Janeway's immunobiology / 7th ed.

Table Of Contents:

Part I AN INTRODUCTION TO IMMUNOBIOLOGY AND INNATE IMMUNITY

Basic Concepts in Immunology 1(38)

Principles of innate and adaptive immunity 3(24)

Functions of the immune response 3(2)

The cells of the immune system derive from precursors in the bone marrow 5(1)

The myeloid lineage comprises most of the cells of the innate immune system 5(3)

The lymphoid lineage comprises the lymphocytes of the adaptive immune system and the natural killer cells of innate immunity 8(1)

Lymphocytes mature in the bone marrow or the thymus and then congregate in lymphoid tissues throughout the body 9(1)

Most infectious agents activate the innate immune system and induce an inflammatory response 10(2)

Activation of specialized antigen-presenting cells is a necessary first step for induction of adaptive immunity 12(1)

The innate immune system provides an initial discrimination between self and nonself 13(1)

Lymphocytes activated by antigen give rise to clones of antigen-specific effector cells that mediate adaptive immunity 13(1)

Clonal selection of lymphocytes is the central principle of adaptive immunity 14(1)

The structure of the antibody molecule illustrates the central puzzle of adaptive immunity 15(1)

Each developing lymphocyte generates a unique antigen receptor by rearranging its receptor gene segments 16(1)

Immunoglobulins bind a wide variety of chemical structures, whereas the T-cell receptor is specialized to recognize foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex 17(1)

The development and survival of lymphocytes is determined by signals received through their antigen receptors 18(1)

Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs 18(5)

Interaction with other cells as well as with antigen is necessary for lymphocyte activation 23(1)

Lymphocytes activated by antigen proliferate in the peripheral lymphoid organs, generating effector cells and immunological memory 23(4)

Summary 27(1)

The effector mechanisms of adaptive immunity 27(12)

Antibodies deal with extracellular forms of pathogens and their toxic products 28(2)

T cells are needed to control intracellular pathogens and to activate B-cell responses to most antigens 30(2)

CD4 and CD8 T cells recognize peptides bound to two different classes of MHC molecules 32(2)

Defects in the immune system result in increased susceptibility to infection 34(1)

Understanding adaptive immune responses is important for the control of allergies, autoimmune disease, and organ graft rejection 34(2)

Vaccination is the most effective means of controlling infectious diseases 36(1)

Summary 37(1)

Summary to Chapter 1 37(2)

Innate Immunity 39(72)

The front line of host defense 40(13)

Infectious diseases are caused by diverse living agents that replicate in their hosts 41(3)

Infectious agents must overcome innate host defenses to establish a focus of infection 44(2)

The epithelial surfaces of the body make up the first lines of defense against infection 46(2)

After entering tissues, many pathogens are recognized, ingested, and killed by phagocytes 48(2)

Pathogen recognition and tissue damage initiate an inflammatory response 50(2)

Summary 52(1)

Pattern recognition in the innate immune system 53(8)

Receptors with specificity for pathogen molecules recognize patterns of repeating structural motifs 54(2)

The Toll-like receptors are signaling receptors that distinguish different types of pathogen and help direct an appropriate immune response 56(1)

The effects of bacterial lipopolysaccharide on macrophages are mediated by CD14 binding to TLR-4 57(1)

The NOD proteins act as intracellular sensors of bacterial infection 58(1)

Activation of Toll-like receptors and NOD proteins triggers the production of pro-inflammatory cytokines and chemokines, and the expression of co-stimulatory molecules 58(1)

Summary 59(2)

The complement system and innate immunity 61(21)

Complement is a system of plasma proteins that is activated by the presence of pathogens 61(1)

Complement interacts with pathogens to mark them for destruction by phagocytes 62(2)

The classical pathway is initiated by activation of the C1 complex 64(1)

The lectin pathway is homologous to the classical pathway 65(2)

Complement activation is largely confined to the surface on which it is initiated 67(2)

Hydrolysis of C3 causes initiation of the alternative pathway of complement 69(1)

Membrane and plasma proteins that regulate the formation and stability of C3 convertases determine the extent of complement activation under different circumstances 69(4)

Surface-bound C3 convertase deposits large numbers of C3b fragments on pathogen surfaces and generates C5 convertase activity 73(1)

Ingestion of complement-tagged pathogens by phagocytes is mediated by receptors for the bound complement proteins 73(2)

Small fragments of some complement proteins can initiate a local inflammatory response 75(1)

The terminal complement proteins polymerize to form pores in membranes that can kill certain pathogens 75(3)

Complement control proteins regulate all three pathways of complement activation and protect the host from its destructive effects 78(3)

Summary 81(1)

Induced innate responses to infection 82(29)

Activated macrophages secrete a range of cytokines that have a variety of local and distant effects 83(1)

Chemokines released by phagocytes and dendritic cells recruit cells to sites of infection 83(4)

Cell-adhesion molecules control interactions between leukocytes and endothelial cells during an inflammatory response 87(1)

Neutrophils make up the first wave of cells that cross the blood vessel wall to enter inflammatory sites 88(2)

TNF-α is an important cytokine that triggers local containment of infection but induces shock when released systemically 90(2)

Cytokines released by phagocytes activate the acute-phase response 92(2)

Interferons induced by viral infection make several contributions to host defense 94(1)

NK cells are activated by interferons and macrophage-derived cytokines to serve as an early defense against certain intracellular infections 95(1)

NK cells possess receptors for self molecules that prevent their activation by uninfected cells 96(3)

NK cells bear receptors that activate their killer function in response to ligands expressed on infected cells or tumor cells 99(1)

The NKG2D receptor activates a different signaling pathway from that of the other activating NK receptors 100(1)

