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  • 1. ix Detailed Contents 1 Elements of the Immune System and their Summary 32 Roles in Defense 1 Summary to Chapter 1 33 Questions 34 Defenses facing invading pathogens 2 1-1 Pathogens are infectious organisms that cause disease 2 2 Antibody Structure and the Generation 1-2 The skin and mucosal surfaces form physical of B-Cell Diversity 37 barriers against infection 5 The structural basis of antibody diversity 38 1-3 The innate immune response causes 2-1 Antibodies are composed of polypeptides inflammation at sites of infection 7 with variable and constant regions 38 1-4 The adaptive immune response adds to an 2-2 Immunoglobulin chains are folded into ongoing innate immune response 8 compact and stable protein domains 40 1-5 Immune system cells with different 2-3 An antigen-binding site is formed from the functions all derive from hematopoietic hypervariable regions of a heavy-chain and stem cells 11 a light-chain V domain 41 1-6 Most lymphocytes are present in specialized 2-4 Antigen-binding sites vary in shape and lymphoid tissues 15 physical properties 42 1-7 Lymphocytes are activated in the secondary 2-5 Monoclonal antibodies are produced from a lymphoid tissues 16 clone of antibody-producing cells 45 Summary 20 Summary 47 Principles of adaptive immunity 20 Generation of immunoglobulin diversity in 1-8 Immunoglobulins and T-cell receptors are the B cells before encounter with antigen 47 highly variable recognition molecules of 2-6 The DNA sequence encoding a V region is adaptive immunity 21 assembled from two or three gene segments 48 1-9 The diversity of immunoglobulins and T-cell 2-7 Random recombination of gene segments receptors is generated by gene produces diversity in the antigen-binding rearrangement 22 sites of immunoglobulins 49 1-10 B cells recognize intact pathogens, whereas 2-8 Recombination enzymes produce additional T cells recognize pathogen-derived peptides diversity in the antigen-binding sites of bound to proteins of the major immunoglobulins 51 histocompatibility complex 23 2-9 Naive B cells use alternative mRNA splicing 1-11 Clonal selection of B and T lymphocytes is to make both IgM and IgD 52 the guiding principle of the adaptive 2-10 Each B cell produces immunoglobulin of immune response 24 a single antigen specificity 52 1-12 Extracellular pathogens and their toxins are 2-11 Immunoglobulin is first made in a membrane- eliminated by antibodies 26 bound form that is present on the B-cell 1-13 Adaptive immune responses generally give surface 54 rise to long-lived immunological memory Summary 54 and protective immunity 28 1-14 The immune system can be compromised Diversification of antibodies after B cells by inherited immunodeficiencies or by encounter antigen 55 the actions of certain pathogens 29 2-12 Secreted antibodies are produced by an 1-15 Unwanted effects of adaptive immunity cause alternative pattern of heavy-chain RNA allergy, autoimmune disease, and rejection of processing 55 transplanted tissues 30 2-13 Rearranged V-region sequences are further
  • 2. x Detailed contents diversified by somatic hypermutation 56 3-18 MHC diversity results from selection by 2-14 Isotype switching produces immunoglobulins infectious disease 90 with different C regions but identical antigen 3-19 MHC polymorphism triggers T-cell reactions specificities 57 that can reject transplanted organs 93 2-15 Antibodies with different C regions have Summary 94 different effector functions 58 Summary to Chapter 3 95 Summary 61 Questions 95 Summary to Chapter 2 61 Questions 63 4 The Development of B Lymphocytes 99 The development of B cells in the 3 Antigen Recognition by T Lymphocytes 67 bone marrow 99 T-cell receptor diversity 68 4-1 B-cell development in the bone marrow 3-1 The T-cell receptor resembles a membrane- proceeds through several stages 100 associated Fab fragment of immunoglobulin 68 4-2 The survival of a developing B cell depends 3-2 T-cell receptor diversity is generated by gene on the productive rearrangement of a rearrangement 69 heavy- and a light-chain gene 102 3-3 Expression of the T-cell receptor on the cell 4-3 Cell-surface expression of the products of surface requires association