Janeway’s Immunobiology, 9th Edition

Description

Icons used throughout the book......Page 2 Title Page......Page 5 Copyright......Page 6 Preface......Page 7 Student Resources......Page 8 Acknowledgments......Page 9 Contents......Page 11 Detailed Contents......Page 12 Chapter 1 Basic Concepts in Immunology......Page 23 The origins of vertebrate immune cells.......Page 24 1-1 Commensal organisms cause little host damage while pathogens damage host tissues by a variety of mechanisms.......Page 25 1-2 Anatomic and chemical barriers are the first defense against pathogens.......Page 27 1-3 The immune system is activated by inflammatory inducers thatindicate the presence of pathogens or tissue damage.......Page 28 1-4 The myeloid lineage comprises most of the cells of the innate immune system.......Page 29 1-5 Sensor cells express pattern recognition receptors that provide an initial discrimination between self and nonself.......Page 30 1-6 Sensor cells induce an inflammatory response by producing mediators such as chemokines and cytokines.......Page 31 Principles of adaptive immunity.......Page 33 1-8 The interaction of antigens with antigen receptors induces lymphocytes to acquire effector and memory activity.......Page 34 1-9 Antibodies and T-cell receptors are composed of constant and variable regions that provide distinct functions.......Page 35 1-10 Antibodies and T-cell receptors recognize antigens by fundamentally different mechanisms.......Page 36 1-12 Lymphocytes activated by antigen give rise to clones of antigen-specific effector cells that mediate adaptive immunity.......Page 37 1-13 Lymphocytes with self-reactive receptors are normally eliminated during development or are functionally inactivated.......Page 38 1-14 Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body.......Page 39 1-15 Adaptive immune responses are initiated by antigen and antigen-presenting cells in secondary lymphoid tissues.......Page 40 1-16 Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs.......Page 41 1-17 Mucosal surfaces have specialized immune structures that orchestrate responses to environmental microbial encounters.......Page 44 1-18 Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory.......Page 45 Summary.......Page 46 The effector mechanisms of immunity.......Page 47 1-19 Innate immune responses can select from several effector modules to protect against different types of pathogens.......Page 48 1-20 Antibodies protect against extracellular pathogens and their toxic products.......Page 49 1-21 T cells orchestrate cell-mediated immunity and regulate B-cell responses to most antigens.......Page 51 1-22 Inherited and acquired defects in the immune system result in increased susceptibility to infection.......Page 53 1-23 Understanding adaptive immune responses is important for the control of allergies, autoimmune disease, and the rejection of transplanted organs.......Page 54 1-24 Vaccination is the most effective means of controlling infectious diseases.......Page 55 Summary to Chapter 1.......Page 56 Questions.......Page 57 References.......Page 58 Chapter 2 Innate Immunity: The First Lines of Defense......Page 59 2-1 Infectious diseases are caused by diverse living agents that replicate in their hosts.......Page 60 2-2 Epithelial surfaces of the body provide the first barrier against infection.......Page 64 2-3 Infectious agents must overcome innate host defenses to establish a focus of infection.......Page 66 2-4 Epithelial cells and phagocytes produce several kinds of antimicrobial proteins.......Page 67 Summary.......Page 70 The complement system and innate immunity.......Page 71 2-5 The complement system recognizes features of microbial surfaces and marks them for destruction by coating them with C3b.......Page 72 2-6 The lectin pathway uses soluble receptors that recognize microbial surfaces to activate the complement cascade.......Page 75 2-7 The classical pathway is initiated by activation of the C1 complex and is homologous to the lectin pathway.......Page 78 2-8 Complement activation is largely confined to the surface on which it is initiated.......Page 79 2-9 The alternative pathway is an amplification loop for C3b formation that is accelerated by properdin in the presence of pathogens.......Page 80 2-10 Membrane and plasma proteins that regulate the formation and stability of C3 convertases determine the extent of complement activation.......Page 82 2-11 Complement developed early in the evolution of multicellular organisms.......Page 83 2-12 Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity.......Page 84 2-13 Ingestion of complement-tagged pathogens by phagocytes is mediated by receptors for the bound complement proteins.......Page 85 2-14 The small fragments of some complement proteins initiate a local inflammatory response.......Page 87 2-15 The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens.......Page 88 2-16 Complement control proteins regulate all three pathways of complement activation and protect the host from their destructive effects.......Page 89 2-17 Pathogens produce several types of proteins that can inhibit complement activation.......Page 93 Summary.......Page 94 Summary to Chapter 2.......Page 95 Questions.......Page 96 References.......Page 97 Pattern recognition by cells of the innateimmune system.......Page 99 3-1 After entering tissues, many microbes are recognized, ingested, and killed by phagocytes.......Page 100 3-2 G-protein-coupled receptors on phagocytes link microbe recognition with increased efficiency of intracellular killing.......Page 103 3-3 Microbial recognition and tissue damage initiate an inflammatory response.......Page 107 3-4 Toll-like receptors represent an ancient pathogen recognition system.......Page 109 3-5 Mammalian Toll-like receptors are activated by many different pathogen-associated molecular patterns.......Page 110 3-7 TLRs activate NFκB, AP-1, and IRF transcription factors to induce the expression of inflammatory cytokines and type I interferons.......Page 114 3-8 The NOD-like receptors are intracellular sensors of bacterial infection