Several lymphocyte subpopulations behave as innate-like lymphocytes 100(2)

Summary 102(1)

Summary to Chapter 2 103(8)

Part II THE RECOGNITION OF ANTIGEN

Antigen Recognition by B-cell and T-cell Receptors 111(32)

The structure of a typical antibody molecule 112(6)

IgG antibodies consist of four polypeptide chains 113(1)

Immunoglobulin heavy and light chains are composed of constant and variable regions 113(1)

The antibody molecule can readily be cleaved into functionally distinct fragments 114(1)

The immunoglobulin molecule is flexible, especially at the hinge region 115(1)

The domains of an immunoglobulin molecule have similar structures 116(2)

Summary 118(1)

The interaction of the antibody molecule with specific antigen 118(5)

Localized regions of hypervariable sequence form the antigen-binding site 118(1)

Antibodies bind antigens via contacts with amino acids in CDRs, but the details of binding depend upon the size and shape of the antigen 119(1)

Antibodies bind to conformational shapes on the surfaces of antigens 120(1)

Antigen--antibody interactions involve a variety of forces 121(1)

Summary 122(1)

Antigen recognition by T cells 123(20)

The T-cell receptor is very similar to a Fab fragment of immunoglobulin 123(2)

A T-cell receptor recognizes antigen in the form of a complex of a foreign peptide bound to an MHC molecule 125(1)

There are two classes of MHC molecules with distinct subunit composition but similar three-dimensional structures 126(2)

Peptides are stably bound to MHC molecules, and also serve to stabilize the MHC molecule on the cell surface 128(1)

MHC class I molecules bind short peptides of 8--10 amino acids by both ends 129(1)

The length of the peptides bound by MHC class II molecules is not constrained 130(2)

The crystal structures of several MHC:peptide:T-cell receptor complexes show a similar T-cell receptor orientation over the MHC:peptide complex 132(1)

The CD4 and CD8 cell-surface proteins of T cells are required to make an effective response to antigen 133(2)

The two classes of MHC molecules are expressed differentially on cells 135(2)

A distinct subset of T cells bears an alternative receptor made up of γ and δ chains 137(1)

Summary 137(1)

Summary to Chapter 3 138(5)

The Generation of Lymphocyte Antigen Receptors 143(38)

Primary immunoglobulin gene rearrangement 144(11)

Immunoglobulin genes are rearranged in antibody-producing cells 144(1)

Complete genes that encode a variable region are generated by the somatic recombination of separate gene segments 145(1)

Multiple contiguous V gene segments are present at each immunoglobulin locus 146(2)

Rearrangement of V, D, and J gene segments is guided by flanking DNA sequences 148(2)

The reaction that recombines V, D, and J gene segments involves both lymphocyte-specific and ubiquitous DNA-modifying enzymes 150(3)

The diversity of the immunoglobulin repertoire is generated by four main processes 153(1)

The multiple inherited gene segments are used in different combinations 153(1)

Variable addition and subtraction of nucleotides at the junctions between gene segments contributes to the diversity of the third hypervariable region 154(1)

Summary 155(1)

T-cell receptor gene rearrangement 155(5)

The T-cell receptor gene segments are arranged in a similar pattern to immunoglobulin gene segments and are rearranged by the same enzymes 156(1)

T-cell receptors concentrate diversity in the third hypervariable region 157(1)

γδ T-cell receptors are also generated by gene rearrangement 158(1)

Summary 159(1)

Structural variation in immunoglobulin constant regions 160(7)

Different classes of immunoglobulins are distinguished by the structure of their heavy-chain constant regions 160(1)

The constant region confers functional specialization on the antibody 161(2)

Mature naive B cells express both IgM and IgD at their surface 163(1)

Transmembrane and secreted forms of immunoglobulin are generated from alternative heavy-chain transcripts 163(1)

IgM and IgA can form polymers 164(2)

Summary 166(1)

Secondary diversification of the antibody repertoire 167(14)

Activation-induced cytidine deaminase introduces mutations in genes transcribed in B cells 168(1)

Rearranged V-region genes are further diversified by somatic hypermutation 169(2)

In some species, most immunoglobulin gene diversification occurs after gene rearrangement 171(1)

Class switching enables the same assembled VH exon to be associated with different CH genes in the course of an immune response 171(4)

Summary 175(1)

Summary to Chapter 4 175(6)

Antigen Presentation to T Lymphocytes 181(38)

The generation of T-cell receptor ligands 182(14)

The MHC class I and class II molecules deliver peptides to the cell surface from two intracellular compartments 182(1)

Peptides that bind to MHC class I molecules are actively transported from the cytosol to the endoplasmic reticulum 183(1)

Peptides for transport into the endoplasmic reticulum are generated in the cytosol 184(2)

Retrograde transport from the endoplasmic reticulum to the cytosol enables exogenous proteins to be processed for cross-presentation by MHC class I molecules 186(1)

Newly synthesized MHC class I molecules are retained in the endoplasmic reticulum until they bind a peptide 187(2)

Many viruses produce immunoevasins that interfere with antigen presentation by MHC class I molecules 189(1)

Peptides presented by MHC class II molecules are generated in acidified endocytic vesicles 190(2)

The invariant chain directs newly synthesized MHC class II molecules to acidified intracellular vesicles 192(1)

A specialized MHC class II-like molecule catalyzes loading of MHC class II molecules with peptides 193(1)

Stable binding of peptides by MHC molecules provides effective antigen presentation at the cell surface 194(1)

Summary 195(1)

The major histocompatibility complex and its functions 196(23)

Many proteins involved in antigen processing and presentation are encoded by genes within the major histocompatibility complex 197(2)

