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(BQ) Part 2 book Basic immunology functions and disorders of the immune system presents the following contents: Effector mechanisms of humoral immunity, immunological tolerance and autoimmunity, immune responses against tumors and transplants, hypersensitivity, congenital and acquired immunodeficiencies.
8 CHAPTER Effector Mechanisms of Humoral Immunity Elimination of Extracellular Microbes and Toxins PROPERTIES OF ANTIBODIES THAT DETERMINE EFFECTOR FUNCTIONâ•… 152 NEUTRALIZATION OF MICROBES AND MICROBIAL TOXINSâ•… 154 OPSONIZATION AND PHAGOCYTOSISâ•… 157 ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITYâ•… 157 IMMUNOGLOBULIN E– AND EOSINOPHIL/MAST CELL–MEDIATED REACTIONSâ•… 157 THE COMPLEMENT SYSTEMâ•… 158 Pathways of Complement Activationâ•… 158 Functions of the Complement Systemâ•… 161 Regulation of Complement Activationâ•… 163 FUNCTIONS OF ANTIBODIES AT SPECIAL ANATOMIC SITESâ•… 164 Mucosal Immunityâ•… 166 Neonatal Immunityâ•… 166 EVASION OF HUMORAL IMMUNITY BY MICROBESâ•… 167 VACCINATIONâ•… 168 SUMMARYâ•… 169 Humoral immunity is the type of host defense mediated by secreted antibodies and necessary for protection against extracellular microbes and their toxins Antibodies prevent infections by blocking the ability of microbes to bind to and enter host cells Antibodies also bind to microbial toxins and prevent them from damaging host cells In addition, antibodies function to eliminate microbes, toxins, and infected cells from the body Although antibodies are a major mechanism of adaptive immunity against extracellular microbes, they cannot reach microbes that live inside cells However, humoral immunity is vital even for defense against microbes that live and divide inside cells, such as viruses, because antibodies can bind to these microbes before they enter host cells or during passage from infected to uninfected cells, thus preventing spread of infection Defects in antibody production are associated with increased susceptibility to infections by many bacteria, viruses, and parasites Most effective vaccines work by stimulating the production of antibodies This chapter describes how antibodies provide defense against infections, addressing the following questions: What are the mechanisms used by secreted antibodies to combat different types of infectious agents and their toxins? l What is the role of the complement system in defense against microbes? l How antibodies combat microbes that enter through the gastrointestinal and respiratory tracts? l How antibodies protect the fetus and newborn from infections? l 151 152 Chapter – Effector Mechanisms of Humoral Immunity Before describing the mechanisms by which antibodies function in host defense, we summarize the features of antibody molecules that are important for these functions PROPERTIES OF ANTIBODIES THAT DETERMINE EFFECTOR FUNCTION Several features of the production and structure of antibodies contribute in important ways to the functions of these molecules in host defense Antibodies function throughout the body and in the lumens of mucosal organs Antibodies are produced after stimulation of B lymphocytes by antigens in peripheral lymphoid organs (lymph nodes, spleen, mucosal lymphoid tissues) and at tissue sites of inflammation Many of the antigen-stimulated B lymphocytes differentiate into antibody-secreting plasma cells, some of which remain in lymphoid organs or inflamed tissues while others migrate to and reside in the bone marrow Plasma cells synthesize and secrete antibodies of different heavychain isotypes (classes) These secreted antibodies enter the blood, from where they may reach any peripheral site of infection, and enter mucosal secretions, where they prevent infections by microbes that try to enter through the epithelia Thus, antibodies are able to perform their functions throughout the body Protective antibodies are produced during the first (primary) response to a microbe and in larger amounts during subsequent (secondary) responses (see Chapter 7, Fig 7–3) Antibody production begins within the first week after infection or vaccination The plasma cells that migrate to the bone marrow continue to produce antibodies for months or years If the microbe again tries to infect the host, the continuously secreted antibodies provide immediate protection Some of the antigenstimulated B lymphocytes differentiate into memory cells, which not secrete antibodies but are ready to respond if the antigen appears again On encounter with the microbe, these memory cells rapidly differentiate into antibodyproducing cells, providing a large burst of antibody for more effective defense against the infection A goal of vaccination is to stimulate the development of long-lived plasma cells and memory cells Antibodies use their