with additional rearranged immunoglobulin genes prevents proteins 71 further gene rearrangement 105 3-4 g and d chains form a second class of T-cell 4-4 The proteins involved in immunoglobulin- receptor expressed by a distinct population gene rearrangement are controlled of T cells 71 developmentally 106 Summary 73 4-5 Many B-cell tumors carry chromosomal translocations that join immunoglobulin Antigen processing and presentation 73 genes to genes regulating cell growth 108 3-5 Two classes of T cell are specialized to respond 4-6 B cells expressing the glycoprotein CD5 to intracellular and extracellular sources of express a distinctive repertoire of receptors 108 infection 74 Summary 110 3-6 Two classes of MHC molecule present antigen to CD8 and CD4 T cells respectively 75 Selection and further development of the 3-7 The two classes of MHC molecule have similar B-cell repertoire 110 three-dimensional structures 76 4-7 Self-reactive immature B cells are altered, 3-8 MHC molecules bind a variety of peptides 77 eliminated, or inactivated by contact with 3-9 Peptides generated in the cytosol are self-antigens 111 transported into the endoplasmic reticulum 4-8 Mature, naive B cells compete for access to where they bind MHC class I molecules 78 lymphoid follicles 112 3-10 Peptides presented by MHC class II molecules 4-9 Encounter with antigen leads to the are generated in acidified intracellular differentiation of activated B cells into vesicles 80 plasma cells and memory B cells 113 3-11 MHC class II molecules are prevented from 4-10 Different types of B-cell tumor reflect B cells binding peptides in the endoplasmic at different stages of development 115 reticulum by the invariant chain 82 Summary 116 3-12 The T-cell receptor specifically recognizes Summary to Chapter 4 117 both peptide and MHC molecule 83 Questions 119 3-13 The two classes of MHC molecule are expressed differentially on cells 83 5 The Development of T Lymphocytes 123 Summary 85 The development of T cells in the thymus 124 The major histocompatibility complex 86 5-1 T cells develop in the thymus 124 3-14 The diversity of MHC molecules in the human 5-2 The two lineages of T cells arise from a population is due to multigene families and common thymocyte progenitor 125 genetic polymorphism 86 5-3 Production of a T-cell receptor b chain leads 3-15 The MHC class I and class II genes occupy to cessation of b-chain gene rearrangement different regions of the MHC 87 and to expression of CD4 and CD8 126 3-16 Other proteins involved in antigen processing 5-4 T-cell receptor a-chain genes can undergo and presentation are encoded in the MHC several successive rearrangements 129 class II region 88 5-5 Cells expressing particular g:d receptors 3-17 MHC polymorphism affects the binding and arise first in embryonic development 131 presentation of peptide antigens to T cells 89
  • 3. Detailed contents xi Summary 131 6-11 Effector T cells can be stimulated by antigen in the absence of co-stimulatory signals 163 Positive and negative selection of the T-cell 6-12 Effector T-cell functions are performed by repertoire 131 cytokines and cytotoxins 164 5-6 T cells that can recognize self-MHC molecules 6-13 Cytotoxic CD8 T cells are selective and serial are positively selected in the thymus 132 killers of target cells at sites of infection 165 5-7 Positive selection controls expression of the 6-14 Cytotoxic T cells kill their target cells by CD4 or CD8 co-receptor 133 inducing apoptosis 168 5-8 Rearrangement of a-chain genes stops 6-15 TH1 CD4 cells induce macrophages to once a cell has been positively selected 134 become activated 169 5-9 T cells specific for self-antigens are removed 6-16 TH1 cells coordinate the host response to in the thymus by negative selection 135 intravesicular pathogens 171 5-10 T cells undergo further differentiation in 6-17 CD4 TH2 cells activate only those B cells that secondary lymphoid tissues after encounter recognize the same antigen as they do 172 with antigen 136 6-18 Regulatory CD4 T cells limit the activities 5-11 The requirements of thymic selection can of effector CD4 and CD8 T cells 173 limit the number of functional class I and Summary 174 class II genes in the MHC 137 Summary to