofHapten-Carrier Conjugation 44
Cross-Reactivity 44
Some Specific Antigens 46
Cell Surface Antigens 47
Autoantigens 48
CHAPTER 5
Destruction ofForeign Material—
The Myeloid System 50
The Myeloid System 51 '
Neutrophils 51
Structure of neutrophils 52
Functions of neutrophils 52
Neutrophil Surfsure Proteins 56
Fate of neutrophils 57
Eosinophils 57
BasophUs 58
Platelets 58Xli Contents
CHAPTER 6
The Mononuclear-PfuigpcyticSystem 61
The Mononuclear-Pha^cytic System 62
The Structure of macrophages 62
I
The Life HistoryofMacrophages 63
The Fictions of macrophages 65
Macrophage Surface Receptors 67
Macrophages and Wound Healing 67
Macrophages as Secretory 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 the body 71
Particles Given Intravenously 71
Soluble Antigens Given Intravenously 72
Fate of antigen Given by Other Routes 72
CHAPTER 7
CeUtdarInteractions 75
cell surface proteins 76
CPU SurfaceDynamics 76
The Endocytic Pathway 76
The Exocytic Pathway 78
The Cell Cycle 78
CPU Surface Receptors and Signal Transduction 79
P^rotein Phosphorylation 81
Transcription Factors 82
Oncogenes 82
CPU Adhesion Molecules(CAMs) 83
The Immunoglobulin Superfamily 83
The Cadherin Family 84
V The Integrin Family 84
The Selectin Family 86
CHAPTER 8
Antigen Processing and
Histocompatibility Antigens 88
Processing ofExc^enous Antigen 89
Antigen Processing CeUs 89
Macrophages 89 ^
Dendritic Cells 89
BCeUs 91
Other Antigen-Presenting Cells 91
The MajorHistocompatOiUtyCo^'"'
MHC ClassIIProteins 92
Structure 92
Gene Arrangement 92
Polymorphism 94
Function 97
Processing of endogenous Antigen 99
MHC Class Proteins 99
Structure 99
Gene Arrangement 99
Polymorphism 99
Function ICQ
Evolutionary Significance ofMHCBinding 103
MHC Classlb Proteins 104
Structure and Gene Arrangement 104
Function 104
MHC ClassIIIProteins 105
CHAPTER 9
TheLymphoid Organs 108
Sources ofLyrnphoid CeUs 109
Bone Marrow 109
Primary Lymphoid Organs 110
Thymus 110 \
Skin 113
Bursa of Fabricius 113
Peyer's Patches 115
Secondary Lymphoid Organs 116
Lymph Nodes 116
Spleen 121
Lymphocyte Trapping 122'
Bone Marrow 122
Other Secondary Lymphoid Organs 122
CHAPTER 10
Lymphocytes 125
TandBLymphocyte 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 • w
Other Lymphocjrtc/Receptors
LymphocyteEnzymes 132
OUterLyrnphpcyte Surjfam Proteins
Lymphocyte MitogenS 134
TheFlow Cytorneter 134
132
133Contents Xlll
CHAPTER 11
The Helper T-cell responses 139
Antigen Presentation 140
Antigen-Presenting Cells 140
The T-CPU Ant^en Receptors 140
Antigen Recognition 140
.TheAccessory Molecules 143
CDS 143
^and t\ Chains 144
FceRI'Y Chain 144
CD4andCDS 144
Costimulators 145
Soluble Factors 145
Cell Adherence Molecules 146
Costimulatory Signals 146
Signal Transduction 147
Biological Consequences 149
Activation Antigens 149
Helper T-CeU Subpopulatums 149
AUemativePathways 151
The Development ofT Cells 151
CHAPTER 12
Lymphokines and Cytokines 155
The Main Classes ofCytokine 156
Cytokines Produced Mainly by Macrophag^ 157
Interleukin-1 157
Interleukin-6 157
Interleukin-12 157
Tumor Necrosis Factor-a 157
LymphokinesProduced Mainly by T Cells 159
LymphokinesProduced Mainly by Thl Cells 159
Interleukin-2 159
Interferon-^ 160
Lymphotoxin(Tumor Necrosis Factor-p) 161
LymphokinesProduced Mainly by Th2 Cells 162
Interleukin-4 162
Interleukin-5 162
Interleukin-9 163
Interleukin-10 163
Interleukin-13 164
LymphocytO'Denved Growth Factors 164
Interleukin-3 164
Interleukim7 164
Interleukin^l 164
Interleukin-14 164
Interleukin-15 164 - .