and cellular damage.......Page 118 3-9 NLRP proteins react to infection or cellular damage through an inflammasome to induce cell death and inflammation.......Page 120 3-10 The RIG-I-like receptors detect cytoplasmic viral RNAs and activate MAVS to induce type I interferon production and pro‑inflammatory cytokines.......Page 123 3-11 Cytosolic DNA sensors signal through STING to induce production of type I interferons.......Page 125 3-12 Activation of innate sensors in macrophages and dendritic cells triggers changes in gene expression that have far‑reaching effects on the immune response.......Page 126 3-13 Toll signaling in Drosophila is downstream of a distinct set of pathogen-recognition molecules.......Page 127 Summary.......Page 128 3-15 Cytokines and their receptors fall into distinct families of structurally related proteins.......Page 129 3-16 Cytokine receptors of the hematopoietin family are associated with the JAK family of tyrosine kinases, which activate STAT transcription factors.......Page 131 3-17 Chemokines released by macrophages and dendritic cells recruit effector cells to sites of infection.......Page 133 3-18 Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response.......Page 135 3-19 Neutrophils make up the first wave of cells that cross the blood vessel wall to enter an inflamed tissue.......Page 138 3-21 Cytokines made by macrophages and dendritic cells induce a systemic reaction known as the acute-phase response.......Page 140 3-22 Interferons induced by viral infection make several contributions to host defense.......Page 143 3-23 Several types of innate lymphoid cells provide protection in early infection.......Page 146 3-24 NK cells are activated by type I interferon and macrophage-derived cytokines.......Page 147 3-25 NK cells express activating and inhibitory receptors to distinguish between healthy and infected cells.......Page 148 3-26 NK-cell receptors belong to several structural families, the KIRs, KLRs, and NCRs.......Page 150 3-27 NK cells express activating receptors that recognize ligands induced on infected cells or tumor cells.......Page 152 Summary to Chapter 3.......Page 153 Questions.......Page 154 References.......Page 155 Chapter 4 Antigen Recognition by B-cell and T-cell Receptors......Page 161 The structure of a typical antibody molecule.......Page 162 4-1 IgG antibodies consist of four polypeptide chains.......Page 163 4-3 The domains of an immunoglobulin molecule have similar structures.......Page 164 4-4 The antibody molecule can readily be cleaved into functionally distinct fragments.......Page 166 Summary.......Page 167 4-6 Localized regions of hypervariable sequence form the antigen-binding site.......Page 168 4-7 Antibodies bind antigens via contacts in CDRs that are complementary to the size and shape of the antigen.......Page 169 4-8 Antibodies bind to conformational shapes on the surfaces of antigens using a variety of noncovalent forces.......Page 170 4-9 Antibody interaction with intact antigens is influenced by steric constraints.......Page 172 4-10 Some species generate antibodies with alternative structures.......Page 173 Antigen recognition by T cells.......Page 174 4-11 The TCRα:β heterodimer is very similar to a Fab fragment of immunoglobulin.......Page 175 4-13 There are two classes of MHC molecules with distinct subunit compositions but similar three-dimensional structures.......Page 177 4-15 MHC class I molecules bind short peptides of 8–10 amino acids by both ends.......Page 180 4-16 The length of the peptides bound by MHC class II molecules is not constrained.......Page 182 4-17 The crystal structures of several peptide:MHC:T-cell receptor complexes show a similar orientation of the T-cell receptor over the peptide:MHC complex.......Page 183 4-18 The CD4 and CD8 cell-surface proteins of T cells directly contact MHC molecules and are required to make an effective response to antigen.......Page 185 4-20 A distinct subset of T cells bears an alternative receptor made up of γ and δ chains.......Page 188 Summary.......Page 189 Summary to Chapter 4.......Page 190 Questions.......Page 191 References.......Page 192 Chapter 5 The Generation of Lymphocyte Antigen Receptors......Page 195 5-1 Immunoglobulin genes are rearranged in the progenitors of antibody-producing cells.......Page 196 5-2 Complete genes that encode a variable region are generated by the somatic recombination of separate gene segments.......Page 197 5-3 Multiple contiguous V gene segments are present at each immunoglobulin locus.......Page 198 5-4 Rearrangement of V, D, and J gene segments is guided by flanking DNA sequences.......Page 200 5-5 The reaction that recombines V, D, and J gene segments involves both lymphocyte-specific and ubiquitous DNA-modifying enzymes.......Page 201 5-7 The multiple inherited gene segments are used in different combinations.......Page 206 5-8 Variable addition and subtraction of nucleotides at the junctions between gene segments contributes to the diversity of the third hypervariable region.......Page 207 Summary.......Page 208 5-9 The T-cell receptor gene segments are arranged in a similar pattern to immunoglobulin gene segments and are rearranged by the same enzymes.......Page 209 5-10 T-cell receptors concentrate diversity in the third hypervariable region.......Page 211 5-11 γ:δ T-cell receptors are also generated by gene rearrangement.......Page 212 Structural variation in immunoglobulinconstant regions.......Page 213 5-12 Different classes of immunoglobulins are distinguished by the structure of their heavychain constant regions.......Page 214 5-13 The constant region confers functional specialization on the antibody.......Page 215 5-14 IgM and IgD are derived from the same pre-mRNA transcript and are both expressed on the surface of mature B cells.......Page 216 5-15 Transmembrane and secreted forms of immunoglobulin are generated from alternative heavy-chain mRNA transcripts.......Page 217 5-16 IgM and IgA can form polymers by interacting with the J chain.......Page 219 5-17 Some invertebrates generate extensive diversity in a repertoire of