Chapter 6 175 5-12 Most T-cell tumors represent early or late Questions 177 stages of T-cell development 139 Summary 139 Summary to Chapter 5 140 7 Immunity Mediated by B Cells and Questions 142 Antibodies 181 Antibody production by B lymphocytes 182 6 T Cell-Mediated Immunity 145 7-1 B-cell activation requires cross-linking of surface immunoglobulin 182 Activation of naive T cells on encounter with 7-2 The antibody response to certain antigens antigen 145 does not require T-cell help 183 6-1 Dendritic cells carry antigens from sites of 7-3 B cells needing T-cell help are activated in infection to secondary lymphoid tissues 146 secondary lymphoid tissues where they 6-2 Naive T cells first encounter antigen on form germinal centers 185 antigen-presenting cells in secondary 7-4 Activated B cells undergo somatic lymphoid tissues 147 hypermutation and affinity maturation in the 6-3 Homing of naive T cells to secondary specialized microenvironment of the lymphoid tissues is determined by cell germinal center 188 adhesion molecules 148 7-5 Interactions with T cells are required for 6-4 Activation of naive T cells requires a isotype switching in B cells 192 co-stimulatory signal delivered by a Summary 193 professional antigen-presenting cell 150 6-5 Secondary lymphoid tissues contain Antibody effector functions 194 three kinds of professional antigen- 7-6 IgM, IgG, and IgA antibodies protect the presenting cell 151 blood and extracellular fluids 194 6-6 When T cells are activated by antigen, signals 7-7 IgA and IgG are transported across epithelial from T-cell receptors and co-receptors barriers by specific receptor proteins 195 alter the pattern of gene transcription 155 7-8 Antibody production is deficient in very 6-7 Proliferation and differentiation of activated young infants 197 T cells are driven by the cytokine 7-9 High-affinity IgG and IgA antibodies are interleukin-2 158 used to neutralize microbial toxins and 6-8 Antigen recognition by a naive T cell in the animal venoms 197 absence of co-stimulation leads to the T cell 7-10 High-affinity neutralizing antibodies prevent becoming nonresponsive 159 viruses and bacteria from infecting cells 199 6-9 On activation, CD4 T cells can acquire different 7-11 The Fc receptors of hematopoietic cells are helper functions 159 signaling receptors that bind the Fc 6-10 Naive CD8 T cells can be activated in different regions of antibodies 200 ways to become cytotoxic effector cells 160 7-12 Phagocyte Fc receptors facilitate the Summary 161 recognition, uptake, and destruction of antibody-coated pathogens 201 The properties and functions of effector 7-13 IgE binds to high-affinity Fc receptors on T cells 163 mast cells, basophils, and activated
  • 4. xii Detailed contents eosinophils 202 8-8 Neutrophils are dedicated phagocytes that 7-14 Fc receptors activate natural killer cells are summoned to sites of infection 243 to destroy antibody-coated human cells 204 8-9 The homing of neutrophils to infected tissues Summary 205 is induced by inflammatory mediators 244 8-10 Neutrophils are potent killers of pathogens The antigen–antibody mediated pathway of and are themselves programmed to die 2496 complement activation 205 8-11 Inflammatory cytokines raise body 7-15 Complement components are plasma temperature and activate hepatocytes to proteins with various functions 206 make the acute-phase response 247 7-16 C1 uses different polypeptides to bind antibody 8-12 Type I interferons inhibit viral replication and to activate complement components 207 and activate host defenses 250 7-17 Fragments of C2 and C4 associate on the 8-13 NK cells provide an early defense against pathogen surface to form the classical intracellular infections 252 C3 convertase 209 8-14 NK-cell receptors differ in the ligands they 7-18 Cleavage of C3 yields C3b covalently bound bind and the signals they generate 253 to pathogen surfaces 210 8-15 Three genetic complexes contribute to 7-19 Partial lack of C4 is the most common NK-cell recognition of ‘missing-self’ 255 immune protein deficiency in humans 210 8-16 Minority subpopulations of B and T cells 7-20 C3b produced by the classical C3 convertase contribute to innate immunity 258 permits the formation of a more