Granulocyte Colony-Stimulating Factor(G-CSF) 165
Macrophage Colony-Stimulating Factor(M-CSF) ^165
Cranulocyte-Macrophage Colony-Stimulating
Factor(GM-CSF) 165
Transforming Growth Factor-p (TGF-p) 165
Cytokine Receptors 166
CHAPTER 13
The Nature of antibodies 170
Properties of antibodies 171
Electrophoretic Mobility 171
Overall Structure 171
Structure ofImmunoghbuUns 172
Immunoglobulin G 172
Primary Structure ofImmunogp) 175
Light-Chain Sequences 175
Heavy-Chain Sequences 175
Variable Regions 175
ConstantRegions 176
Hinge Region 177
TheImmuno^bulin Superfamily 178
Immuno^obuHn Classes 179
Immunoglobulin G
Imnlimoglobulin M
Immunoglobulin A
Immunoglobulin D
Immunoglobulin E.
Secondary Structure ofImmuno^obulins 183
Immunoglobulin Variatums 184
Antigen-Antibody Binding 185
Strength of binding 185
Biological Significance of antibody Affinity 186
Biolo^al Consequences ofAntigen-Antibody
179
180
181
182
183
Interaction 188
CHAPTER 14
The Response of Cells to Antigen 192
CUmalSelection 193
B Cells 193
The B Cell Antigen Receptor 193
The CD19(I!ompl€;x 194
Helper T Cells and B Cells 196
TheResponse of Cells to Ardigen 196^
Stough One—CeUr-CeUInterhctions 196
Helper T-Cell-B-Cell Interaction 196
Antigen Processing byB Cells 197
Stage Two—Activation by Cytokines 198
Helper(>11 Subpopulations 198XIV Contents
Interleukins that stimulate B Cells 198
St€^ Three—TheB cell responses 199
Thymus-IndependentAndgens 201
Plasma Cells"203
Memory Cells 205
Germinal Centers 205
B Cell OnU}g^y 207
TheRole of lap 208
MyeUm^,208
Hybridomas 210
CHAPTER 15
The GeneticBasisofAntigen Recognition 215
Immuno^Mrulin Diversity 216
Immunoglobulin Gene Structure 217
Generation ofV Region Diversity 218
PotendalImmunoglobulin Diversity 222
constant region Diversity 222
TCR diversity 227
TCR Gene Structure 227
Generation ofTCR V Region Diversity 228
Where Does This Happen? 229
PotendalTCR Diversity 230
CHAPTER 16
The complement system 233
Complement 234
Complement Components 235
Classical complement pathway 235
Third ComponentofComplement 238
Altemadve ComplementPathway 239
Terminal ComplementPathway 240
Mannose-BindingProteins 241
ReguUaion of the complement system 242
ComplementReceptors 243
Consequences ofComplement Activation 244
Complement-Mediated Opsonizadon 244
RemovaJI of immune Complexes 244
Complement-MediatedImmuneReguladon 244
Complement-Mediated Cytolysis. 245
'Complement-Mediated Chemotaxis 245
Complement-Mediated Inflammation 245
Complement Genetics _.246
CtmplementDeficiencUs 246
CmplementFixalUm Test 247
Cytotoxicity Tests 2^
CHAPTER 17
The MeasurementofAntigen and
Antibody Combination 251
ReagentsEmployed 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 Binding Tests 258
Precipitation 258
Titration ofAndbodies 262
Aggludnadon 262
Diagnostic Applications ofImrnunologp:al Tests 265
CHAPTER 18
Effector T-CeU Function 268
Antigens ThatProvoke Cytotoxic T-cell responses
EndogenousAndgens 269
Superandgens 269
Apoptosis 270
Apoptosis in Inflammadon 272
Apoptosisin Immunity 272^ •
Cytotoxic T-CeU Responses 272
The Adhesion Phase 273
Target Cell Perforadon 275
Cytotoxic Factors 275
Target Cell Apoptosis 277
Reguladon ofCytotoxicity 277
Macrophage Cytotoxicity 278 ^
OtherMechanisms ofCytotoxicity 278
Other CeUrKleduUedImmuneReactions 279
Immunity to Intracellular Bacteria 279
Cell-Mediated Resistance to\^ruses 280
Delayed Hypersensitivity Reactions 282
Tuberculin Reacdon 282 -
T-CeU Memory 284
Measurement ofCell-MediatedImmunity 284
CHAPTER 19
Organ Transplantation 288 -
Why AUografts Are Rejected 289
AUograft Rejection 290
Pathology ofAUograft Rejecdon 290
MechanismsolAUograftRejecdon 291
GrafbVerstis-Host Disease 294
269Contents XV
Orafis That Are Not Rejected 295
Privileged Sites 295
Sperm 295
Pregnanq' 295
Cultured or Stored Organs 296
Immimologically Favored Organs'297
Suppression ofthe AUogrqfi Response 297