antigen-binding (Fab) regions to bind to and block the harmful effects of microbes and toxins, and they use their Fc regions to activate diverse effector mechanisms that eliminate these microbes and toxins (Fig 8–1) This spatial segregation of the antigen recognition and effector functions of antibody molecules was introduced in Chapter Antibodies sterically block the infectivity of microbes and the injurious effects of microbial toxins simply by binding to the microbes and toxins, using only their Fab regions to so Other functions of antibodies require the participation of various components of host defense, such as phagocytes and the complement system The Fc portions of immunoglobulin (Ig) molecules, made up of the heavy-chain constant regions, contain the binding sites for Fc receptors on phagocytes and for complement proteins The binding of antibodies to Fc and complement receptors occurs only after several Ig molecules recognize and become attached to a microbe or microbial antigen Therefore, even the Fc-dependent functions of antibodies require antigen recognition by the Fab regions This feature of antibodies ensures that they activate effector mechanisms only when needed, that is, when they recognize their target antigens Heavy-chain isotype (class) switching and affinity maturation enhance the protective functions of antibodies Isotype switching and affinity maturation are two changÂ� es that occur in the antibodies produced by antigen-stimulated B lymphocytes, especially during responses to protein antigens (see Chapter 7) Heavy-chain isotype switching results in the production of antibodies with distinct Fc regions, capable of different effector functions (see Fig 8–1) By switching to different antibody isotypes in response to various microbes, the humoral immune system is able to engage host mechanisms that are optimal for combating these microbes Affinity maturation is induced by prolonged or repeated stimulation with protein antigens, and it leads to the production of antibodies with higher and higher affinities for the antigen This change increases the ability of antibodies to bind to and neutralize or eliminate microbes, especially if the microbes are persistent or capable of recurrent infections This is one of the reasons for the recommended practice of giving multiple rounds of immunizations with Chapter – Effector Mechanisms of Humoral Immunity A 153 Neutralization of microbe and toxins B cell Phagocyte Antibodies Opsonization and phagocytosis of microbes Fc receptor Microbe Antibodydependent cellular cytotoxicity NK cell Lysis of microbes Complement activation B C3b receptor Phagocytosis of microbes opsonized with complement fragments (e.g., C3b) Inflammation Antibody Effector functions isotype IgG Neutralization of microbes and toxins Opsonization of antigens for phagocytosis by macrophages and neutrophils Activation of the classical pathway of complement Antibody-dependent cellular cytotoxicity mediated by NK cells Neonatal immunity: transfer of maternal antibody across placenta and gut Feedback inhibition of B cell activation IgM Activation of the classical pathway of complement IgA Mucosal immunity: secretion of IgA into lumens of gastrointestinal and respiratory tracts, neutralization of microbes and toxins IgE Defense against helminths Mast cell degranulation (immediate hypersensitivity reactions) FIGURE 8–1 Effector functions of antibodies Antibodies are produced by the activation of B lymphocytes by antigens and other signals (not shown) Antibodies of different heavy-chain classes (isotypes) perform different effector functions, as illustrated schematically in A and summarized in B (Some properties of antibodies are listed in Figure 4–3.) Ig, Immunoglobulin; NK, natural killer 154 Chapter – Effector Mechanisms of Humoral Immunity IgG released from FcRn by extracellular pH Plasma protein Endocytic vesicle IgG Recycling endosome IgG binds to FcRn in endosome FIGURE 8–2 Neonatal Fc receptor (FcRn) contributes to the long half-life of IgG molecules Circulating IgG mole- FcRn cules are ingested by endothelial cells and bind the FcRn, an IgG-binding receptor present in the acidic environment of endosomes In endothelial cells, FcRn sequesters IgG molecules in endosomal vesicles (pH ~4) The FcRn-IgG complexes recycle back to the cell surface, where they are exposed to the neutral pH (~7) of the blood, which releases the bound antibody back into the circulation the same antigen for generating protective immunity Switching to the IgG isotype prolongs the duration an antibody lasts in the blood and therefore increases the functional activity of the antibody The neonatal Fc receptor (FcRn) is expressed in placenta, endothelium, phagocytes, and a few other cell types In the endothelium, FcRn plays a special role in