powerful Summary 259 alternative C3 convertase 211 7-21 Fragments of C3 and C4 on pathogen Adaptive immune responses to infection 260 surfaces are recognized by receptors on 8-17 Adaptive immune responses start with T-cell various cell types 212 activation in secondary lymphoid tissues 260 7-22 Complement receptors remove immune 8-18 Microfold cells in the gut deliver antigens complexes from the circulation 214 to Peyer’s patches 262 7-23 The terminal complement proteins lyse 8-19 Primary CD4 T-cell responses are influenced pathogens by forming a membrane pore 215 by the cytokines made by cells of innate 7-24 Small peptides released during complement immunity 263 activation induce local inflammation 216 8-20 Effector T cells are guided to sites of 7-25 Regulatory proteins in plasma limit the infection by newly expressed cell adhesion extent of complement activation 217 molecules 264 7-26 Regulatory proteins on human cell surfaces 8-21 Antibody responses develop in lymphoid protect them from the effects of tissues under the direction of TH2 cells 265 complement activation 220 8-22 Antibody secretion by plasma cells occurs at Summary 221 sites distinct from those at which B cells Summary to Chapter 7 222 are activated by TH2 cells 267 Questions 224 Summary 268 Immunological memory and the secondary 8 The Body’s Defenses Against Infection 227 immune response 268 8-23 Immunological memory after infection is Innate immunity 227 long lived 269 8-1 Infectious diseases are caused by pathogens 8-24 Pathogen-specific memory B cells are more of diverse types that live and replicate in the abundant and make better antibodies than human body 228 naive B cells 269 8-2 Surface epithelia present a formidable 8-25 T-cell memory is maintained by T cells that barrier to infection 232 have different cell-surface markers from 8-3 Complement activation by the alternative naive T cells 270 pathway tags microorganisms for 8-26 Maintenance of immunological memory does destruction 233 not require stimulation with antigen 272 8-4 Several classes of plasma protein limit 8-27 The second and subsequent responses to a the spread of infection 236 pathogen are mediated solely by memory 8-5 Phagocytosis by macrophages provides a lymphocytes and not by naive lymphocytes 273 first line of cellular defense against invading Summary 275 microorganisms 237 Summary to Chapter 8 275 8-6 Receptors that detect microbial products Questions 276 signal macrophage activation 238 8-7 Activation of resident macrophages induces inflammation at sites of infection 239
  • 5. Detailed contents xiii 9 Failures of the Body’s Defenses 279 10 Over-reactions of the Immune System 311 Evasion and subversion of the immune 10-1 Four types of hypersensitivity reaction are system by pathogens 279 caused by different effector mechanisms 9-1 Genetic variation within some species of of adaptive immunity 311 pathogen prevents effective long-term immunity 280 Type I hypersensitivity reactions 313 9-2 Mutation and recombination allow influenza 10-2 IgE binds irreversibly to Fc receptors on mast virus to escape from immunity 280 cells, basophils, and activated eosinophils 313 9-3 Trypanosomes use gene rearrangement to 10-3 Tissue mast cells orchestrate IgE-mediated change their surface antigens 281 allergic reactions through the release of 9-4 Herpes viruses persist in human hosts inflammatory mediators 314 by hiding from the immune response 283 10-4 Eosinophils and basophils are specialized 9-5 Certain pathogens sabotage or subvert granulocytes that release toxic mediators immune defense mechanisms 284 in IgE-mediated responses 317 9-6 Bacterial superantigens stimulate a massive 10-5 Mast cells, basophils, and eosinophils but ineffective T-cell response 286 can amplify an IgE response started by 9-7 Immune responses can contribute to TH2 cells 319 disease 286 10-6 Common allergens are small proteins Summary 287 inhaled in particulate form that stimulate an IgE response 320 Inherited immunodeficiency diseases 287 10-7 Predisposition to allergy has a genetic basis 321 9-8 Most inherited immunodeficiency diseases 10-8 IgE-mediated allergic reactions consist are caused by recessive gene defects 287 of an immediate response followed by 