Immunobiology

IMMUNOBIOLOGY, 5TH ED.......Page 1
Short Contents......Page 2
Full Contents......Page 3
Copyright Page......Page 8
Acknowledgments......Page 9
Introduction to Chapter 1......Page 14
The components of the immune system......Page 15
1-1. The white blood cells of the immune system derive from precursors in the bone marrow......Page 16
1-2. Lymphocytes mature in the bone marrow or the thymus......Page 20
1-3. The peripheral lymphoid organs are specialized to trap antigen, to allow the initiation of adaptive immune responses, and to provide signals that sustain recirculating lymphocytes......Page 21
1-4. Lymphocytes circulate between blood and lymph......Page 24
Summary......Page 25
1-5. Most infectious agents induce inflammatory responses by activating innate immunity......Page 26
1-6. Activation of specialized antigen-presenting cells is a necessary first step for induction of adaptive immunity......Page 27
1-7. Lymphocytes activated by antigen give rise to clones of antigen-specific cells that mediate adaptive immunity......Page 28
1-8. Clonal selection of lymphocytes is the central principle of adaptive immunity......Page 29
1-9. The structure of the antibody molecule illustrates the central puzzle of adaptive immunity......Page 30
1-10. Each developing lymphocyte generates a unique antigen receptor by rearranging its receptor genes......Page 31
1-11. Lymphocyte development and survival are determined by signals received through their antigen receptors......Page 32
1-12. Lymphocytes proliferate in response to antigen in peripheral lymphoid organs, generating effector cells and immunological memory......Page 33
1-13. Interaction with other cells as well as with antigen is necessary for lymphocyte activation......Page 35
The recognition and effector mechanisms of adaptive immunity......Page 38
1-14. Antibodies deal with extracellular forms of pathogens and their toxic products......Page 39
1-15. T cells are needed to control intracellular pathogens and to activate B-cell responses to most antigens......Page 41
1-16. T cells are specialized to recognize foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex......Page 43
1-17. Two major types of T cell recognize peptides bound to proteins of two different classes of MHC molecule......Page 44
1-18. Defects in the immune system result in increased susceptibility to infection......Page 46
1-20. Vaccination is the most effective means of controlling infectious diseases......Page 47
Summary......Page 48
References to Chapter 1......Page 49
Introduction to Chapter 2......Page 52
2-1. Infectious agents must overcome innate host defenses to establish a focus of infection......Page 53
2-2. The epithelial surfaces of the body are the first defenses against infection......Page 54
2-3. After entering tissues, many pathogens are recognized, ingested, and killed by phagocytes......Page 55
Summary......Page 59
The complement system and innate immunity......Page 60
2-5. Complement is a system of plasma proteins that interacts with pathogens to mark them for destruction by phagocytes......Page 61
2-6. The classical pathway is initiated by activation of the C1 complex......Page 64
2-7. The mannan-binding lectin pathway is homologous to the classical pathway......Page 66
2-8. Complement activation is largely confined to the surface on which it is initiated......Page 67
2-9. Hydrolysis of C3 causes initiation of the alternative pathway of complement......Page 69
2-10. Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity......Page 73
2-11. Phagocyte ingestion of complement-tagged pathogens is mediated by receptors for the bound complement proteins......Page 74
2-12. Small fragments of some complement proteins can initiate a local inflammatory response......Page 76
2-13. The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens......Page 77
2-14. Complement control proteins regulate all three pathways of complement activation and protect the host from its destructive effects......Page 79
Summary......Page 82
Receptors of the innate immune system......Page 83
2-15. Receptors with specificity for pathogen surfaces recognize patterns of repeating structural motifs......Page 84
2-17. The effects of bacterial lipopolysaccharide on macrophages are mediated by CD14 binding to Toll-like receptor 4......Page 85
2-18. Activation of Toll-like receptors triggers the production of pro-inflammatory cytokines and chemokines, and the expression of co-stimulatory molecules......Page 87
Induced innate responses to infection......Page 88
2-19. Activated macrophages secrete a range of cytokines that have a variety of local and distant effects......Page 89
2-20. Chemokines released by phagocytes recruit cells to sites of infection......Page 90
2-21. Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response......Page 92
2-22. Neutrophils make up the first wave of cells that cross the blood vessel wall to enter inflammatory sites......Page 96
2-23. Tumor necrosis factor-αis an important cytokine that triggers local containment of infection, but induces shock when released systemically......Page 97
2-24. Cytokines released by phagocytes activate the acute-phase response......Page 99
2-25. Interferons induced by viral infection make several contributions to host defense......Page 101