immunoglobulin-like genes.......Page 220 5-18 Agnathans possess an adaptive immune system that uses somatic gene rearrangement to diversify receptors built from LRR domains.......Page 222 5-19 RAG-dependent adaptive immunity based on a diversified repertoire of immunoglobulin-like genes appeared abruptly in the cartilaginous fishes.......Page 224 5-20 Different species generate immunoglobulin diversity in different ways.......Page 225 5-22 MHC class I and class II molecules are also first found in the cartilaginous fishes.......Page 228 Summary to Chapter 5.......Page 229 Questions.......Page 230 References.......Page 231 Chapter 6 Antigen Presentation to T Lymphocytes......Page 235 6-1 Antigen presentation functions both in arming effector T cells and in triggering their effector functions to attack pathogen-infected cells.......Page 236 6-2 Peptides are generated from ubiquitinated proteins in the cytosol by the proteasome.......Page 238 6-3 Peptides from the cytosol are transported by TAP into the endoplasmic reticulum and further processed before binding to MHC class I molecules.......Page 240 6-4 Newly synthesized MHC class I molecules are retained in the endoplasmic reticulum until they bind a peptide.......Page 241 6-5 Dendritic cells use cross-presentation to present exogenous proteins on MHC class I molecules to prime CD8 T cells.......Page 244 6-6 Peptide:MHC class II complexes are generated in acidified endocytic vesicles from proteins obtained through endocytosis, phagocytosis, and autophagy.......Page 245 6-7 The invariant chain directs newly synthesized MHC class II molecules to acidified intracellular vesicles.......Page 247 6-8 The MHC class II-like molecules HLA-DM and HLA-DO regulate exchange of CLIP for other peptides.......Page 248 6-9 Cessation of antigen processing occurs in dendritic cells after their activation through reduced expression of the MARCH-1 E3 ligase.......Page 251 Summary.......Page 252 6-10 Many proteins involved in antigen processing and presentation are encoded by genes within the MHC.......Page 253 6-11 The protein products of MHC class I and class II genes are highly polymorphic.......Page 256 6-12 MHC polymorphism affects antigen recognition by T cells by influencing both peptide binding and the contacts between T-cell receptor and MHC molecule.......Page 257 6-13 Alloreactive T cells recognizing nonself MHC molecules are very abundant.......Page 261 6-14 Many T cells respond to superantigens.......Page 262 6-15 MHC polymorphism extends the range of antigens to which the immune system can respond.......Page 263 Generation of ligands for unconventional T-cell subsets.......Page 264 6-16 A variety of genes with specialized functions in immunity are also encoded in the MHC.......Page 265 6-17 Specialized MHC class I molecules act as ligands for theactivation and inhibition of NK cells and unconventionalT-cell subsets.......Page 267 6-18 Members of the CD1 family of MHC class I-like molecules present microbial lipids to invariant NKT cells.......Page 268 6-19 The nonclassical MHC class I molecule MR1 presents microbial folate metabolites to MAIT cells.......Page 270 6-20 γ:δ T cells can recognize a variety of diverse ligands.......Page 271 Summary to Chapter 6.......Page 272 Questions.......Page 273 References.......Page 274 General principles of signal transduction and propagation.......Page 279 7-1 Transmembrane receptors convert extracellular signals into intracellular biochemical events.......Page 280 7-2 Intracellular signal propagation is mediated by large multiprotein signaling complexes.......Page 282 7-4 Signaling proteins are recruited to the membrane by a variety of mechanisms.......Page 284 7-5 Post-translational modifications of proteins can both activate and inhibit signaling responses.......Page 285 7-6 The activation of some receptors generates smallmolecule second messengers.......Page 286 Antigen receptor signaling and lymphocyte activation.......Page 287 7-7 Antigen receptors consist of variable antigen-binding chains associated with invariant chains that carry out the signaling function of the receptor.......Page 288 7-8 Antigen recognition by the T-cell receptor and its co-receptors transduces a signal across the plasma membrane to initiate signaling.......Page 289 7-9 Antigen recognition by the T-cell receptor and its co-receptors leads to phosphorylation of ITAMs by Src-family kinases, generating the first intracellular signal in a signaling cascade.......Page 290 7-11 ITAMs are also found in other receptors on leukocytes that signal for cell activation.......Page 292 7-12 Activated ZAP-70 phosphorylates scaffold proteins and promotes PI 3-kinase activation.......Page 293 7-13 Activated PLC-γ generates the second messengers diacylglycerol and inositol trisphosphate that lead to transcription factor activation.......Page 294 7-14 Ca2+ entry activates the transcription factor NFAT.......Page 295 7-15 Ras activation stimulates the mitogen-activated protein kinase (MAPK) relay and induces expression of the transcription factor AP-1.......Page 296 7-16 Protein kinase C activates the transcription factors NFκB and AP-1.......Page 298 7-17 PI 3-kinase activation upregulates cellular metabolic pathways via the serine/threonine kinase Akt.......Page 299 7-18 T-cell receptor signaling leads to enhanced integrinmediated cell adhesion.......Page 300 7-20 The logic of B-cell receptor signaling is similar to that of T-cell receptor signaling, but some of the signaling components are specific to B cells.......Page 301 Co-stimulatory and inhibitory receptors modulate antigen receptor signaling in T and B lymphocytes.......Page 304 7-21 The cell-surface protein CD28 is a required co-stimulatory signaling receptor for naive T-cell activation.......Page 305 7-23 TNF receptor superfamily members augment T-cell and B-cell activation.......Page 306 7-24 Inhibitory receptors on lymphocytes downregulate immune responses by interfering with co-stimulatory signaling pathways.......Page 308 7-25 Inhibitory receptors on lymphocytes downregulate immune responses by recruiting protein