The protein products of MHC class I and class II genes are highly polymorphic 199(2)

MHC polymorphism affects antigen recognition by T cells by influencing both peptide binding and the contacts between T-cell receptor and MHC molecule 201(3)

Alloreactive T cells recognizing nonself MHC molecules are very abundant 204(2)

Many T cells respond to superantigens 206(1)

MHC polymorphism extends the range of antigens to which the immune system can respond 207(1)

A variety of genes with specialized functions in immunity are also encoded in the MHC 208(1)

Specialized MHC class I molecules act as ligands for the activation and inhibition of NK cells 209(2)

The CD1 family of MHC class I-like molecules is encoded outside the MHC and presents microbial lipids to CD1-restricted T cells 211(1)

Summary 212(1)

Summary to Chapter 5 212(7)

Part III THE DEVELOPMENT OF MATURE LYMPHOCYTE RECEPTOR REPERTOIRES

Signaling Through Immune System Receptors 219(38)

General principles of signal transduction 220(7)

Transmembrane receptors convert extracellular signals into intracellular biochemical events 220(1)

Intracellular signal transduction often takes place in large multiprotein signaling complexes 221(1)

The activation of some receptors generates small-molecule second messengers 222(2)

Small G proteins act as molecular switches in many different signaling pathways 224(1)

Signaling proteins are recruited to the membrane by a variety of mechanisms 224(1)

Signal transduction proteins are organized in the plasma membrane in structures called lipid rafts 225(1)

Protein degradation has an important role in terminating signaling responses 226(1)

Summary 227(1)

Antigen receptor signaling and lymphocyte activation 227(17)

The variable chains of antigen receptors are associated with invariant accessory chains that carry out the signaling function of the receptor 228(1)

Lymphocytes are extremely sensitive to their specific antigens 229(2)

Antigen binding leads to phosphorylation of the ITAM sequences associated with the antigen receptors 231(2)

In T cells, fully phosphorylated ITAMs bind the kinase ZAP-70 and enable it to be activated 233(1)

Activated Syk and ZAP-70 phosphorylate scaffold proteins that mediate many of the downstream effects of antigen receptor signaling 233(1)

PLC-γ is activated by Tec tyrosine kinases 234(1)

Activation of the small G protein Ras activates a MAP kinase cascade, resulting in the production of the transcription factor AP-1 235(1)

The transcription factor NFAT is indirectly activated by Ca2+ 236(1)

The transcription factor NFkB is activated by the actions of protein kinase C 237(2)

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 239(1)

ITAMs are also found in other receptors on leukocytes that signal for cell activation 240(1)

The cell-surface protein CD28 is a co-stimulatory receptor for naive T cells 240(2)

Inhibitory receptors on lymphocytes help regulate immune responses 242(2)

Summary 244(1)

Other receptors and signaling pathways 244(13)

Cytokines typically activate fast signaling pathways that end in the nucleus 245(1)

Cytokine receptors form dimers or trimers on ligand binding 245(1)

Cytokine receptors are associated with the JAK family of tyrosine kinases which activate STAT transcription factors 245(1)

Cytokine signaling is terminated by a negative feedback mechanism 246(1)

The receptors that induce apoptosis activate specialized intracellular proteases called caspases 247(2)

The intrinsic pathway of apoptosis is mediated by release of cytochrome c from mitochondria 249(1)

Microbes and their products act via Toll-like receptors to activate NFkB 249(2)

Bacterial peptides, mediators of inflammatory responses, and chemokines signal through members of the G-protein-coupled receptor family 251(2)

Summary 253(1)

Summary to Chapter 6 253(4)

The Development and Survival of Lymphocytes 257(66)

Development of B lymphocytes 259(14)

Lymphocytes derive from hematopoietic stem cells in the bone marrow 259(3)

B-cell development begins by rearrangement of the heavy-chain locus 262(2)

The pre-B-cell receptor tests for successful production of a complete heavy chain and signals for proliferation of pro-B cells 264(2)

Pre-B-cell receptor signaling inhibits further heavy-chain locus rearrangement and enforces allelic exclusion 266(1)

Pre-B cells rearrange the light-chain locus and express cell-surface immunoglobulin 266(2)

Immature B cells are tested for autoreactivity before they leave the bone marrow 268(4)

Summary 272(1)

T-cell development in the thymus 273(15)

T-cell progenitors originate in the bone marrow, but all the important events in their development occur in the thymus 274(1)

T-cell precursors proliferate extensively in the thymus but most die there 275(2)

Successive stages in the development of thymocytes are marked by changes in cell-surface molecules 277(2)

Thymocytes at different developmental stages are found in distinct parts of the thymus 279(1)

T cells with α:β or γδ receptors arise from a common progenitor 280(2)

T cells expressing particular γ- and δ-chain V regions arise in an ordered sequence early in life 282(1)

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 283(3)

T-cell α-chain genes undergo successive rearrangements until positive selection or cell death intervenes 286(2)

Summary 288(1)

Positive and negative selection of T cells 288(11)

The MHC type of the thymic stroma selects a repertoire of mature T cells that can recognize foreign antigens presented by the same MHC type 289(1)

Only thymocytes whose receptors interact with self-peptide:self-MHC complexes can survive and mature 290(1)

Positive selection acts on a repertoire of T-cell receptors with inherent specificity for MHC molecules 291(1)

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 292(1)

Thymic cortical epithelial cells mediate positive selection of developing thymocytes 293(1)

T cells that react strongly with ubiquitous self antigens are deleted in the thymus 294(2)

Negative selection is driven most efficiently by bone marrow derived antigen-presenting cells 296(1)

The specificity and/or the strength of signals for negative and positive selection must differ 297(1)

Summary 298(1)