2-26. Natural killer cells are activated by interferons and macrophage-derived cytokines to serve as an early defense against certain intracellular infections......Page 102
2-27. NK cells possess receptors for self molecules that inhibit their activation against uninfected host cells......Page 103
2-28. Several lymphocyte subpopulations and 'natural antibodies' behave like intermediates between adaptive and innate immunity......Page 105
Summary to Chapter 2......Page 107
References......Page 108
Introduction to Chapter 3......Page 115
The structure of a typical antibody molecule......Page 116
3-1. IgG antibodies consist of four polypeptide chains......Page 117
3-3. The antibody molecule can readily be cleaved into functionally distinct fragments......Page 118
3-4. The immunoglobulin molecule is flexible, especially at the hinge region......Page 120
3-5. The domains of an immunoglobulin molecule have similar structures......Page 121
3-6. Localized regions of hypervariable sequence form the antigenbinding site......Page 122
3-7. Antibodies bind antigens via contacts with amino acids in CDRs, but the details of binding depend upon the size and shape of the antigen......Page 124
3-8. Antibodies bind to conformational shapes on the surfaces of antigens......Page 125
3-9. Antigen-antibody interactions involve a variety of forces......Page 126
Antigen recognition by T cells......Page 127
3-10. The antigen receptor on T cells is very similar to a Fab fragment of immunoglobulin......Page 128
3-11. A T-cell receptor recognizes antigen in the form of a complex of a foreign peptide bound to an MHC molecule......Page 130
3-12. T cells with different functions are distinguished by CD4 and CD8 cell-surface proteins and recognize peptides bound to different classes of MHC molecule......Page 131
3-13. The two classes of MHC molecule are expressed differentially on cells......Page 134
3-14. The two classes of MHC molecule have distinct subunit structures but similar three-dimensional structures......Page 135
3-16. MHC class I molecules bind short peptides of 8 10 amino acids by both ends......Page 138
3-17. The length of the peptides bound by MHC class II molecules is not constrained......Page 140
3-18. The crystal structures of several MHC:peptide:T-cell receptor complexes all show the same T-cell receptor orientation over the MHC:peptide complex......Page 141
Summary to Chapter 3......Page 144
References to Chapter 3......Page 145
Introduction to Chapter 4......Page 150
4-1. Immunoglobulin genes are rearranged in antibody-producing cells......Page 151
4-2. The DNA sequence encoding a complete V region is generated by the somatic recombination of separate gene segments......Page 152
4-3. There are multiple different V-region gene segments......Page 153
4-4. Rearrangement of V, D, and J gene segments is guided by flanking DNA sequences......Page 154
4-5. The reaction that recombines V, D, and J gene segments involves both lymphocyte-specific and ubiquitous DNA-modifying enzymes......Page 156
4-8. Variable addition and subtraction of nucleotides at the junctions between gene segments contributes to
diversity in the third hypervariable region.......Page 159
4-9. Rearranged V genes are further diversified by somatic hypermutation......Page 162
4-10. In some species most immunoglobulin gene diversification occurs after gene rearrangement......Page 163
T-cell receptor gene rearrangement......Page 164
4-11. The T-cell receptor loci comprise sets of gene segments and are rearranged by the same enzymes as the immunoglobulin loci......Page 165
4-12. T-cell receptors concentrate diversity in the third hypervariable region......Page 167
4-14. Somatic hypermutation does not generate diversity in T-cell receptors......Page 168
4-15. The immunoglobulin heavy-chain isotypes are distinguished by the structure of their constant regions......Page 169
4-16. The same V H exon can associate with different C H genes in the course of an immune response......Page 171
4-17. Transmembrane and secreted forms of immunoglobulin are generated from alternative heavy-chain transcripts......Page 174
4-18. Antibody C regions confer functional specialization......Page 176
4-19. IgM and IgA can form polymers......Page 178
4-20. Various differences between immunoglobulins can be detected by antibodies......Page 179
Summary......Page 180
Summary to Chapter 4......Page 181
References to Chapter 4......Page 182
The generation of T-cell receptor ligands......Page 187
5-1. The MHC class I and class II molecules deliver peptides to the cell surface from two distinct intracellular compartments......Page 188
5-2. Peptides that bind to MHC class I molecules are actively transported from the cytosol to the endoplasmic reticulum......Page 189
5-3. Peptides for transport into the endoplasmic reticulum are generated in the cytosol......Page 190
5-4. Newly synthesized MHC class I molecules are retained in the endoplasmic reticulum until they bind peptide......Page 191
5-6. The invariant chain directs newly synthesized MHC class II molecules to acidified intracellular vesicles......Page 194
5-7. A specialized MHC class II-like molecule catalyzes loading of MHC class II molecules with peptides......Page 196
5-8. Stable binding of peptides by MHC molecules provides effective antigen presentation at the cell surface......Page 198
The major histocompatibility complex and its functions......Page 199