or lipid phosphatases.......Page 309 Summary.......Page 310 Summary to Chapter 7.......Page 311 Questions.......Page 312 References.......Page 313 Chapter 8 The Development of B and T Lymphocytes......Page 317 Development of B lymphocytes.......Page 318 8-1 Lymphocytes derive from hematopoietic stem cells in the bone marrow.......Page 319 8-2 B-cell development begins by rearrangement of the heavy-chain locus.......Page 321 8-3 The pre-B-cell receptor tests for successful production of a complete heavy chain and signals for the transition from the pro-B cell to the pre-B cell stage.......Page 324 8-4 Pre-B-cell receptor signaling inhibits further heavy-chain locus rearrangement and enforces allelic exclusion.......Page 325 8-5 Pre-B cells rearrange the light-chain locus and express cell-surface immunoglobulin.......Page 326 8-6 Immature B cells are tested for autoreactivity before they leave the bone marrow.......Page 327 8-7 Lymphocytes that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated.......Page 330 8-8 Immature B cells arriving in the spleen turn over rapidly and require cytokines and positive signals through the B-cell receptor for maturation and long-term survival.......Page 331 8-9 B-1 B cells are an innate lymphocyte subset that arises early in development.......Page 334 Summary.......Page 335 8-10 T-cell progenitors originate in the bone marrow, but all the important events in their development occur in the thymus.......Page 337 8-12 T-cell precursors proliferate extensively in the thymus, but most die there.......Page 339 8-13 Successive stages in the development of thymocytes are marked by changes in cell-surface molecules.......Page 341 8-14 Thymocytes at different developmental stages are found in distinct parts of the thymus.......Page 343 8-16 T cells expressing γ:δ T-cell receptors arise in two distinct phases during development.......Page 344 8-17 Successful synthesis of a rearranged β chain allows the production of a pre-T-cell receptor that triggers cell proliferation and blocks further β-chain gene rearrangement.......Page 346 8-18 T-cell α-chain genes undergo successive rearrangements until positive selection or cell death intervenes.......Page 348 8-19 Only thymocytes whose receptors interact with self peptide:self MHC complexes can survive and mature.......Page 350 8-20 Positive selection acts on a repertoire of T-cell receptors with inherent specificity for MHC molecules.......Page 351 8-21 Positive selection coordinates the expression of CD4 or CD8 with the specificity of the T-cell receptor and the potential effector functions of the T cell.......Page 352 8-22 Thymic cortical epithelial cells mediate positive selection of developing thymocytes.......Page 353 8-23 T cells that react strongly with ubiquitous self antigens are deleted in the thymus.......Page 354 8-25 The specificity and/or the strength of signals for negative and positive selection must differ.......Page 356 8-26 Self-recognizing regulatory T cells and innate T cells develop in the thymus.......Page 357 8-28 T cells that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated.......Page 358 Summary to Chapter 8.......Page 359 Questions.......Page 361 References.......Page 362 Chapter 9 T-cell-Mediated Immunity......Page 367 9-1 T and B lymphocytes are found in distinct locations in secondary lymphoid tissues.......Page 369 9-2 The development of secondary lymphoid tissues is controlled by lymphoid tissue inducer cells and proteins of the tumor necrosis factor family.......Page 371 9-3 T and B cells are partitioned into distinct regions of secondary lymphoid tissues by the actions of chemokines.......Page 372 9-4 Naive T cells migrate through secondary lymphoid tissues, sampling peptide:MHC complexes on dendritic cells.......Page 373 9-5 Lymphocyte entry into lymphoid tissues depends on chemokines and adhesion molecules.......Page 374 9-6 Activation of integrins by chemokines is responsible for the entry of naive T cells into lymph nodes.......Page 375 9-7 The exit of T cells from lymph nodes is controlled by a chemotactic lipid.......Page 377 9-8 T-cell responses are initiated in secondary lymphoid organs by activated dendritic cells.......Page 378 9-9 Dendritic cells process antigens from a wide array of pathogens.......Page 380 9-10 Microbe-induced TLR signaling in tissue-resident dendritic cells induces their migration to lymphoid organs and enhances antigen processing.......Page 383 9-12 Macrophages are scavenger cells that can be induced by pathogens to present foreign antigens to naive T cells.......Page 385 9-13 B cells are highly efficient at presenting antigens that bind to their surface immunoglobulin.......Page 386 Priming of naive T cells by pathogen-activated dendritic cells.......Page 388 9-14 Cell-adhesion molecules mediate the initial interaction of naive T cells with antigenpresenting cells.......Page 389 9-16 CD28-dependent co-stimulation of activated T cells induces expression of interleukin-2 and the high-affinity IL-2 receptor.......Page 390 9-17 Additional co-stimulatory pathways are involved in T-cell activation.......Page 391 9-18 Proliferating T cells differentiate into effector T cells that do not require co-stimulation to act.......Page 392 9-20 CD4 T cells differentiate into several subsets of functionally different effector cells.......Page 394 9-21 Cytokines induce the differentiation of naive CD4 T cells down distinct effector pathways.......Page 397 9-22 CD4 T-cell subsets can cross-regulate each other’s differentiation through the cytokines they produce.......Page 399 9-23 Regulatory CD4 T cells are involved in controlling adaptive immune responses.......Page 401 General properties of effector T cells and their cytokines.......Page 402 9-25 An immunological synapse forms between effector T cells and their targets to regulate signaling and to direct the release of effector molecules.......Page 403 9-27 Cytokines can act locally or at a distance.......Page 405 Summary.......Page 408 9-29 Cytotoxic T cells induce target cells to undergo programmed cell death via extrinsic and intrinsic