9-9 Antibody deficiency leads to an inability to a late-phase response 322 clear extracellular bacteria 289 10-9 The effects of IgE-mediated allergic reactions 9-10 Diminished antibody production also results vary with the site of mast-cell activation 323 from inherited defects in T-cell help 291 10-10 Systemic anaphylaxis is caused by allergens 9-11 Defects in complement components impair in the blood 324 antibody responses and cause the accumulation 10-11 Rhinitis and asthma are caused by inhaled of immune complexes 291 allergens 325 9-12 Defects in phagocytes result in enhanced 10-12 Urticaria, angioedema, and eczema are susceptibility to bacterial infection 292 allergic reactions in the skin 326 9-13 Defects in T-cell function result in severe 10-13 Food allergies cause systemic effects as combined immune deficiencies 294 well as gut reactions 328 9-14 Some inherited immunodeficiencies lead to 10-14 People with parasite infections and high specific disease susceptibilities 295 levels of IgE rarely develop allergic disease 328 9-15 Hematopoietic stem cell transplantation is 10-15 Allergic reactions are prevented and treated by used to correct genetic defects of the three complementary approaches 329 immune system 295 Summary 330 Summary 296 Type II, III, and IV hypersensitivity Acquired immune deficiency syndrome 296 reactions 331 9-16 HIV is a retrovirus that causes slowly 10-16 Type II hypersensitivity reactions are caused progressing disease 297 by antibodies specific for altered components 9-17 HIV infects CD4 T cells, macrophages, and of human cells 331 dendritic cells 298 10-17 Type III hypersensitivity reactions are caused 9-18 Most people who become infected with HIV by immune complexes formed from IgG progress in time to develop AIDS 299 and soluble antigens 333 9-19 Genetic deficiency of the CCR5 co-receptor for 10-18 Systemic disease caused by immune HIV confers resistance to infection 302 complexes can follow the administration 9-20 HIV escapes the immune response and of large quantities of soluble antigens 334 develops resistance to antiviral drugs by 10-19 Type IV hypersensitivity reactions are rapid mutation 302 mediated by antigen-specific effector T cells 336 9-21 Clinical latency is a period of active infection Summary 338 and renewal of CD4 T cells 304 Summary to Chapter 10 339 9-22 HIV infection leads to immunodeficiency and Questions 339 death from opportunistic infections 305 Summary 306 Summary to Chapter 9 306 Questions 307
  • 6. xiv Detailed contents 11 Disruption of Healthy Tissue by the 11-21 Senescence of the T-cell population can Immune Response 343 contribute to autoimmunity 373 11-22 Do the current increases in hypersensitivity Autoimmune diseases 343 and autoimmune disease have a common 11-1 The effector mechanisms of autoimmunity cause? 373 resemble those causing certain Summary 374 hypersensitivity reactions 344 Summary to Chapter 11 374 11-2 Endocrine glands contain specialized cells Questions 375 that are targets for organ-specific autoimmunity 346 11-3 Autoimmune diseases of the thyroid can 12 Manipulation of the Immune Response 379 cause either underproduction or Prevention of infectious disease by overproduction of thyroid hormones 347 vaccination 379 11-4 The cause of autoimmune disease can 12-1 Viral vaccines are made from whole viruses be revealed by the transfer of disease or viral components 380 with immune effectors 348 12-2 Bacterial vaccines are made from whole 11-5 Insulin-dependent diabetes mellitus is bacteria, their secreted toxins, or capsular caused by the selective destruction of polysaccharides 381 insulin-producing cells in the pancreas 350 12-3 Adjuvants nonspecifically enhance the 11-6 Autoantibodies against common immune response 383 components of human cells can cause 12-4 Vaccination can inadvertently cause disease 384 systemic autoimmune disease 351 12-5 The need for a vaccine and the demands 11-7 Most rheumatological diseases are caused placed on it change with the prevalence by autoimmunity 352 of the disease 385 11-8 Multiple sclerosis and myasthenia gravis 12-6 Vaccines have yet to be found for many are autoimmune diseases of the chronic pathogens 387 nervous system 352 12-7 Genome sequences