protecting IgG antibodies from intracellular catabolism (Fig 8–2) FcRn is found in the endosomes of endothelial cells, where it binds to IgG that has been taken up by the cells Once bound to the FcRn, the IgG is recycled back into the circulation, thus avoiding lysosomal degradation This unique mechanism for protecting a blood protein is the reason why IgG antibodies have a half-life of about weeks, much longer than that of other Ig isotypes and most other plasma proteins This property of Fc regions of IgG has been exploited to increase the half-life of other proteins by coupling the proteins to an IgG Fc region One of several therapeutic agents based on this principle is the tumor necrosis factor (TNF) receptor–Fc fusion protein, which functions as an antagonist of TNF and is used to treat various IgG-FcRn complexes sorted to recycling endosome Lysosome Other proteins degraded in lysosomes inflammatory diseases By coupling the soluble receptor to the Fc portion of a human IgG molecule, the half-life of the protein becomes much greater than that of the receptor by itself With this introduction, we proceed to a discussion of the mechanisms used by antibodies to combat infections Much of the chapter is devoted to effector mechanisms that are not influenced by anatomic considerations; that is, they may be active anywhere in the body At the end of the chapter, we describe the special features of antibody functions at particular anatomic locations NEUTRALIZATION OF MICROBES AND MICROBIAL TOXINS Antibodies bind to and block, or neutralize, the infectivity of microbes and the interactions of microbial toxins with host cells (Fig 8–3) Most microbes use molecules in their envelopes or cell walls to bind to and gain entry into host cells Antibodies may attach to these microbial surface molecules, thereby preventing the Chapter – Effector Mechanisms of Humoral Immunity Without antibody 155 With antibody A Microbe entry through epithelial barrier Microbe Antibody blocks penetration of microbe through epithelial barrier Epithelial barrier cells B Infection of cell by microbe Antibody blocks binding of microbe and infection of cells Cell surface receptor for microbe Infected tissue cell Tissue cell C Release of microbe from infected cell and infection of adjacent cell Release of microbe from dead cell Infected tissue cell Uninfected adjacent cell Antibody blocks infection of adjacent cell Spread of infection D Pathologic effect of toxin Cell surface receptor for toxin Antibody blocks binding of toxin to cellular receptor Toxin Pathologic effect of toxin (e.g., cell necrosis) FIGURE 8–3 Neutralization of microbes and toxins by antibodies A, Antibodies at epithelial surfaces, such as in the gastrointestinal and respiratory tracts, block the entry of ingested and inhaled microbes, respectively B, Antibodies prevent the binding of microbes to cells, thereby blocking the ability of the microbes to infect host cells C, Antibodies inhibit the spread of microbes from an infected cell to an adjacent uninfected cell D, Antibodies block the binding of toxins to cells, thereby inhibiting the pathologic effects of the toxins 156 Chapter – Effector Mechanisms of Humoral Immunity microbes from infecting the host The most effective vaccines available today work by stimulating the production of neutralizing antibodies, which bind microbes and prevent them from infecting cells Microbes that are able to enter host cells may be released from these infected cells and go on to infect other neighboring cells Antibodies can neutralize the microbes during their transit from cell to cell and thus limit the spread of infection If an infectious microbe does colonize the host, its harmful effects may be caused by endotoxins or exotoxins, which often bind to specific receptors on host cells in order to mediate their effects Antibodies against toxins prevent binding of the toxins to host cells and thus block the harmful effects of the toxins Emil von Behring’s demonstration of this type of protection mediated by the administration of antibodies against diphtheria toxin was the first formal demonstration of therapeutic immunity against a microbe or its toxin, then called serum therapy, and the basis for awarding von Behring the first Nobel Prize in Physiology or Medicine in 1901 A Fc receptor Binding of Opsonization opsonized microbes signals of microbe activate to phagocyte by IgG Fc receptors (FcγRI) phagocyte Phagocytosis of microbe Killing of ingested microbe IgG antibody FcγRI Signals Phagocyte B Fc Receptor Affinity for Ig Cell distribution Function FcγRI (CD64) High (Kd ~10-9 M); binds IgG1 and IgG3; can bind monomeric IgG Macrophages, neutrophils; also eosinophils Phagocytosis; activation of phagocytes FcγRIIA (CD32) Low (Kd ~0.6–2.5×10-6 M) Macrophages, neutrophils; eosinophils, platelets