5-10. A variety of genes with specialized functions in immunity are also encoded in the MHC......Page 200
5-12. The protein products of MHC class I and class II genes are highly polymorphic......Page 202
5-13. MHC polymorphism affects antigen recognition by T cells by influencing both peptide binding and the contacts between T-cell receptor and MHC molecule......Page 204
5-14. Nonself MHC molecules are recognized by 1–10% of T cells......Page 208
5-15. Many T cells respond to superantigens......Page 209
5-17. Multiple genetic processes generate MHC polymorphism......Page 211
5-18. Some peptides and lipids generated in the endocytic pathway can be bound by MHC class I-like molecules that are encoded outside the MHC......Page 213
Summary to Chapter 5......Page 214
References to Chapter 5......Page 215
General principles of transmembrane signaling......Page 220
6-1. Binding of antigen leads to clustering of antigen receptors on lymphocytes......Page 221
6-2. Clustering of antigen receptors leads to activation of intracellular signal molecules......Page 223
6-3. Phosphorylation of receptor cytoplasmic tails by tyrosine kinases concentrates intracellular signaling molecules around the receptors......Page 225
6-4. Intracellular signaling components recruited to activated receptors transmit the signal onward from the membrane and amplify it......Page 226
6-5. Small G proteins activate a protein kinase cascade that transmits the signal to the nucleus......Page 228
6-6. The variable chains of lymphocyte antigen receptors are associated with invariant accessory chains that carry out the signaling function of the receptor......Page 229
6-7. The ITAMs associated with the B-cell and T-cell receptors are phosphorylated by protein tyrosine kinases of the Src family......Page 232
6-8. Antigen receptor signaling is enhanced by co-receptors that bind the same ligand......Page 234
6-9. Fully phosphorylated ITAMs bind the protein tyrosine kinases Syk and ZAP-70 and enable them to be activated......Page 236
6-10. Downstream events are mediated by proteins that associate with the phosphorylated tyrosines and bind to and activate other proteins......Page 237
6-11. Antigen recognition leads ultimately to the induction of new gene synthesis by activating transcription factors......Page 240
6-12. Not all ligands for the T-cell receptor produce a similar response......Page 242
6-13. Other receptors on leukocytes also use ITAMs to signal activation......Page 243
6-14. Antigen-receptor signaling can be inhibited by receptors associated with ITIMs......Page 244
6-15. Microbes and their products release NFκB from its site in the cytosol through an ancient pathway of host defense against infection......Page 245
6-16. Bacterial peptides, mediators of inflammatory responses, and chemokines signal through members of the seven-transmembrane-domain, trimeric G protein-coupled receptor family......Page 247
6-17. Cytokines signal lymphocytes by binding to cytokine receptors and triggering Janus kinases to phosphorylate and activate STAT proteins......Page 248
6-18. Programmed cell death of activated lymphocytes is triggered mainly through the receptor Fas......Page 249
6-19. Lymphocyte survival is maintained by a balance between death-promoting and death-inhibiting members of the Bcl-2 family of proteins......Page 250
6-20. Homeostasis of lymphocyte populations is maintained by signals that lymphocytes are continually receiving through their antigen receptors......Page 251
Summary to Chapter 6......Page 252
References to Chapter 6......Page 253
Introduction to Chapter 7......Page 258
Generation of lymphocytes in bone marrow and thymus......Page 260
7-1. Lymphocyte development occurs in specialized environments and is regulated by the somatic rearrangement of the antigen-receptor genes......Page 261
7-2. B cells develop in the bone marrow with the help of stromal cells and achieve maturity in peripheral lymphoid organs......Page 262
7-3. Stages in B-cell development are distinguished by the expression of immunoglobulin chains and particular cell-surface proteins......Page 264
7-4. T cells also originate in the bone marrow, but all the important events in their development occur in the thymus......Page 266
7-5. Most developing T cells die in the thymus......Page 269
7-6. Successive stages in the development of thymocytes are marked by changes in cell-surface molecules......Page 270
7-7. Thymocytes at different developmental stages are found in distinct parts of the thymus......Page 273
7-8. B cells undergo a strictly programmed series of gene rearrangements in the bone marrow......Page 274
7-9. Successful rearrangement of heavy-chain immunoglobulin gene segments leads to the formation of a pre-B-cell receptor that halts further V H to DJ H rearrangement and triggers the cell to divide......Page 278
7-10. Rearrangement at the immunoglobulin light-chain locus leads to cell-surface expression of the B-cell receptor......Page 280
7-11. The expression of proteins regulating immunoglobulin gene rearrangement and function is developmentally programmed......Page 282
7-12. T cells in the thymus undergo a series of gene segment rearrangements similar to those of B cells......Page 285
7-13. T cells with α:β or γ:δ receptors arise from a common progenitor......Page 286