Survival and maturation of lymphocytes in peripheral lymphoid tissues 299(9)

Different lymphocyte subsets are found in particular locations in peripheral lymphoid tissues 299(1)

The development and organization of peripheral lymphoid tissues are controlled by proteins of the tumor necrosis factor family 300(2)

The homing of lymphocytes to specific regions of peripheral lymphoid tissues is mediated by chemokines 302(1)

Lymphocytes that encounter sufficient quantities of self antigens for the first time in the periphery are eliminated or inactivated 303(1)

Most immature B cells arriving in the spleen are short-lived and require cytokines and positive signals through the B-cell receptor for maturation and survival 304(2)

B-1 cells and marginal zone B cells are distinct B-cell subtypes with unique antigen receptor specificity 306(1)

T-cell homeostasis in the periphery is regulated by cytokines and self-MHC interactions 307(1)

Summary 307(1)

Lymphoid tumors 308(15)

B-cell tumors often occupy the same site as their normal counterparts 308(3)

T-cell tumors correspond to a small number of stages of T-cell development 311(1)

B-cell lymphomas frequently carry chromosomal translocations that join immunoglobulin loci to genes that regulate cell growth 312(1)

Summary 312(1)

Summary to Chapter 7 313(10)

Part IV THE ADAPTIVE IMMUNE RESPONSE

T Cell-Mediated Immunity 323(56)

Entry of naive T cells and antigen-presenting cells into peripheral lymphoid organs 325(18)

Naive T cells migrate through peripheral lymphoid tissues, sampling the peptide: MHC complexes on dendritic cell surfaces 325(1)

Lymphocyte entry into lymphoid tissues depends on chemokines and adhesion molecules 326(1)

Activation of integrins by chemokines is responsible for the entry of naive T cells into lymph nodes 327(4)

T-cell responses are initiated in peripheral lymphoid organs by activated dendritic cells 331(1)

There are two different functional classes of dendritic cells 332(2)

Dendritic cells process antigens from a wide array of pathogens 334(2)

Pathogen-induced TLR signaling in immature dendritic cells induces their migration to lymphoid organs and enhances antigen processing 336(2)

Plasmacytoid dendritic cells detect viral infections and generate abundant type I interferons and pro-inflammatory cytokines 338(1)

Macrophages are scavenger cells that can be induced by pathogens to present foreign antigens to naive T cells 339(1)

B cells are highly efficient at presenting antigens that bind to their surface immunoglobulin 340(2)

Summary 342(1)

Priming of naive T cells by pathogen-activated dendritic cells 343(13)

Cell-adhesion molecules mediate the initial interaction of naive T cells with antigen-presenting cells 343(1)

Antigen-presenting cells deliver three kinds of signals for clonal expansion and differentiation of naive T cells 344(1)

CD28-dependent co-stimulation of activated T cells induces expression of the T-cell growth factor interleukin-2 and the high-affinity IL-2 receptor 345(1)

Signal 2 can be modified by additional co-stimulatory pathways 346(1)

Antigen recognition in the absence of co-stimulation I eads to functional inactivation or clonal deletion of peripheral T cells 347(2)

Proliferating T cells differentiate into effector T cells that do not require co-stimulation to act 349(1)

T cells differentiate into several subsets of functionally different effector cells 349(3)

CD8 T cells can be activated in different ways to become cytotoxic effector cells 352(1)

Various forms of signal 3 induce the differentiation of naive CD4 T cells down distinct effector pathways 352(2)

Regulatory CD4 T cells are involved in controlling adaptive immune responses 354(2)

Summary 356(1)

General properties of effector T cells and their cytokines 356(8)

Effector T-cell interactions with target cells are initiated by antigen-nonspecific cell-adhesion molecules 357(1)

Binding of the T-cell receptor complex directs the release of effector molecules and focuses them on the target cell 357(1)

The effector functions of T cells are determined by the array of effector molecules that they produce 358(1)

Cytokines can act locally or at a distance 359(2)

Cytokines and their receptors fall into distinct families of structurally related proteins 361(1)

The TNF family of cytokines are trimeric proteins that are usually associated with the cell surface 362(1)

Summary 363(1)

T cell-mediated cytotoxicity 364(4)

Cytotoxic T cells can induce target cells to undergo programmed cell death 364(1)

Cytotoxic effector proteins that trigger apoptosis are contained in the granules of CD8 cytotoxic T cells 365(2)

Cytotoxic T cells are selective and serial killers of targets expressing a specific antigen 367(1)

Cytotoxic T cells also act by releasing cytokines 368(1)

Summary 368(1)

Macrophage activation by TH1 cells 368(11)

TH1 cells have a central role in macrophage activation 369(1)

Activation of macrophages by TH1 cells promotes microbial killing and must be tightly regulated to avoid tissue damage 370(1)

TH1 cells coordinate the host response to intracellular pathogens 371(1)

Summary 372(1)

Summary to Chapter 8 372(7)

The Humoral Immune Response 379(42)

B-cell activation and antibody production 381(19)

The humoral immune response is initiated when B cells that bind antigen are signaled by helper T cells or by certain microbial antigens alone 381(1)

B-cell responses to antigen are enhanced by co-ligation of the B-cell co-receptor 382(1)

Helper T cells activate B cells that recognize the same antigen 383(1)

Antigenic peptides bound to self-MHC class II molecules on B cells trigger helper T cells to make membrane-bound and secreted molecules that can activate a B cell 384(2)

B cells that have bound antigen via their B-cell receptor are trapped in the T-cell zones of secondary lymphoid tissues 386(1)

Antibody-secreting plasma cells differentiate from activated B cells 387(1)

The second phase of a primary B-cell immune response occurs when activated B cells migrate to follicles and proliferate to form germinal centers 388(2)