Phagocytosis; cell activation (inefficient) FcγRIIB (CD32) Low (Kd ~0.6–2.5×10-6 M) B lymphocytes, DCs, mast cells, neutrophils, macrophages Feedback inhibition of B cells, attenuation of inflammation FcγRIIIA (CD16) Low (Kd ~0.6–2.5×10-6 M) NK cells Antibody-dependent cellular cytotoxicity (ADCC) FcεRI High (Kd ~10-10 M); binds monomeric IgE Mast cells, basophils, Activation (degranulation) eosinophils of mast cells and basophils FIGURE 8–4 Antibody-mediated opsonization and phagocytosis of microbes A, Antibodies of certain IgG subclasses bind to microbes and are then recognized by Fc receptors on phagocytes Signals from the Fc receptors promote the phagocytosis of the opsonized microbes and activate the phagocytes to destroy these microbes B, Table lists the different types of human Fc receptors and their cellular distribution and principal functions DCs, Dendritic cells; Ig, immunoglobulin; NK, natural killer OPSONIZATION AND PHAGOCYTOSIS Antibodies coat microbes and promote their ingestion by phagocytes (Fig 8–4) The process of coating particles for subsequent phagocytosis is called opsonization, and the molecules that coat microbes and enhance their phagocytosis are called opsonins When several antibody molecules bind to a microbe, an array of Fc regions is formed projecting away from the microbial surface If the antibodies belong to certain isotypes (IgG1 and IgG3 in humans), their Fc regions bind to a high-affinity receptor for the Fc regions of γ heavy chains, called FcγRI (CD64), which is expressed on neutrophils and macrophages The phagocyte extends its plasma membrane around the attached microbe and ingests the microbe into a vesicle called a phagosome, which fuses with lysosomes The binding of antibody Fc tails to FcγRI also activates the phagocytes, because the FcγRI contains a signaling chain that triggers numerous biochemical pathways in the phagocytes The activated neutrophil or macrophage produces, in its lysosomes, large amounts of reactive oxygen species, nitric oxide, and proteolytic enzymes, all of which combine to destroy the ingested microbe Antibody-mediated phagocytosis is the major mechanism of defense against encapsulated bacteria, such as pneumococci The polysacchariderich capsules of these bacteria protect the organisms from phagocytosis in the absence of antibody, but opsonization by antibody promotes phagocytosis and destruction of the bacteria The spleen contains large numbers of phagocytes and is an important site of phagocytic clearance of opsonized bacteria This is why patients who have undergone splenectomy for traumatic rupture of the organ are susceptible to disseminated infections by encapsulated bacteria One of the Fcγ receptors, FcγRIIB, is important not for the effector function of antibodies but for shutting down antibody production and reducing inflammation The role of FcγRIIB in feedback inhibition of B cell activation was discussed in Chapter (see Fig 7–15) FcγRIIB also inhibits activation of macrophages and dendritic cells and may thus serve an antiinflammatory function as well Pooled IgG from healthy donors is given intravenously to patients with various inflammatory diseases This preparation is called intravenous immune Chapter – Effector Mechanisms of Humoral Immunity Surface antigen IgG Antibodycoated cell 157 Low-affinity FcγRIIIA (CD16) NK cell Killing of antibodycoated cell FIGURE 8–5 Antibody-dependent cellular cytotoxicity (ADCC) Antibodies of certain immunoglobulin G (IgG) subclasses bind to cells (e.g., infected cells), and the Fc regions of the bound antibodies are recognized by an Fcγ receptor on natural killer (NK) cells The NK cells are activated and kill the antibody-coated cells globulin (IVIG), and its beneficial effect in these diseases may be partly mediated by its binding to FcγRIIB on various cells ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY Natural killer (NK) cells and other leukocytes may bind to antibody-coated cells and destroy these cells (Fig 8–5) NK cells express an Fcγ receptor called FcγRIII (CD16), which is one of several kinds of NK cell– activating receptors (see Chapter 2) FcγRIII binds to arrays of IgG antibodies attached to the surface of a cell, generating signals that cause the NK cell to discharge its granule proteins, which kill the opsonized cell This process is called antibody-dependent cellular cytotoxicity (ADCC) Cells infected with enveloped viruses typically express viral glycoproteins on their surface that can be recognized by specific antibodies and this may facilitate ADCCmediated destruction of the infected cells ADCC is also one of the mechanisms by which therapeutic antibodies used to treat cancers eliminate tumor cells IMMUNOGLOBULIN E– AND EOSINOPHIL/ MAST CELL–MEDIATED REACTIONS Immunoglobulin E