Radiadon 297
Cordcosteroids 298
Cytotoxic Drugs 299
Cyclosporine 300
Depledon ofLymphocytes 301
Blood Transfusions 302
TheEthics ofOrgan Orafling 302
CHAPTER 20
Resistance to Tumors 306
309
Tumors as AUografts 307
Tumor Andgens 307
ImmuneResponses to TumorAntigens
NaturcU Killer Cells 309
Basic Features 309
Surface Markers 310
Funcdons 311
Control ofNK Acdvity 311
Other CellvlarDefenses 312
T-Cell-Mediated Immunity 312
Macrophage-Mediated Immunity 312
Andbody-Mediated Immunity 313
Failure ofImmunity to Tumor Cells 313
Immunosuppression 313
Tumor-Cell Selecdon 314
TumorImmurwtherapy 314
Immime Sdmuladon 314
Acdve Immunizadon 315
Cytokine Therapy 315
LAKand TIL Cell Therapy
Antibody Therapy 316
Successful Andtumor Vaccines
Lymphmd Tumors 317
Burkitt's Lymphoma 317
316
317
CJIAFTER 21
Tolerance 321
Tolerance 322
T-CeU Tolerance 324
Selecdon ofthe TCR
Clonal Anergy 327
T Suppression 329
324
330
B-Cell Tolerance 329
Clonal Abortion and Anergy
Clonal Exhaustion 331
Blockage ofB-Cell Receptors 331
Incomplete Tolerance 331
Duration ofTolerance 331
CHAPTER 22
Regulation oftheImmune Response 334
Antigen RegulatesIrnmune Responses 335
Antigen Processing and Immune Regulation 336
Regulation by Epitopes 336
Antibody RegulatesImmune Responses 336
Idiotype Networks 338
Immune Response Genes 339
Non-MHCImmune Response Genes 340
Regulatory cell function 340
suppressor Cells 340
IJ Antigens 340
Macrophage-Mediated Suppression 341
Natural Suppressor Cells 341
When Do Suppressor Cells Work? 341
Cellular Regulatory Networks 341
Contrasuppressor Cells/ 341 .
Do suppressors Cells Exist?' 342
NeuralRegukUion ofImmunity 342
Conclusion 343
CHAPTER 23
Immunity atBody Surfaces 347
NonimmunologicalSurface-Protective Mechanisms 348
ImmunohgicalSurface-Protective Mechanisms 350"
ImmunoglobulinsA and E 350
Control ofIgA Production 354
Immimityin the Gastrointestinal Tract 354
Immunityin the Mammary Gland 355
Immunityin the Urogenital Tract 356
Immunity iii the RespiratoiyTract 356
Immiinity in the Skin 357
CHAPTER 24
Vaccirm and VitccmatUm 359
Types ofImmunization Procedures ^61
PassiveImmunization 362
ActiveImmunization 364XVI Contents
S(yme New Approaches to VacdneProduction 366
Genetically Modified Organisms 366
Recombinant Vaccines 367
Synthetic Peptides 368
Naked DNA 368
Anti-Idiotype Vaccines 368
Use of Vaccines 368
Route ofAdministration 368
Vaccination Schedules 370
Failures in Vaccination 371
Adverse Consequences ofVaccination 372
TheBenefits ofVaccination 373
CHAPTER 25
Imrnumty to Infection yil
FactorsInfluencing Resistance 378
Immunity to Bacteria 378
Nonspecific Immunity 378
Specific Immunity 380
Immunity to Exotoxigenic Bacteria 380
Immunity to Systemically 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 Inununity 386
Destruction by Antibody 386
Cell-Mediated Immunity 387
Modification ofViral Disease by the
Immune Response 387
^ Evasion oftheImmime Response by Viruses 387
Immunity to Protozoa 389
Nonspecific Immunity 389
Specific Immunity 390
I Evasion of the Immune Response by Protozoa 390
Immunity to Helminth^ 392
,.f Nonspecific Immunity 392
Specific Immunity 393
Evasion of the Immune Response by Helminths 395
CHAPTER 26
Defects fit theImmuneI^Uem 399
Defects in Phagocytosis and Antigen Processing 400
Neutrophil Deficiencies 400
Neutrophil Dysfunction 400
Primary Immunodeficiencies 403
Stem-Cell Deficiency Diseases 403
Deficiencies of the T-Cell System 406
Deficiencies ofthe B-Cell System 406
Complex ImmunodeficiencySyndromes 406
TheDiGeorge Anomaly 407
Immunodeficient 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 Immunodeficiencies 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 Immune Deficiencies 410
CHAPTER 27
AcquiredImmune Deficiency
Syndrome(AIDS) 413
The Current State ofAIDS 414
United States 414
Worldwide 415
TheAIDS Viruses 416
HIV-1 416
HIV-2 418
Genetic Variability ofHIV-1 418