Germinal center B cells undergo V-region somatic hypermutation, and cells with mutations that improve affinity for antigen are selected 390(2)

Class switching in thymus-dependent antibody responses requires expression of CD40 ligand by the helper T cell and is directed by cytokines 392(2)

Ligation of the B-cell receptor and CD40, together with direct contact with T cells, are all required to sustain germinal center B cells 394(1)

Surviving germinal center B cells differentiate into either plasma cells or memory cells 395(1)

B-cell responses to bacterial antigens with intrinsic ability to activate B cells do not require T-cell help 396(1)

B-cell responses to bacterial polysaccharides do not require peptide-specific T-cell help 397(2)

Summary 399(1)

The distribution and functions of immunoglobulin isotypes 400(9)

Antibodies of different isotypes operate in distinct places and have distinct effector functions 400(2)

Transport proteins that bind to the Fc regions of antibodies carry particular isotypes across epithelial barriers 402(2)

High-affinity IgG and IgA antibodies can neutralize bacterial toxins 404(1)

High-affinity IgG and IgA antibodies can inhibit the infectivity of viruses 405(1)

Antibodies can block the adherence of bacteria to host cells 406(1)

Antibody: antigen complexes activate the classical pathway of complement by binding to C1q 406(2)

Complement receptors are important in the removal of immune complexes from the circulation 408(1)

Summary 409(1)

The destruction of antibody-coated pathogens via Fc receptors 409(12)

The Fc receptors of accessory cells are signaling receptors specific for immunoglobulins of different classes 410(1)

Fc receptors on phagocytes are activated by antibodies bound to the surface of pathogens and enable the phagocytes to ingest and destroy pathogens 411(1)

Fc receptors activate NK cells to destroy antibody-coated targets 412(1)

Mast cells, basophils, and activated eosinophils bind IgE antibody via the high-affinity Fcε receptor 413(1)

IgE-mediated activation of accessory cells has an important role in resistance to parasite infection 414(1)

Summary 415(1)

Summary to Chapter 9 416(5)

Dynamics of Adaptive Immunity 421(38)

The course of the immune response to infection 422(20)

The course of an infection can be divided into several distinct phases 422(3)

The nonspecific responses of innate immunity are necessary for an adaptive immune response to be initiated 425(1)

Cytokines made in the earliest phase of an infection influence differentiation of CD4 T cells toward the TH17 subset 426(1)

Cytokines made in the later stages of an infection influence differentiation of CD4 T cells toward TH1 or TH2 cells 427(3)

The distinct subsets of CD4 T cells can regulate each other's differentiation 430(2)

Effector T cells are guided to sites of infection by chemokines and newly expressed adhesion molecules 432(2)

Differentiated effector T cells are not a static population but continue to respond to signals as they carry out their effector functions 434(1)

Primary CD8 T-cell responses to pathogens can occur in the absence of CD4 help 435(2)

Antibody responses develop in lymphoid tissues under the direction of CD4 helper T cells 437(1)

Antibody responses are sustained in medullary cords and bone marrow 438(1)

The effector mechanisms used to clear an infection depend on the infectious agent 439(2)

Resolution of an infection is accompanied by the death of most of the effector cells and the generation of memory cells 441(1)

Summary 441(1)

Immunological memory 442(17)

Immunological memory is long-lived after infection or vaccination 442(2)

Memory B-cell responses differ in several ways from those of naive B cells 444(1)

Repeated immunization leads to increasing affinity of antibody due to somatic hypermutation and selection by antigen in germinal centers 445(1)

Memory T cells are increased in frequency compared with naive T cells specific for the same antigen and have distinct activation requirements and cell-surface proteins that distinguish them from effector T cells 446(3)

Memory T cells are heterogeneous and include central memory and effector memory subsets 449(1)

CD4 T-cell help is required for CD8 T-cell memory and involves CD40 and IL-2 signaling 450(2)

In immune individuals, secondary and subsequent responses are mainly attributable to memory lymphocytes 452(1)

Summary 453(1)

Summary to Chapter 10 454(5)

The Mucosal Immune System 459(38)

The organization of the mucosal immune system 459(17)

The mucosal immune system protects the internal surfaces of the body 4459

The mucosal immune system may be the original vertebrate immune system 461(1)

Mucosa-associated lymphoid tissue is located in anatomically defined compartments in the gut 462(2)

The intestine has distinctive routes and mechanisms of antigen uptake 464(2)

The mucosal immune system contains large numbers of effector lymphocytes even in the absence of disease 466(1)

The circulation of lymphocytes within the mucosal immune system is controlled by tissue-specific adhesion molecules and chemokine receptors 467(2)

Priming of lymphocytes in one mucosal tissue can induce protective immunity at other mucosal surfaces 469(1)

Secretory IgA is the class of antibody associated with the mucosal immune system 469(3)

IgA deficiency is common in humans but may be overcome by secretory IgM 472(1)

The mucosal immune system contains unusual T lymphocytes 472(3)

Summary 475(1)

The mucosal response to infection and regulation of mucosal immune responses 476(21)

Enteric pathogens cause a local inflammatory response and the development of protective immunity 476(2)

The outcome of infection by intestinal pathogens is determined by a complex interplay between the microorganism and the host immune response 478(2)

The mucosal immune system must maintain a balance between protective immunity and homeostasis to a large number of different foreign antigens 480(2)

The healthy intestine contains large quantities of bacteria but does not generate productive immunity against them 482(3)

Full immune responses to commensal bacteria provoke intestinal disease 485(1)

Intestinal helminths provoke strong TH2-mediated immune responses 485(3)

Other eukaryotic parasites provoke protective immunity and pathology in the gut 488(1)