7-14. T cells expressing particular γ- and δ-chain V regions arise in an ordered sequence early in life......Page 288
7-15. Rearrangement of the β-chain locus and production of a β-chain trigger several events in developing thymocytes......Page 290
7-16. T-cell α-chain genes undergo successive rearrangements until positive selection or cell death intervenes......Page 294
Summary......Page 295
7-17. Immature B cells that bind self antigens undergo further receptor rearrangement, or die, or are inactivated......Page 296
7-18. Mature B cells can also be rendered self-tolerant......Page 300
7-19. Only thymocytes whose receptors can interact with self MHC:self peptide complexes can survive and mature......Page 301
7-21. Positive selection acts on a repertoire of receptors with inherent specificity for MHC molecules......Page 303
7-22. Positive selection coordinates the expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the cell......Page 304
7-23. Thymic cortical epithelial cells mediate positive selection of developing thymocytes......Page 306
7-24. T cells that react strongly with ubiquitous self antigens are deleted in the thymus......Page 309
7-25. Negative selection is driven most efficiently by bone marrow-derived antigen-presenting cells......Page 310
7-26. Endogenous superantigens mediate negative selection of T-cell receptors derived from particular V β gene segments......Page 311
7-27. The specificity and strength of signals for negative and positive selection must differ......Page 312
7-28. The B-1 subset of B cells has a distinct developmental history and expresses a distinctive repertoire of receptors......Page 315
Survival and maturation of lymphocytes in peripheral lymphoid tissues......Page 317
7-29. Newly formed lymphocytes home to particular locations in peripheral lymphoid tissues......Page 318
7-30. The development and organization of peripheral lymphoid tissues is controlled by cytokines and chemokines......Page 321
7-31. Only a small fraction of immature B cells mature and survive in peripheral lymphoid tissues......Page 323
7-33. B-cell tumors often occupy the same site as their normal counterparts......Page 325
7-34. A range of tumors of immune system cells throws light on different stages of T-cell development......Page 328
7-35. Malignant lymphocyte tumors frequently carry chromosomal translocations that join immunoglobulin loci to genes regulating cell growth......Page 329
Summary......Page 330
Summary to Chapter 7......Page 331
References to Chapter 7......Page 334
Introduction to Chapter 8......Page 343
The production of armed effector T cells......Page 344
8-1. T-cell responses are initiated in peripheral lymphoid organs by activated antigen-presenting cells......Page 345
8-2. Naive T cells sample the MHC:peptide complexes on the surface of antigen-presenting cells as they migrate through peripheral lymphoid tissue......Page 348
8-3. Lymphocyte migration, activation, and effector function depend on cell-cell interactions mediated by celladhesion molecules......Page 349
8-4. The initial interaction of T cells with antigen-presenting cells is mediated by cell-adhesion molecules......Page 353
8-5. Both specific ligand and co-stimulatory signals provided by an antigen-presenting cell are required for the clonal expansion of naive T cells......Page 355
8-6. Dendritic cells specialize in taking up antigen and activating naive T cells......Page 358
8-7. Macrophages are scavenger cells that can be induced by pathogens to present foreign antigens to naive T cells......Page 361
8-8. B cells are highly efficient at presenting antigens that bind to their surface immunoglobulin......Page 362
8-9. Activated T cells synthesize the T-cell growth factor interleukin-2 and its receptor......Page 364
8-10. The co-stimulatory signal is necessary for the synthesis and secretion of IL-2......Page 366
8-11. Antigen recognition in the absence of co-stimulation leads to T-cell tolerance......Page 367
8-12. Proliferating T cells differentiate into armed effector T cells that do not require co-stimulation to act......Page 368
8-13. The differentiation of CD4 T cells into T H 1 or T H 2 cells determines whether humoral or cell-mediated immunity will predominate......Page 369
8-14. Naive CD8 T cells can be activated in different ways to become armed cytotoxic effector cells......Page 370
General properties of armed effector T cells......Page 371
8-15. Effector T-cell interactions with target cells are initiated by antigen-nonspecific cell-adhesion molecules......Page 372
8-16. Binding of the T-cell receptor complex directs the release of effector molecules and focuses them on the target cell......Page 374
8-17. The effector functions of T cells are determined by the array of effector molecules they produce......Page 376
8-18. Cytokines can act locally or at a distance......Page 378
8-19. Cytokines and their receptors fall into distinct families of structurally related proteins......Page 380
8-20. The TNF family of cytokines are trimeric proteins that are often associated with the cell surface......Page 382
8-21. Cytotoxic T cells can induce target cells to undergo programmed cell death......Page 383
8-22. Cytotoxic effector proteins that trigger apoptosis are contained in the granules of CD8 cytotoxic T cells......Page 384
8-23. Activated CD8 T cells and some CD4 effector T cells express Fas ligand, which can also activate apoptosis......Page 386