pathways of apoptosis.......Page 409 9-30 The intrinsic pathway of apoptosis is mediated by the release of cytochrome c from mitochondria.......Page 411 9-31 Cytotoxic effector proteins that trigger apoptosis are contained in the granules of CD8 cytotoxic T cells.......Page 412 9-32 Cytotoxic T cells are selective serial killers of targets expressing a specific antigen.......Page 413 Summary to Chapter 9.......Page 414 Questions.......Page 415 References.......Page 417 Chapter 10 The Humoral Immune Response......Page 421 10-1 Activation of B cells by antigen involves signals from the B-cell receptor and either TFH cells or microbial antigens.......Page 422 10-2 Linked recognition of antigen by T cells and B cells promotes robust antibody responses.......Page 424 10-3 B cells that encounter their antigens migrate toward the boundaries between B-cell and T-cell areas in secondary lymphoid tissues.......Page 425 10-5 Activated B cells differentiate into antibody-secreting plasmablasts and plasma cells.......Page 428 10-6 The second phase of a primary B-cell immune response occurs when activated B cells migrate into follicles and proliferate to form germinal centers.......Page 430 10-7 Germinal center B cells undergo V-region somatic hypermutation, and cells with mutations that improve affinity for antigen are selected.......Page 432 10-8 Positive selection of germinal center B cells involves contact with TFH cells and CD40 signaling.......Page 434 10-9 Activation-induced cytidine deaminase (AID) introduces mutations into genes transcribed in B cells.......Page 435 10-10 Mismatch and base-excision repair pathways contribute to somatic hypermutation following initiation by AID.......Page 436 10-11 AID initiates class switching to allow the same assembled VH exon to be associated with different CH genes in the course of an immune response.......Page 437 10-12 Cytokines made by TFH cells direct the choice of isotype for class switching in T-dependent antibody responses.......Page 440 10-14 Some antigens do not require T-cell help to induce B-cell responses.......Page 441 Summary.......Page 443 The distributions and functions of immunoglobulin classes.......Page 444 10-15 Antibodies of different classes operate in distinct places and have distinct effector functions.......Page 445 10-16 Polymeric immunoglobulin receptor binds to the Fc regions of IgA and IgM and transports them across epithelial barriers.......Page 447 10-18 High-affinity IgG and IgA antibodies can neutralize toxins and block the infectivity of viruses and bacteria.......Page 448 10-19 Antibody:antigen complexes activate the classical pathway of complement by binding to C1q.......Page 451 10-20 Complement receptors and Fc receptors both contribute to removal of immune complexes from the circulation.......Page 452 Summary.......Page 453 10-21 The Fc receptors of accessory cells are signaling receptors specific for immunoglobulins of different classes.......Page 454 10-22 Fc receptors on phagocytes are activated by antibodies bound to the surface of pathogens and enable the phagocytes to ingest and destroy pathogens.......Page 455 10-23 Fc receptors activate NK cells to destroy antibody-coated targets.......Page 457 10-24 Mast cells and basophils bind IgE antibody via the high‑affinity Fcε receptor.......Page 458 10-25 IgE-mediated activation of accessory cells has an important role in resistance to parasite infection.......Page 459 Summary.......Page 460 Summary to Chapter 10.......Page 461 Questions.......Page 462 References.......Page 463 Chapter 11 Integrated Dynamics of Innate and Adaptive Immunity......Page 467 11-1 The course of an infection can be divided into several distinct phases.......Page 468 11-2 The effector mechanisms that are recruited to clear an infection depend on the infectious agent.......Page 471 Effector T cells augment the effector functions of innate immune cells.......Page 474 11-3 Effector T cells are guided to specific tissues and sites of infection by changes in their expression of adhesion molecules and chemokine receptors.......Page 475 11-4 Pathogen-specific effector T cells are enriched at sites of infection as adaptive immunity progresses.......Page 479 11-5 TH1 cells coordinate and amplify the host response to intracellular pathogens through classical activation of macrophages.......Page 480 11-6 Activation of macrophages by TH1 cells must be tightly regulated to avoid tissue damage.......Page 482 11-8 Defects in type 1 immunity reveal its important role in the elimination of intracellular pathogens.......Page 483 11-9 TH2 cells coordinate type 2 responses to expel intestinal helminths and repair tissue injury.......Page 484 11-10 TH17 cells coordinate type 3 responses to enhance the clearance of extracellular bacteria and fungi.......Page 487 11-11 Differentiated effector T cells continue to respond to signals as they carry out their effector functions.......Page 488 11-12 Effector T cells can be activated to release cytokines independently of antigen recognition.......Page 489 11-13 Effector T cells demonstrate plasticity and cooperativity that enable adaptation during anti-pathogen responses.......Page 490 11-14 Integration of cell- and antibody-mediated immunity is critical for protection against many types of pathogens.......Page 491 11-15 Primary CD8 T-cell responses to pathogens can occur in the absence of CD4 T-cell help.......Page 492 11-16 Resolution of an infection is accompanied by the death of most of the effector cells and the generation of memory cells.......Page 493 Summary.......Page 494 11-17 Immunological memory is long lived after infection or vaccination.......Page 495 11-18 Memory B-cell responses are more rapid and have higher affinity for antigen compared with responses of naive B cells.......Page 497 11-19 Memory B cells can reenter germinal centers and undergo additional somatic hypermutation and affinity maturation during secondary immune responses.......Page 498 11-20 MHC tetramers identify memory T cells that persist at an increased frequency relative to their frequency as naive T cells.......Page 