Dendritic cells at mucosal surfaces favor the induction of tolerance under physiological conditions and maintain the presence of physiological inflammation 488(1)

Summary 489(1)

Summary to Chapter 11 490(7)

Part V THE IMMUNE SYSTEM IN HEALTH AND DISEASE

Failures of Host Defense Mechanisms 497(58)

Evasion and subversion of immune defenses 498(9)

Antigenic variation allows pathogens to escape from immunity 498(3)

Some viruses persist in vivo by ceasing to replicate until immunity wanes 501(1)

Some pathogens resist destruction by host defense mechanisms or exploit them for their own purposes 502(2)

Immunosuppression or inappropriate immune responses can contribute to persistent disease 504(2)

Immune responses can contribute directly to pathogenesis 506(1)

Regulatory T cells can affect the outcome of infectious disease 506(1)

Summary 507(1)

Immunodeficiency diseases 507(20)

A history of repeated infections suggests a diagnosis of immunodeficiency 507(1)

Inherited immunodeficiency diseases are caused by recessive gene defects 508(1)

The main effect of low levels of antibody is an inability to clear extracellular bacteria 509(3)

Some antibody deficiencies can be due to defects in either B-cell or T-cell function 512(2)

Defects in complement components cause defective humoral immune function 514(1)

Defects in phagocytic cells permit widespread bacterial infections 515(2)

Defects in T-cell differentiation can result in severe combined immunodeficiencies 517(2)

Defects in antigen receptor gene rearrangement result in SCID 519(1)

Defects in signaling from T-cell antigen receptors can cause severe immunodeficiency 520(1)

Genetic defects in thymic function that block T-cell development result in severe immunodeficiencies 520(2)

The normal pathways for host defense against intracellular bacteria are pinpointed by genetic deficiencies of IFN-γ and IL-12 and their receptors 522(1)

X-linked lymphoproliferative syndrome is associated with fatal infection by Epstein--Barr virus and with the development of lymphomas 523(1)

Genetic abnormalities in the secretory cytotoxic pathway of lymphocytes cause uncontrolled lymphoproliferation and inflammatory responses to viral infections 523(2)

Bone marrow transplantation or gene therapy can be useful to correct genetic defects 525(1)

Secondary immunodeficiencies are major predisposing causes of infection and death 526(1)

Summary 527(1)

Acquired immune deficiency syndrome 527(28)

Most individuals infected with HIV progress over time to AIDS 528(2)

HIV is a retrovirus that infects CD4 T cells, dendritic cells, and macrophages 530(2)

Genetic variation in the host can alter the rate of progression of disease 532(1)

A genetic deficiency of the co-receptor CCR5 confers resistance to HIV infection in vivo 532(2)

HIV RNA is transcribed by viral reverse transcriptase into DNA that integrates into the host-cell genome 534(2)

Replication of HIV occurs only in activated T cells 536(1)

Lymphoid tissue is the major reservoir of HIV infection 537(1)

An immune response controls but does not eliminate HIV 538(2)

The destruction of immune function as a result of HIV infection leads to increased susceptibility to opportunistic infection and eventually to death 540(1)

Drugs that block HIV replication lead to a rapid decrease in titer of infectious virus and an increase in CD4 T cells 540(2)

HIV accumulates many mutations in the course of infection, and drug treatment is soon followed by the outgrowth of drug-resistant variants 542(1)

Vaccination against HIV is an attractive solution but poses many difficulties 543(2)

Prevention and education are one way in which the spread of HIV and AIDS can be controlled 545(1)

Summary 545(1)

Summary to Chapter 12 546(9)

Allergy and Hypersensitivity 555(44)

Sensitization and the production of Ig E 557(9)

Allergens are often delivered transmucosally at low dose, a route that favors IgE production 557(1)

Enzymes are frequent triggers of allergy 558(1)

Class switching to IgE in B lymphocytes is favored by specific signals 559(1)

Both genetic and environmental factors contribute to the development of IgE-mediated allergy 560(5)

Regulatory T cells can control allergic responses 565(1)

Summary 565(1)

Effector mechanisms in allergic reactions 566(17)

Most IgE is cell-bound and engages effector mechanisms of the immune system by different pathways from other antibody isotypes 567(1)

Mast cells reside in tissues and orchestrate allergic reactions 567(2)

Eosinophils are normally under tight control to prevent inappropriate toxic responses 569(2)

Eosinophils and basophils cause inflammation and tissue damage in allergic reactions 571(1)

Allergic reactions can be divided into immediate and late-phase responses 571(1)

The clinical effects of allergic reactions vary according to the site of mast-cell activation 572(2)

Allergen inhalation is associated with the development of rhinitis and asthma 574(2)

Skin allergy is manifested as urticaria or chronic eczema 576(1)

Allergy to foods causes systemic reactions as well as symptoms limited to the gut 577(1)

Celiac disease is a model of antigen-specific immunopathology 578(2)

Allergy can be treated by inhibiting either IgE production or the effector pathways activated by the cross-linking of cell-surface IgE 580(3)

Summary 583(1)

Hypersensitivity diseases 583(16)

Innocuous antigens can cause type II hypersensitivity reactions in susceptible individuals by binding to the surfaces of circulating blood cells 583(1)

Systemic disease caused by immune-complex formation can follow the administration of large quantities of poorly catabolized antigens 583(2)

Delayed-type hypersensitivity reactions are mediated by TH1 cells and CD8 cytotoxic T cells 585(3)

Mutation in the molecular regulators of inflammation can cause hypersensitive inflammatory responses resulting in `autoinflammatory disease' 588(2)

Crohn's disease is a relatively common inflammatory disease with a complex etiology 590(1)