8-24. Cytotoxic T cells are selective and serial killers of targets expressing specific antigen......Page 387
Summary......Page 389
8-26. Armed T H 1 cells have a central role in macrophage activation......Page 390
8-28. Activation of macrophages by armed T H 1 cells promotes microbial killing and must be tightly regulated to avoid tissue damage......Page 391
8-29. T H 1 cells coordinate the host response to intracellular pathogens......Page 392
Summary......Page 394
References to Chapter 8......Page 395
Introduction to Chapter 9......Page 401
B-cell activation by armed helper T cells......Page 402
9-1. The humoral immune response is initiated when B cells that bind antigen are signaled by helper T cells or by certain microbial antigens alone......Page 403
9-2. Armed helper T cells activate B cells that recognize the same antigen......Page 404
9-3. Antigenic peptides bound to self MHC class II molecules trigger armed helper T cells to make membranebound and secreted molecules that can activate a B cell......Page 407
9-4. Isotype switching requires expression of CD40L by the helper T cell and is directed by cytokines......Page 408
9-5. Antigen-binding B cells are trapped in the T-cell zone of secondary lymphoid tissues and are activated by encounter with armed helper T cells......Page 412
9-6. The second phase of the primary B-cell immune response occurs when activated B cells migrate to follicles and proliferate to form germinal centers......Page 416
9-7. Germinal center B cells undergo V-region somatic hypermutation and cells with mutations that improve affinity for antigen are selected......Page 419
9-8. Ligation of the B-cell receptor and CD40, together with direct contact with T cells, are all required to sustain germinal center B cells......Page 421
9-9. Surviving germinal center B cells differentiate into either plasma cells or memory cells......Page 422
9-10. B-cell responses to bacterial antigens with intrinsic ability to activate B cells do not require T-cell help......Page 423
9-11. B-cell responses to bacterial polysaccharides do not require peptide-specific T-cell help......Page 424
The distribution and functions of immunoglobulin isotypes......Page 426
9-12. Antibodies of different isotype operate in distinct places and have distinct effector functions......Page 427
9-13. Transport proteins that bind to the Fc regions of antibodies carry particular isotypes across epithelial barriers......Page 429
9-14. High-affinity IgG and IgA antibodies can neutralize bacterial toxins......Page 432
9-16. Antibodies can block the adherence of bacteria to host cells......Page 434
9-17. Antibody:antigen complexes activate the classical pathway of complement by binding to C1q......Page 435
9-18. Complement receptors are important in the removal of immune complexes from the circulation......Page 437
The destruction of antibody-coated pathogens via Fc receptors......Page 439
9-19. The Fc receptors of accessory cells are signaling receptors specific for immunoglobulins of different isotypes......Page 441
9-20. Fc receptors on phagocytes are activated by antibodies bound to the surface of pathogens and enable the phagocytes to ingest and destroy pathogens......Page 442
9-22. Mast cells, basophils, and activated eosinophils bind IgE antibody via the high-affinity Fcε receptor......Page 444
9-23. IgE-mediated activation of accessory cells has an important role in resistance to parasite infection......Page 447
Summary to Chapter 9......Page 448
References to Chapter 9......Page 449
Introduction to Chapter 10......Page 455
10-1. The course of an infection can be divided into several distinct phases......Page 456
10-2. Infectious diseases are caused by diverse living agents that replicate in their hosts......Page 458
10-3. The nonspecific responses of innate immunity are necessary for an adaptive immune response to be initiated......Page 462
10-4. An adaptive immune response is initiated when circulating T cells encounter their corresponding antigen in draining lymphoid tissues and become activated......Page 465
10-5. Cytokines made in the early phases of an infection influence the functional differentiation of CD4 T cells......Page 470
10-6. Distinct subsets of T cells can regulate the growth and effector functions of other T-cell subsets......Page 471
10-7. The nature and amount of antigenic peptide can also affect the differentiation of CD4 T cells......Page 472
10-8. Armed effector T cells are guided to sites of infection by chemokines and newly expressed adhesion molecules......Page 475
10-9. Antibody responses develop in lymphoid tissues under the direction of armed helper T cells......Page 477
10-10. Antibody responses are sustained in medullary cords and bone marrow......Page 479
10-11. The effector mechanisms used to clear an infection depend on the infectious agent......Page 480
Summary......Page 482
10-13. Mucosa-associated lymphoid tissue is located in anatomically defined microcompartments throughout the gut......Page 483
10-14. The mucosal immune system contains a distinctive repertoire of lymphocytes......Page 484
10-15. Secretory IgA is the antibody isotype associated with the mucosal immune system......Page 487
10-17. The mucosal immune system can mount an immune response to the normal bacterial flora of the gut......Page 488