499 11-21 Memory T cells arise from effector T cells that maintain sensitivity to IL-7 or IL-15.......Page 500 11-22 Memory T cells are heterogeneous and include central memory, effector memory, and tissueresident subsets.......Page 502 11-23 CD4 T-cell help is required for CD8 T-cell memory and involves CD40 and IL-2 signaling.......Page 504 11-24 In immune individuals, secondary and subsequent responses are mainly attributable to memory lymphocytes.......Page 506 Summary.......Page 507 Summary to Chapter 11.......Page 508 Questions.......Page 509 References.......Page 510 12-1 The mucosal immune system protects the internal surfaces of the body.......Page 515 12-2 Cells of the mucosal immune system are located both in anatomically defined compartments and scattered throughout mucosal tissues.......Page 518 12-3 The intestine has distinctive routes and mechanisms of antigen uptake.......Page 521 12-4 The mucosal immune system contains large numbers of effector lymphocytes even in the absence of disease.......Page 522 12-5 The circulation of lymphocytes within the mucosal immune system is controlled by tissue-specific adhesion molecules and chemokine receptors.......Page 523 12-6 Priming of lymphocytes in one mucosal tissue may induce protective immunity at other mucosal surfaces.......Page 524 12-7 Distinct populations of dendritic cells control mucosal immune responses.......Page 525 12-9 Antigen-presenting cells in the intestinal mucosa acquire antigen by a variety of routes.......Page 527 12-10 Secretory IgA is the class of antibody associated with the mucosal immune system.......Page 528 12-12 IgA deficiency is relatively common in humans but may be compensated for by secretory IgM.......Page 531 12-13 The intestinal lamina propria contains antigenexperienced T cells and populations of unusual innate lymphoid cells.......Page 532 12-14 The intestinal epithelium is a unique compartment of the immune system.......Page 533 The mucosal response to infection and regulation of mucosal immune responses.......Page 536 12-15 Enteric pathogens cause a local inflammatory response and the development of protective immunity.......Page 537 12-17 Effector T-cell responses in the intestine protect the function of the epithelium.......Page 540 12-18 The mucosal immune system must maintain tolerance to harmless foreign antigens.......Page 541 12-19 The normal intestine contains large quantities of bacteria that are required for health.......Page 542 12-20 Innate and adaptive immune systems control microbiota while preventing inflammation without compromising the ability to react to invaders.......Page 543 12-21 The intestinal microbiota plays a major role in shaping intestinal and systemic immune function.......Page 544 12-22 Full immune responses to commensal bacteria provoke intestinal disease.......Page 546 Summary to Chapter 12.......Page 547 Questions.......Page 548 References.......Page 549 Immunodeficiency diseases.......Page 555 13-2 Primary immunodeficiency diseases are caused by inherited gene defects.......Page 556 13-3 Defects in T-cell development can result in severe combined immunodeficiencies.......Page 557 13-5 Defects in antigen receptor gene rearrangement can result in SCID.......Page 560 13-7 Genetic defects in thymic function that block T-cell development result in severe immunodeficiencies.......Page 561 13-8 Defects in B-cell development result in deficiencies in antibody production that cause an inability to clear extracellular bacteria and some viruses.......Page 563 13-9 Immune deficiencies can be caused by defects in B-cell or T-cell activation and function that lead to abnormal antibody responses.......Page 565 13-10 Normal pathways for host defense against different infectious agents are pinpointed by genetic deficiencies of cytokine pathways central to type 1/TH1 and type 3/TH17 responses.......Page 568 13-11 Inherited defects in the cytolytic pathway of lymphocytes can cause uncontrolled lymphoproliferation and inflammatory responses to viral infections.......Page 570 13-12 X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein–Barr virus and with the development of lymphomas.......Page 572 13-13 Immunodeficiency is caused by inherited defects in the development of dendritic cells.......Page 573 13-14 Defects in complement components and complementregulatory proteins cause defective humoral immune function and tissue damage.......Page 574 13-15 Defects in phagocytic cells permit widespread bacterial infections.......Page 575 13-16 Mutations in the molecular regulators of inflammation can cause uncontrolled inflammatory responses that result in ‘autoinflammatory disease.’......Page 578 13-17 Hematopoietic stem cell transplantation or gene therapy can be useful to correct genetic defects.......Page 579 13-18 Noninherited, secondary immunodeficiencies are major predisposing causes of infection and death.......Page 580 Summary.......Page 581 13-19 Extracellular bacterial pathogens have evolved different strategies to avoid detection by pattern recognition receptors and destruction by antibody, complement, and antimicrobial peptides.......Page 582 13-20 Intracellular bacterial pathogens can evade the immune system by seeking shelter within phagocytes.......Page 585 13-21 Immune evasion is also practiced by protozoan parasites.......Page 587 13-22 RNA viruses use different mechanisms of antigenic variation to keep a step ahead of the adaptive immune system.......Page 588 13-23 DNA viruses use multiple mechanisms to subvert NK-cell and CTL responses.......Page 590 13-24 Some latent viruses persist in vivo by ceasing to replicate until immunity wanes.......Page 593 Acquired immune deficiency syndrome.......Page 595 13-25 HIV is a retrovirus that establishes a chronic infection that slowly progresses to AIDS.......Page 596 13-26 HIV infects and replicates within cells of the immune system.......Page 598 13-27 Activated CD4 T cells are the major source of HIV replication.......Page 600 13-28 There are several routes by which HIV is transmitted and establishes infection.......Page 601 13-29 HIV variants