Immunolo^alLesions in AIDS 419
T-Cell Abnormalities 421
B-Cell Abnormalities 421
NK-Cell Abnormalities 422
Machrophage Abnormalities 422
HIV in Other Cells 422
AIDS—TheDisease 423
Secondary Infections 423
Neurologic Lesions 425
Kaposi's Sarcoma 425
Diagnosisj3fHIV Infection 426
TreatmentofHIV Infection 426
An AIDS Vaccine? 427
AIDSin Animals 427
OtherHuman Viruses AfecHng theJmn\%ne System 427
AIDSPrevention and Its SocialImpUcations 428Contents xvii
CHAPTER 28
Inflammation 432
AcuteInflamnuUwn 433
Changes in Vascular Permeability 433
Cellular Emigration 433
Chemokines 436
The Coagulation System in Inflammation 438
VasoactiveFactors 439
Factors Derived from Mast Cells 439
Factors Derived from Arachidonic Acid 439
Vasoactive Peptides 439
Factors Derived from Neutrophils 440
Factors Derived froni Platelets 441
Control ofAcuteInflammaiim 441
Inflammation as a-Result ofImmune Reactions 441
Type I(Immediate) Hypersensitivity 441
Eosinophils 441
Type II (Cytotoxic) Hypersensitivity 444
Type III(Immune Complex) Hypersensitivity 444
Type IV (Delayed) Hypersensitivity 444
ChronicInflammation 444
Cytokines and Inflammation 446
AmyUndosis 449
CHAPTER 30
Other Hypersensitivities 468
Type IIHypersensitivity 469
Blood Groups 469
Blood Transfusions 469
Blood Groups ofHumans 470
Blood Groups and Disease 472
Hemolytic Disease ofthe Newborn 474
Diagnosis 474
Prevention 474
Blood Groups and Hemolytic Disease ofAnimals 475
Type IIIHypersensitivity 476
Classitication ofType III Hypersensitivity 476
Iccal Type IIIHypersensitivity Reactions 476
Arthus Reaction 476
Hypersensitivity Pneumonitis 478
Generalized Type IIIHypersensitivity Reactions 479
Acute Serum Sickness 479
Chronic Serum Sickness 480
Immune Complex-Mediated Diseases 481
TypeIVHypersensitivity 482
Allergic Contact Dermatitis 483
CHAPTER 29
AUer^es: TypeIHypersensitivity 454
TypeIHypersensitivity 455
Induction ofTypeIHypersensitivity 455
ImmunoglobulinE 456
Mast Cells and Basophils 456
IgE Receptors 457
Response ofMast Cells to Antigen 458
Biologically Active Molecules Released by Mast
Cells 460
Control ofTypeIHypersensitivity 462
Regulation ofthe IgE Response 462
Regulation of Mast-Cell Degranulation 462
Regulation ofthe Response to Mediators 462
Function ofEosinophils in Type I
Hypersensitivity 462
Clinical Manifestations ofTypeIHypersensitivity 463
Acute Anaphylaxis 463
Respiratory Allergy 464
Food Allefgy 464
The Late-Phase Reaction 465
Diagnosis ofTypeIHypersensitivity 65
Prevention ofTypeIHypersensitivity 465
CHAPTER 31
Autoimmunity:Breahdoxm in SelfTolerance 488
Physiologic Autoimmunity 489
Recognition ofSelf-Idiotypes 489
Removal ofAged Cells 489
Induction ofAutoimmunity 489
Exposure ofHidden Antigens 490
Formation ofNew Epitopes 490
Cross-Reactivity with Microorganisms 490
Loss of Control ofLymphocyte Responses 491
Viruses as Inducers ofAutoimmunity 492
Genetic Factors and Autoimmune Disease 492
Hormonal Factors 493
Clinical Associations Between Autoimmune
Diseases 493
Mechanisms'ofTissueDamage in Autoimmunity 494
Type I Hypersensitivity 494
Type II Hypersensitivity 494
Type III Hypersensitivity 494
Type IV Hypersensitivity 494
Some Selected AutoimmuneDiseases 495
Autoimmune Thyroiditis 495
Multiple Sclerosis 495XVUl Contents
Myasthenia Gravis 497
Systemic Lupus Erythematosus 497

TrmtrnmtsforAutoimmuneDiseases 501
CHAPTER 32
TheFhylogeny ofiheImmuneSystem 504
Immunity in Invertdnates 505
Phagoqtosis 505
HumoralImmuiiity 505
The Prophenoloxidase System 506
Cell-Mediated Immunity 506
TheEvolution of Vertebrates 507
TheEvolution ofLymphoid Organs 508
Lymphocytes 510
TheEvolution ofHumoralImmunity 510
Immunoglobulins 510
The Evolution ofComplement 512
The Antibody Response 513
TheEvolution ofCellrMediated Immunity 513
Temperature and theImmune Response 514
Inflammation in Fish 514
Hypersensitivity 515
Glossaiy 519
Index 529