10-18. Enteric pathogens cause a local inflammatory response and the development of protective immunity......Page 489
10-20. In the absence of inflammatory stimuli, the normal response of the mucosal immune system to foreign antigens is tolerance......Page 492
Summary......Page 494
10-21. Immunological memory is long-lived after infection or vaccination......Page 495
10-22. Both clonal expansion and clonal differentiation contribute to immunological memory in B cells......Page 496
10-23. Repeated immunizations lead to increasing affinity of antibody owing to somatic hypermutation and selection by antigen in germinal centers......Page 497
10-24. Memory T cells are increased in frequency and have distinct activation requirements and cell-surface proteins that distinguish them from armed effector T cells......Page 498
10-25. In immune individuals, secondary and subsequent responses are mediated solely by memory lymphocytes and not by naive lymphocytes......Page 501
Summary to Chapter 10......Page 502
References to Chapter 10......Page 504
11-1. Antigenic variation allows pathogens to escape from immunity......Page 510
11-2. Some viruses persist in vivo by ceasing to replicate until immunity wanes......Page 514
11-3. Some pathogens resist destruction by host defense mechanisms or exploit them for their own purposes......Page 516
11-4. Immunosuppression or inappropriate immune responses can contribute to persistent disease......Page 517
11-5. Immune responses can contribute directly to pathogenesis......Page 520
Summary......Page 521
11-6. A history of repeated infections suggests a diagnosis of immunodeficiency......Page 522
11-7. Inherited immunodeficiency diseases are caused by recessive gene defects......Page 523
11-8. The main effect of low levels of antibody is an inability to clear extracellular bacteria......Page 524
11-9. T-cell defects can result in low antibody levels......Page 527
11-10. Defects in complement components cause defective humoral immune function......Page 528
11-11. Defects in phagocytic cells permit widespread bacterial infections......Page 529
11-12. Defects in T-cell function result in severe combined immunodeficiencies......Page 531
11-13. Defective T-cell signaling, cytokine production, or cytokine action can cause immunodeficiency......Page 533
11-14. The normal pathways for host defense against intracellular bacteria are illustrated by genetic deficiencies of IFN- and IL-12 and their receptors......Page 534
11-16. Bone marrow transplantation or gene therapy can be useful to correct genetic defects......Page 535
Acquired immune deficiency syndrome......Page 537
11-17. Most individuals infected with HIV progress over time to AIDS......Page 538
11-18. HIV is a retrovirus that infects CD4 T cells, dendritic cells, and macrophages......Page 540
11-20. HIV RNA is transcribed by viral reverse transcriptase into DNA that integrates into the host cell genome......Page 542
11-21. Transcription of the HIV provirus depends on host cell transcription factors induced upon the activation of infected T cells......Page 544
11-22. Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells......Page 545
11-23. HIV accumulates many mutations in the course of infection in a single individual and drug treatment is soon followed by the outgrowth of drug-resistant variants of the virus......Page 546
11-24. Lymphoid tissue is the major reservoir of HIV infection......Page 547
11-25. An immune response controls but does not eliminate HIV......Page 548
11-26. HIV infection leads to low levels of CD4 T cells, increased susceptibility to opportunistic infection, and eventually to death......Page 549
11-27. Vaccination against HIV is an attractive solution but poses many difficulties......Page 550
Summary......Page 551
References to Chapter 11......Page 552
Introduction to Chapter 12......Page 564
12-1. Allergens are often delivered transmucosally at low dose, a route that favors IgE production......Page 566
12-2. Enzymes are frequent triggers of allergy......Page 567
12-3. Class switching to IgE in B lymphocytes is favored by specific signals......Page 568
12-4. Genetic factors contribute to the development of IgE-mediated allergy, but environmental factors may also be important......Page 570
Effector mechanisms in allergic reactions......Page 571
12-5. Most IgE is cell-bound and engages effector mechanisms of the immune system by different pathways from other antibody isotypes......Page 572
12-6. Mast cells reside in tissues and orchestrate allergic reactions......Page 573
12-7. Eosinophils are normally under tight control to prevent inappropriate toxic responses......Page 575
12-10. The clinical effects of allergic reactions vary according to the site of mast-cell activation......Page 578
12-11. Allergen inhalation is associated with the development of rhinitis and asthma......Page 580
12-12. Skin allergy is manifest as urticaria or chronic eczema......Page 581
12-14. Allergy can be treated by inhibiting either IgE production or the effector pathways activated by crosslinking of cell-surface IgE......Page 582
Hypersensitivity diseases......Page 583
12-16. Systemic disease caused by immune complex formation can follow the administration of large quantities of poorly catabolized antigens......Page 584
12-17. Delayed-type hypersensitivity reactions are mediated by T H 1 cells and CD8 cytotoxic T cells......Page 586