with tropism for different co-receptors play different roles in transmission and progression of disease.......Page 602 13-30 A genetic deficiency of the co-receptor CCR5 confers resistance to HIV infection.......Page 604 13-31 An immune response controls but does not eliminate HIV.......Page 605 13-33 Genetic variation in the host can alter the rate of disease progression.......Page 607 13-34 The destruction of immune function as a result of HIV infection leads to increased susceptibility to opportunistic infection and eventually to death.......Page 609 13-35 Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells.......Page 610 13-36 In the course of infection HIV accumulates many mutations, which can result in the outgrowth of drug-resistant variants.......Page 612 13-37 Vaccination against HIV is an attractive solution but poses many difficulties.......Page 613 13-38 Prevention and education are important in controlling the spread of HIV and AIDS.......Page 614 Summary.......Page 615 Questions.......Page 616 References.......Page 617 Chapter 14 Allergy and Allergic Diseases......Page 623 IgE and IgE-mediated allergic diseases.......Page 624 14-1 Sensitization involves class switching to IgE production on first contact with an allergen.......Page 625 14-2 Although many types of antigens can cause allergic sensitization, proteases are common sensitizing agents.......Page 627 14-3 Genetic factors contribute to the development of IgE‑mediated allergic disease.......Page 629 14-4 Environmental factors may interact with genetic susceptibility to cause allergic disease.......Page 631 14-5 Regulatory T cells can control allergic responses.......Page 633 Effector mechanisms in IgE-mediated allergic reactions.......Page 634 14-7 Mast cells reside in tissues and orchestrate allergic reactions.......Page 635 14-8 Eosinophils and basophils cause inflammation and tissue damage in allergic reactions.......Page 638 14-9 IgE-mediated allergic reactions have a rapid onset but can also lead to chronic responses.......Page 639 14-10 Allergen introduced into the bloodstream can cause anaphylaxis.......Page 641 14-11 Allergen inhalation is associated with the development of rhinitis and asthma.......Page 643 14-12 Allergy to particular foods causes systemic reactions as well as symptoms limited to the gut.......Page 646 14-13 IgE-mediated allergic disease can be treated by inhibiting the effector pathways that lead to symptoms or by desensitization techniques that aim at restoring biological tolerance to the allergen.......Page 647 Summary.......Page 649 14-15 Systemic disease caused by immune-complex formation can follow the administration of large quantities of poorly catabolized antigens.......Page 650 14-16 Hypersensitivity reactions can be mediated by TH1 cells and CD8 cytotoxic T cells.......Page 652 14-17 Celiac disease has features of both an allergic response and autoimmunity.......Page 656 Summary to Chapter 14.......Page 658 Questions.......Page 659 References.......Page 660 15-1 A critical function of the immune system is to discriminate self from nonself.......Page 665 15-2 Multiple tolerance mechanisms normally prevent autoimmunity.......Page 667 15-3 Central deletion or inactivation of newly formed lymphocytes is the first checkpoint of self-tolerance.......Page 668 15-4 Lymphocytes that bind self antigens with relatively low affinity usually ignore them but in some circumstances become activated.......Page 669 15-5 Antigens in immunologically privileged sites do not induce immune attack but can serve as targets.......Page 670 15-6 Autoreactive T cells that express particular cytokines may be nonpathogenic or may suppress pathogenic lymphocytes.......Page 671 15-7 Autoimmune responses can be controlled at various stages by regulatory T cells.......Page 672 15-8 Specific adaptive immune responses to self antigens can cause autoimmune disease.......Page 674 15-9 Autoimmunity can be classified into either organspecific or systemic disease.......Page 675 15-10 Multiple components of the immune system are typically recruited in autoimmune disease.......Page 676 15-11 Chronic autoimmune disease develops through positive feedback from inflammation, inability to clear the self antigen, and a broadening of the autoimmune response.......Page 679 15-12 Both antibody and effector T cells can cause tissue damage in autoimmune disease.......Page 681 15-14 The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response.......Page 683 15-15 Autoantibodies against receptors cause disease by stimulating or blocking receptor function.......Page 684 15-16 Autoantibodies against extracellular antigens cause inflammatory injury.......Page 685 15-17 T cells specific for self antigens can cause direct tissue injury and sustain autoantibody responses.......Page 687 Summary.......Page 690 15-18 Autoimmune diseases have a strong genetic component.......Page 691 15-19 Genomics-based approaches are providing new insight into the immunogenetic basis of autoimmunity.......Page 692 15-21 Monogenic defects of immune tolerance.......Page 696 15-22 MHC genes have an important role in controlling susceptibility to autoimmune disease.......Page 698 15-23 Genetic variants that impair innate immune responses can predispose to T-cell-mediated chronic inflammatory disease.......Page 700 15-24 External events can initiate autoimmunity.......Page 701 15-26 Cross-reactivity between foreign molecules on pathogens and self molecules can lead to antiself responses and autoimmune disease.......Page 702 Summary.......Page 704 15-29 Graft rejection is an immunological response mediated primarily by T cells.......Page 705 15-30 Transplant rejection is caused primarily by the strong immune response to nonself MHC molecules.......Page 706 15-31 In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules.......Page 707 15-32 There are two ways of presenting alloantigens on the transplanted donor organ to the recipient’s T lymphocytes.......Page 708 15-34 Late failure of transplanted organs is caused by chronic injury to the graft.......Page 710 15-35 A variety of organs