of human pathogens Summary 354 open up new avenues of vaccine design 389 Genetic and environmental factors that 12-8 A useful vaccine against HIV has yet to predispose to autoimmune disease 355 be found 390 11-9 All autoimmune diseases involve breaking Summary 390 T-cell tolerance 355 Transplantation of tissues and organs 391 11-10 Incomplete deletion of self-reactive T cells 12-9 Transplant rejection and graft-versus-host in the thymus causes autoimmune disease 356 reaction are immune responses caused by 11-11 Insufficient control of T-cell co-stimulation genetic differences between transplant favors autoimmunity 357 donor and recipient 391 11-12 Regulatory T cells protect cells and tissues 12-10 In blood transfusion, donors and recipients from autoimmunity 358 are matched for the A,B,O system of blood 11-13 HLA is the dominant genetic factor affecting group antigens 392 susceptibility to autoimmune disease 359 12-11 Antibodies against A,B,O or HLA antigens 11-14 Different combinations of HLA class II cause hyperacute rejection of transplanted allotypes confer susceptibility and resistance organs 394 to diabetes 361 12-12 Anti-HLA antibodies can arise from pregnancy, 11-15 Autoimmunity can be initiated by disease- blood transfusion, or previous transplants 394 associated HLA allotypes presenting 12-13 Organ transplantation involves procedures antigens to autoimmune T cells 362 that inflame the donated organ and the 11-16 Noninfectious environmental factors influence transplant recipient 395 the course of autoimmune diseases 363 12-14 Acute rejection is caused by effector T cells 11-17 Loss of oral tolerance leads to inflammation responding to HLA differences between and autoimmunity 364 donor and recipient 396 11-18 Infections are environmental factors that 12-15 Chronic rejection of organ transplants is due can trigger autoimmune disease 366 to the indirect pathway of allorecognition 397 11-19 Autoimmune T cells can be activated in a 12-16 Matching donor and recipient for HLA pathogen-specific or nonspecific manner class I and class II allotypes improves the by infection 368 outcome of transplantation 400 11-20 In the course of autoimmune disease the 12-17 Allogeneic transplantation is made possible specificity of the autoimmune response by the use of immunosuppressive drugs 400 broadens 370
  • 7. Detailed contents xv 12-18 Corticosteroids change patterns of gene 12-29 The immune system is insensitive to expression 401 emerging cancer 417 12-19 Cytotoxic drugs kill proliferating cells 403 12-30 Allogeneic bone marrow transplantation 12-20 Cyclosporin A, tacrolimus, and rapamycin is the preferred treatment for many cancer selectively inhibit T-cell activation 404 patients 417 12-21 Antibodies specific for T cells are used to 12-31 Patients receiving an HLA-identical bone control acute rejection 406 marrow transplant can still get GVHD 418 12-22 Patients needing a transplant outnumber the 12-32 Some GVHD helps engraftment and prevents available organs 407 relapse of malignant disease 420 12-23 Bone marrow transplantation is a treatment for 12-33 NK cells can also mediate GVL effects 420 genetic diseases of blood cells 408 12-34 Cancer cells continue to acquire mutations 12-24 The alloreactions in bone marrow throughout the cancer’s lifetime 421 transplantation attack the patient, not the 12-35 Vaccination with tumor antigens can produce transplant 409 regression of cancer 423 12-25 The impact of alloreactions on transplantation 12-36 Tumors frequently evade immunity by depends on the type of tissue or organ downregulation of HLA class I 425 transplanted 411 12-37 Heat-shock proteins can provide natural Summary 411 adjuvants of tumor immunity 426 12-38 Vaccination against oncogenic viruses 427 Cancer and its interactions with the immune 12-39 Monoclonal antibodies against cell-surface system 412 tumor antigens can be used for diagnosis 12-26 Cancer results from mutations that cause and immunotherapy 428 uncontrolled cell growth 412 Summary 429 12-27 A cancer arises from a single cell that has Summary to Chapter 12 429 accumulated multiple mutations 414 Questions 430 12-28 Exposure to chemicals, radiation, and viruses can facilitate the progression to cancer 415