References to Chapter 12......Page 590
Autoimmune responses are directed against self antigens......Page 599
13-1. Specific adaptive immune responses to self antigens can cause autoimmune disease......Page 601
13-2. Autoimmune diseases can be classified into clusters that are typically either organ-specific or systemic......Page 602
13-3. Susceptibility to autoimmune disease is controlled by environmental and genetic factors, especially MHC genes......Page 603
13-4. The genes that have been associated with the development of systemic lupus erythematosus provide important clues to the etiology of the disease......Page 607
13-6. Autoantibodies against blood cells promote their destruction......Page 609
13-7. The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response......Page 610
13-8. Autoantibodies against receptors cause disease by stimulating or blocking receptor function......Page 611
13-9. Autoantibodies against extracellular antigens cause inflammatory injury by mechanisms akin to type II and type III hypersensitivity reactions......Page 612
13-10. Environmental cofactors can influence the expression of autoimmune disease......Page 614
13-11. The pattern of inflammatory injury in autoimmunity can be modified by anatomical constraints......Page 615
13-12. The mechanism of autoimmune tissue damage can often be determined by adoptive transfer......Page 616
13-13. T cells specific for self antigens can cause direct tissue injury and have a role in sustained autoantibody responses......Page 618
13-14. Autoantibodies can be used to identify the target of the autoimmune process......Page 619
13-15. The target of T cell-mediated autoimmunity is difficult to identify owing to the nature of T-cell ligands......Page 621
13-16. Graft rejection is an immunological response mediated primarily by T cells......Page 624
13-17. Matching donor and recipient at the MHC improves the outcome of transplantation......Page 625
13-18. In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules......Page 626
13-19. There are two ways of presenting alloantigens on the transplant to the recipient's T lymphocytes......Page 627
13-20. Antibodies reacting with endothelium cause hyperacute graft rejection......Page 629
13-21. The converse of graft rejection is graft-versus-host disease......Page 631
13-22. Chronic organ rejection is caused by inflammatory vascular injury to the graft......Page 632
13-24. The fetus is an allograft that is tolerated repeatedly......Page 634
13-25. Many autoantigens are not so abundantly expressed that they induce clonal deletion or anergy but are not so rare as to escape recognition entirely......Page 636
13-26. The induction of a tissue-specific response requires the presentation of antigen by antigenpresenting cells with co-stimulatory activity......Page 640
13-27. In the absence of co-stimulation, tolerance is induced......Page 642
13-28. Dominant immune suppression can be demonstrated in models of tolerance and can affect the course of autoimmune disease......Page 644
13-29. Antigens in immunologically privileged sites do not induce immune attack but can serve as targets......Page 646
13-30. B cells with receptors specific for peripheral autoantigens are held in check by a variety of mechanisms......Page 647
13-31. Autoimmunity may sometimes be triggered by infection......Page 650
Summary......Page 653
References to Chapter 13......Page 654
Extrinsic regulation of unwanted immune responses......Page 666
14-1. Corticosteroids are powerful anti-inflammatory drugs that alter the transcription of many genes......Page 667
14-3. Cyclosporin A, FK506 (tacrolimus), and rapamycin (sirolimus) are powerful immunosuppressive agents that interfere with T-cell signaling......Page 669
14-4. Immunosuppressive drugs are valuable probes of intracellular signaling pathways in lymphocytes......Page 670
14-6. Antibodies can be engineered to reduce their immunogenicity in humans......Page 672
14-7. Monoclonal antibodies can be used to inhibit allograft rejection......Page 673
14-8. Antibodies can be used to alleviate and suppress autoimmune disease......Page 674
14-9. Modulation of the pattern of cytokine expression by T lymphocytes can inhibit autoimmune disease......Page 675
14-10. Controlled administration of antigen can be used to manipulate the nature of an antigen-specific response......Page 676
Summary......Page 677
14-11. The development of transplantable tumors in mice led to the discovery that mice could mount a protective immune response against tumors......Page 678
14-12. T lymphocytes can recognize specific antigens on human tumors......Page 679
14-13. Tumors can escape rejection in many ways......Page 682
14-14. Monoclonal antibodies against tumor antigens, alone or linked to toxins, can control tumor growth......Page 685
14-15. Enhancing the immunogenicity of tumors holds promise for cancer therapy......Page 687
Manipulating the immune response to fight infection......Page 689
14-16. There are several requirements for an effective vaccine......Page 691
14-17. The history of vaccination against Bordetella pertussis illustrates the importance of developing an effective vaccine that is perceived to be safe......Page 693
14-18. Conjugate vaccines have been developed as a result of understanding how T and B cells collaborate in an immune response......Page 694