Summary 591(1)

Summary to Chapter 13 591(8)

Autoimmunity and Transplantation 599(56)

The making and breaking of self-tolerance 600(10)

A critical function of the immune system is to discriminate self from nonself 600(2)

Multiple tolerance mechanisms normally prevent autoimmunity 602(1)

Central deletion or inactivation of newly formed lymphocytes is the first checkpoint of self-tolerance 603(1)

Lymphocytes that bind self antigens with relatively low affinity usually ignore them but in some circumstances become activated 603(2)

Antigens in immunologically privileged sites do not induce immune attack but can serve as targets 605(1)

Autoreactive T cells that express particular cytokines may be nonpathogenic or may suppress pathogenic lymphocytes 606(1)

Autoimmune responses can be controlled at various stages by regulatory T cells 607(2)

Summary 609(1)

Autoimmune diseases and pathogenic mechanisms 610(16)

Specific adaptive immune responses to self antigens can cause autoimmune disease 610(1)

Autoimmune diseases can be classified into clusters that are typically either organ-specific or systemic 611(1)

Multiple aspects of the immune system are typically recruited in autoimmune disease 612(3)

Chronic autoimmune disease develops through positive feedback from inflammation, inability to clear the self antigen, and a broadening of the autoimmune response 615(2)

Both antibody and effector T cells can cause tissue damage in autoimmune disease 617(1)

Autoantibodies against blood cells promote their destruction 617(2)

The fixation of sublytic doses of complement to cells in tissues stimulates a powerful inflammatory response 619(1)

Autoantibodies against receptors cause disease by stimulating or blocking receptor function 620(1)

Autoantibodies against extracellular antigens cause inflammatory injury by mechanisms akin to type II and type III hypersensitivity reactions 621(1)

T cells specific for self antigens can cause direct tissue injury and sustain autoantibody responses 622(3)

Summary 625(1)

The genetic and environmental basis of autoimmunity 626(11)

Autoimmune diseases have a strong genetic component 626(1)

A defect in a single gene can cause autoimmune disease 627(1)

Several approaches have given us insight into the genetic basis of autoimmunity 628(3)

Genes that predispose to autoimmunity fall into categories that affect one or more of the mechanisms of tolerance 631(1)

MHC genes have an important role in controlling susceptibility to autoimmune disease 631(3)

External events can initiate autoimmunity 634(1)

Infection can lead to autoimmune disease by providing an environment that promotes lymphocyte activation 634(1)

Cross-reactivity between foreign molecules on pathogens and self molecules can lead to anti-self responses and autoimmune disease 635(1)

Drugs and toxins can cause autoimmune syndromes 636(1)

Random events may be required for the initiation of autoimmunity 637(1)

Summary 637(1)

Responses to alloantigens and transplant rejection 637(18)

Graft rejection is an immunological response mediated primarily by T cells 638(1)

Matching donor and recipient at the MHC improves the outcome of transplantation 639(1)

In MHC-identical grafts, rejection is caused by peptides from other alloantigens bound to graft MHC molecules 640(1)

There are two ways of presenting alloantigens on the transplant to the recipient's T lymphocytes 641(1)

Antibodies reacting with endothelium cause hyperacute graft rejection 642(1)

Chronic organ rejection is caused by inflammatory vascular injury to the graft 643(1)

A variety of organs are transplanted routinely in clinical medicine 644(1)

The converse of graft rejection is graft-versus-host disease 645(1)

Regulatory T cells are involved in alloreactive immune responses 646(1)

The fetus is an allograft that is tolerated repeatedly 647(1)

Summary 648(1)

Summary to Chapter 14 648(7)

Manipulation of the Immune Response 655(56)

Extrinsic regulation of unwanted immune responses 655(17)

Corticosteroids are powerful anti-inflammatory drugs that alter the transcription of many genes 656(1)

Cytotoxic drugs cause immunosuppression by killing dividing cells and have serious side-effects 657(1)

Cyclosporin A, tacrolimus (FK506), and rapamycin (sirolimus) are powerful immunosuppressive agents that interfere with T-cell signaling 658(1)

Immunosuppressive drugs are valuable probes of intracellular signaling pathways in lymphocytes 659(2)

Antibodies against cell-surface molecules have been used to remove specific lymphocyte subsets or to inhibit cell function 661(1)

Antibodies can be engineered to reduce their immunogenicity in humans 661(1)

Monoclonal antibodies can be used to prevent allograft rejection 662(2)

Biological agents can be used to alleviate and suppress autoimmune disease 664(2)

Depletion or inhibition of autoreactive lymphocytes can treat autoimmune disease 666(2)

Interference with co-stimulatory pathways for the activation of lymphocytes could be a treatment for autoimmune disease 668(1)

Induction of regulatory T cells by antibody therapy can inhibit autoimmune disease 668(1)

A number of commonly used drugs have immunomodulatory properties 669(2)

Controlled administration of antigen can be used to manipulate the nature of an antigen-specific response 671(1)

Summary 672(1)

Using the immune response to attack tumors 672(15)

The development of transplantable tumors in mice led to the discovery of protective immune responses to tumors 673(1)

Tumors can escape rejection in many ways 674(4)

T lymphocytes can recognize specific antigens on human tumors, and adoptive T-cell transfer is being tested in cancer patients 678(4)

Monoclonal antibodies against tumor antigens, alone or linked to toxins, can control tumor growth 682(2)

Enhancing the immune response to tumors by vaccination holds promise for cancer prevention and therapy 684(3)

Summary 687(1)

Manipulating the immune response to fight infection 687(24)

There are several requirements for an effective vaccine 689(1)

The history of vaccination against Bordetella pertussis illustrates the importance of developing an effective vaccine that is perceived to be safe 690(1)