are transplanted routinely in clinical medicine.......Page 711 15-36 The converse of graft rejection is graft-versushost disease.......Page 713 15-37 Regulatory T cells are involved in alloreactive immune responses.......Page 714 15-38 The fetus is an allograft that is tolerated repeatedly.......Page 715 Summary to Chapter 15.......Page 716 Questions.......Page 717 References.......Page 718 Treatment of unwanted immune responses.......Page 723 16-1 Corticosteroids are powerful anti-inflammatory drugs that alter the transcription of many genes.......Page 724 16-2 Cytotoxic drugs cause immunosuppression by killing dividing cells and have serious side-effects.......Page 725 16-3 Cyclosporin A, tacrolimus, rapamycin, and JAK inhibitors are effective immunosuppressive agents that interfere with various T-cell signaling pathways.......Page 726 16-4 Antibodies against cell-surface molecules can be used to eliminate lymphocyte subsets or to inhibit lymphocyte function.......Page 728 16-5 Antibodies can be engineered to reduce their immunogenicity in humans.......Page 729 16-6 Monoclonal antibodies can be used to prevent allograft rejection......Page 730 16-7 Depletion of autoreactive lymphocytes can treat autoimmune disease.......Page 732 16-8 Biologics that block TNF-α, IL-1, or IL-6 can alleviate autoimmune diseases.......Page 733 16-9 Biologic agents can block cell migration to sites of inflammation and reduce immune responses.......Page 734 16-11 Some commonly used drugs have immunomodulatory properties.......Page 735 Summary.......Page 736 16-13 The development of transplantable tumors in mice led to the discovery of protective immune responses to tumors.......Page 738 16-14 Tumors are ‘edited’ by the immune system as they evolve and can escape rejection in many ways.......Page 739 16-15 Tumor rejection antigens can be recognized by T cells and form the basis of immunotherapies.......Page 742 16-16 T cells expressing chimeric antigen receptors are an effective treatment in some leukemias.......Page 745 16-17 Monoclonal antibodies against tumor antigens, alone or linked to toxins, can control tumor growth.......Page 746 16-18 Enhancing the immune response to tumors by vaccination holds promise for cancer prevention and therapy.......Page 748 16-19 Checkpoint blockade can augment immune responses to existing tumors.......Page 749 Summary.......Page 750 Fighting infectious diseases with vaccination.......Page 751 16-20 Vaccines can be based on attenuated pathogens or material from killed organisms.......Page 752 16-21 Most effective vaccines generate antibodies that prevent the damage caused by toxins or that neutralize the pathogen and stop infection.......Page 753 16-23 Live-attenuated viral vaccines are usually more potent than ‘killed’ vaccines and can be made safer by the use of recombinant DNA technology.......Page 754 16-24 Live-attenuated vaccines can be developed by selecting nonpathogenic or disabled bacteria or by creating genetically attenuated parasites (GAPs).......Page 756 16-25 The route of vaccination is an important determinant of success.......Page 757 16-26 Bordetella pertussis vaccination illustrates the importance of the perceived safety of a vaccine.......Page 758 16-27 Conjugate vaccines have been developed as a result of linked recognition between T and B cells.......Page 759 16-28 Peptide-based vaccines can elicit protective immunity, but they require adjuvants and must be targeted to the appropriate cells and cell compartment to be effective.......Page 760 16-29 Adjuvants are important for enhancing the immunogenicity of vaccines, but few are approved for use in humans.......Page 761 16-30 Protective immunity can be induced by DNA-based vaccination.......Page 762 16-31 Vaccination and checkpoint blockade may be useful in controlling existing chronic infections.......Page 763 Summary to Chapter 16.......Page 764 Questions.......Page 765 References.......Page 766 A-1. Immunization.......Page 771 A-2 Antibody responses.......Page 774 A-4 Radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), and competitive inhibition assay.......Page 775 A-5 Hemagglutination and blood typing.......Page 777 A-6 Coombs tests and the detection of rhesus incompatibility.......Page 778 A-7 Monoclonal antibodies.......Page 779 A-8 Phage display libraries for antibody V-region production.......Page 780 A-9 Generation of human monoclonal antibodies from vaccinated individuals.......Page 781 A-10 Microscopy and imaging using fluorescent dyes.......Page 782 A-11 Immunoelectron microscopy.......Page 783 A-13 Immunoprecipitation and co-immunoprecipitation.......Page 784 A-15 Use of antibodies in the isolation and characterization of multiprotein complexes by mass spectrometry.......Page 786 A-17 Isolation of lymphocytes from tissues other than blood.......Page 788 A-18 Flow cytometry and FACS analysis.......Page 789 A-20 Isolation of homogeneous T-cell lines.......Page 792 A-21 Limiting-dilution culture.......Page 793 A-23 Identification of functional subsets of T cells based on cytokine production or transcription factor expression.......Page 795 A-24 Identification of T-cell receptor specificity using peptide:MHC tetramers.......Page 798 A-25 Biosensor assays for measuring the rates of association and dissociation of antigen receptors for their ligands.......Page 799 A-26 Assays of lymphocyte proliferation.......Page 800 A-27 Measurements of apoptosis.......Page 801 A-28 Assays for cytotoxic T cells.......Page 802 A-30 Transfer of protective immunity.......Page 804 A-31 Adoptive transfer of lymphocytes.......Page 805 A-32 Hematopoietic stem-cell transfers.......Page 806 A-33 In vivo administration of antibodies.......Page 807 A-35 Gene knockout by targeted disruption.......Page 808 A-36 Knockdown of gene expression by RNA interference (RNAi).......Page 812 Appendix II CD antigens......Page 813 Appendix III Cytokines and their Receptors......Page 833 Appendix IV Chemokines and their Receptors......Page 836 Biographies......Page 838 Photograph Acknowledgments......Page 839 Glossary......Page 840 Movie List......Page 877