14-19. The use of adjuvants is another important approach to enhancing the immunogenicity of vaccines......Page 695
14-20. Live-attenuated viral vaccines are usually more potent than 'killed' vaccines and can be made safer by using recombinant DNA technology......Page 696
14-22. Attenuated microorganisms can serve as vectors for vaccination against many pathogens......Page 698
14-23. Synthetic peptides of protective antigens can elicit protective immunity......Page 699
14-25. Protective immunity can be induced by injecting DNA encoding microbial antigens and human cytokines into muscle......Page 702
14-26. The effectiveness of a vaccine can be enhanced by targeting it to sites of antigen presentation......Page 703
14-27. An important question is whether vaccination can be used therapeutically to control existing chronic infections......Page 704
Summary......Page 706
References to Chapter 14......Page 707
Introduction to afterword......Page 716
Sophisticated means of host defense were hard-wired in the genome by the time organisms diverged into plants and animals......Page 717
Many genes that operate in fruit fly immunity also operate in humans and plants and appear to be universal components of host defense......Page 718
Evolution of the adaptive immune response......Page 719
Adaptive immunity appears abruptly in the cartilaginous fish......Page 720
Animals generate antigen receptor diversity in many different ways......Page 721
The importance of immunological memory in fixing adaptive immunity in the genome......Page 722
Immunological memory is the hallmark of adaptive immunity......Page 723
Immunological memory allows survival in a world filled with pathogens......Page 724
Future studies should vastly expand our knowledge of innate immunity......Page 726
Future studies should refine our knowledge of adaptive immunity......Page 727
Future studies of autoimmunity and graft rejection should allow control of immune responses to one's own body or to a piece borrowed from someone else......Page 728
Summary of the Afterword......Page 729
Immunization......Page 730
A-1. Haptens......Page 733
A-2. Routes of immunization......Page 734
A-4. Adjuvants......Page 735
The detection, measurement, and characterization of antibodies and their use as research and diagnostic tools......Page 736
A-6. Radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), and competitive inhibition assay......Page 737
A-7. Hemagglutination and blood typing......Page 740
A-8. Precipitin reaction......Page 741
A-9. Equilibrium dialysis: measurement of antibody affinity and avidity......Page 743
A-10. Anti-immunoglobulin antibodies......Page 745
A-11. Coombs tests and the detection of Rhesus incompatibility......Page 746
A-12. Monoclonal antibodies......Page 747
A-13. Phage display libraries for antibody V-region production......Page 749
A-14. Immunofluorescence microscopy......Page 750
A-16. Immunohistochemistry......Page 752
A-17. Immunoprecipitation and co-immunoprecipitation......Page 753
A-18. Immunoblotting (Western blotting)......Page 754
A-19. Use of antibodies in the isolation and identification of genes and their products......Page 755
A-20. Isolation of peripheral blood lymphocytes by Ficoll-Hypaque TM gradient......Page 757
A-21. Isolation of lymphocytes from tissues other than blood.......Page 758
A-22. Flow cytometry and FACS analysis......Page 759
A-23. Lymphocyte isolation using antibody-coated magnetic beads......Page 762
A-24. Isolation of homogeneous T-cell lines......Page 763
Characterization of lymphocyte specificity, frequency, and function......Page 765
A-25. Limiting-dilution culture......Page 766
A-26. ELISPOT assays......Page 767
A-27. Identification of functional subsets of T cells by staining for cytokines......Page 769
A-28. Identification of T-cell receptor specificity using MHC:peptide tetramers......Page 770
A-30. Biosensor assays for measuring the rates of association and disassociation of antigen receptors for their ligands......Page 772
A-31. Stimulation of lymphocyte proliferation by treatment with polyclonal mitogens or specific antigen......Page 774
A-32. Measurements of apoptosis by the TUNEL assay......Page 776
A-34. Assays for CD4 T cells......Page 777
A-35. DNA microarrays......Page 778
A-36. Assessment of protective immunity......Page 779
A-37. Transfer of protective immunity......Page 780
A-39. Testing for allergic responses......Page 781
A-40. Assessment of immune responses and immunological competence in humans......Page 782
A-44. In vivo depletion of T cells......Page 784
A-46. Transgenic mice......Page 785
A-47. Gene knockout by targeted disruption......Page 787
Appendix II. CD antigens......Page 792
Appendix III. Cytokines and their receptors......Page 812
Appendix IV. Chemokines and their receptors......Page 814
Appendix V. Immunological Constants......Page 816
Appendix IV. Chemokines and their receptors......Page 817
Appendix V. Immunological Constants......Page 819
Biographies......Page 820
A......Page 822
B......Page 828
C......Page 830
D......Page 839
E......Page 840
F......Page 843
G......Page 844
H......Page 846
I......Page 849
L......Page 856
M......Page 860
N......Page 864
O......Page 865
P......Page 866
R......Page 871
S......Page 872
T......Page 876
V......Page 881
W......Page 882
Z......Page 883
Back Cover......Page 884