Conjugate vaccines have been developed as a result of understanding how T and B cells collaborate in an immune response 691(2)

The use of adjuvants is another important approach to enhancing the immunogenicity of vaccines 693(2)

Live-attenuated viral vaccines are usually more potent than `killed' vaccines and can be made safer by the use of recombinant DNA technology 695(1)

Live-attenuated bacterial vaccines can be developed by selecting nonpathogenic or disabled mutants 696(1)

Synthetic peptides of protective antigens can elicit protective immunity 696(1)

The route of vaccination is an important determinant of success 697(1)

Protective immunity can be induced by injecting DNA encoding microbial antigens and human cytokines into muscle 698(1)

The effectiveness of a vaccine can be enhanced by targeting it to sites of antigen presentation 699(1)

An important question is whether vaccination can be used therapeutically to control existing chronic infections 700(1)

Modulation of the immune system might be used to inhibit immunopathological responses to infectious agents 701(1)

Summary 702(1)

Summary to Chapter 15 703(8)

Part VI THE ORIGINS OF IMMUNE RESPONSES

Evolution of the Immune System 711(24)

Evolution of the innate immune system 712(8)

The evolution of the immune system can be studied by comparing the genes expressed by different species 712(1)

Antimicrobial peptides are likely to be the most ancient immune defenses 713(1)

Toll-like receptors may represent the most ancient pathogen-recognition system 714(2)

Toll-like receptor genes have undergone extensive diversification in some invertebrate species 716(1)

A second recognition system in Drosophila homologous to the mammalian TNF receptor pathway provides protection from Gram-negative bacteria 717(1)

An ancestral complement system opsonizes pathogens for uptake by phagocytic cells 717(2)

The lectin pathway of complement activation evolved in invertebrates 719(1)

Summary 720(1)

Evolution of the adaptive immune response 720(15)

Some invertebrates generate extensive diversity in a repertoire of immunoglobulin-like genes 721(1)

Agnathans possess an adaptive immune system that uses somatic gene rearrangement to diversify receptors built from LRR domains 722(2)

Adaptive immunity based on a diversified repertoire of immunoglobulin-like genes appeared abruptly in the cartilaginous fish 724(1)

The target of the transposon is likely to have been a gene encoding a cell-surface receptor containing an immunoglobulin-like V domain 725(1)

Different species generate immunoglobulin diversity in different ways 726(1)

Both α:β and γδ T-cell receptors are present in cartilaginous fish 727(1)

MHC class I and class II molecules are also first found in the cartilaginous fishes 728(1)

Summary 729(1)

Summary to Chapter 16 729(6)

Appendix I Immunologists' Toolbox 735(48)

Immunization 735(5)

Haptens 736(2)

Routes of immunization 738(1)

Effects of antigen dose 738(1)

Adjuvants 738(2)

The detection, measurement, and characterization of antibodies and their use as research and diagnostic tools 740(18)

Affinity chromatography 741(1)

Radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), and competitive inhibition assay 741(2)

Hemagglutination and blood typing 743(1)

Precipitin reaction 744(1)

Equilibrium dialysis: measurement of antibody affinity and avidity 745(1)

Anti-immunoglobulin antibodies 746(1)

Coombs tests and the detection of Rhesus incompatibility 747(2)

Monoclonal antibodies 749(1)

Phage display libraries for antibody V-region production 750(1)

Immunofluorescence microscopy 751(2)

Immunoelectron microscopy 753(1)

Immunohistochemistry 753(1)

Immunoprecipitation and co-immunoprecipitation 754(1)

Immunoblotting (Western blotting) 755(1)

Use of antibodies in the isolation and identification of genes and their products 756(2)

Isolation of lymphocytes 758(4)

Isolation of peripheral blood lymphocytes by Ficoll-Hypaque™ gradient 758(1)

Isolation of lymphocytes from tissues other than blood 758(1)

Flow cytometry and FACS analysis 759(2)

Lymphocyte isolation using antibody-coated magnetic beads 761(1)

Isolation of homogeneous T-cell lines 761(1)

Characterization of lymphocyte specificity, frequency, and function 762(10)

Limiting-dilution culture 763(1)

ELISPOT assays 763(1)

Identification of functional subsets of T cells by staining for cytokines 764(1)

Identification of T-cell receptor specificity using MHC: peptide tetramers 765(1)

Assessing the diversity of the T-cell repertoire by `spectratyping' 766(1)

Biosensor assays for measuring the rates of association and disassociation of antigen receptors for their ligands 767(2)

Stimulation of lymphocyte proliferation by treatment with polyclonal mitogens or specific antigen 769(1)

Measurements of apoptosis by the TUNEL assay 770(1)

Assays for cytotoxic T cells 770(1)

Assays for CD4 T cells 770(2)

DNA microarrays 772(1)

Detection of immunity in vivo 772(5)

Assessment of protective immunity 772(1)

Transfer of protective immunity 773(1)

The tuberculin test 774(1)

Testing for allergic responses 774(1)

Assessment of immune responses and immunological competence in humans 775(1)

The Arthus reaction 776(1)

Manipulation of the immune system 777(6)

Adoptive transfer of lymphocytes 777(1)

Hematopoietic stem-cell transfers 777(1)

In vivo depletion of T cells 777(1)

In vivo depletion of B cells 778(1)

Transgenic mice 778(1)

Gene knockout by targeted disruption 779(4)
Appendix II CD Antigens 783(16)
Appendix III Cytokines and their receptors 799(3)
Appendix IV Chemokines and their receptors 802(2)
Appendix V Immunological constants 804(1)
Biographies 805(1)
Glossary 806(29)
Index 835