antibodies activate mast cell and eosinophil–mediated reactions that provide defense against helminthic parasites and are involved in allergic diseases Most helminths are too large to be phagocytosed, 158 Chapter – Effector Mechanisms of Humoral Immunity IL-5 FcεRI IgE Helminth Eosinophil activation TH2 cell Eosinophil Eosinophil granule contents Helminth death FIGURE 8–6 IgE- and eosinophil-mediated killing of helminths IgE antibody binds to helminths and recruits and activates eosinophils via FcεRI, leading to degranulation of the cells and release of toxic mediators IL-5 secreted by TH2 cells enhances the ability of eosinophils to kill the parasites and their thick integument makes them resistant to many of the microbicidal substances produced by neutrophils and macrophages The humoral immune response to helminths is dominated by IgE antibodies The IgE antibody binds to the worms and promotes the attachment of eosinophils through the high-affinity Fc receptor for IgE, FcεRI, expressed on eosinophils and mast cells Engagement of FcεRI, together with the cytokine interleukin-5 (IL-5) produced by TH2 helper T cells reacting against the helminths, leads to activation of the eosinophils, which release their granule contents, including proteins that can kill the worms (Fig 8–6) IgE antibodies may also bind to and activate mast cells, which secrete cytokines, including chemokines, that attract more leukocytes that function to destroy the helminths This IgE-mediated reaction illustrates how Ig isotype switching optimizes host defense B cells respond to helminths by switching to IgE, which is useful against helminths, but B cells respond to most bacteria and viruses by switching to IgG antibodies, which promote phagocytosis by FcγRI As discussed in Chapters and 7, these patterns of isotype switching are determined by the cytokines produced by helper T cells responding to the different types of microbes IgE antibodies also are involved in allergic diseases (see Chapter 11) THE COMPLEMENT SYSTEM The complement system is a collection of circulating and cell membrane proteins that play important roles in host defense against microbes and in antibody-mediated tissue injury The term complement refers to the ability of these proteins to assist, or complement, the antimicrobial activity of antibodies The complement system may be activated by microbes in the absence of antibody, as part of the innate immune response to infection, and by antibodies attached to microbes, as part of adaptive immunity (see Fig 2–13) The activation of complement proteins inÂ� volves sequential proteolytic cleavage of these proteins, leading to the generation of effector molecules that participate in eliminating microbes in different ways This cascade of complement protein activation, as with all enzymatic cascades, is capable of achieving tremendous amplification; therefore an initially small number of activated complement molecules produced early in the cascade may generate a large number of effector molecules Activated complement proteins become covalently attached to the cell surfaces where the activation occurs, ensuring that complement effector functions are limited to the correct sites The complement system is tightly regulated by molecules present on normal host cells, and this regulation prevents uncontrolled and potentially harmful complement activation Pathways of Complement Activation Of the three major pathways of complement activation, two, called the alternative and lectin pathways, are initiated by microbes in the absence of antibody, and the third, called the classical pathway, is initiated by certain isotypes of antibodies attached to antigens (Fig 8–7) Several proteins in each pathway interact in a precise sequence The most abundant complement protein in the plasma, C3, plays a central role in all three pathways C3 is spontaneously hydrolyzed in plasma at a low level, but its products are unstable, rapidly broken down, and lost The alternative pathway of complement activation is triggered when a breakdown prodÂ� uct of C3 hydrolysis, called C3b, is deposited on the surface of a microbe Here, the C3b forms stable covalent bonds with microbial proteins or polysaccharides and is thus protected from further degradation (As described later, C3b is prevented from binding stably to normal host cells by several regulatory proteins present on host cells but absent from microbes.) The A Alternative Pathway Lectin Pathway Classical Pathway Microbe Binding of complement proteins to microbial cell surface or antibody C3b C3 IgG antibody C4 C1 C4b Formation of C3 convertase C2 C4 C2 2a C4b 2a C4b 2a C3bBb C3 convertase C4b 2a C4b 2a C3 C3 C3 C3b C3b C3a Covalent binding of C3b to microbe; Formation of C5 convertase C3 convertase C3 convertase C4b 2a C3bBb Cleavage of C3 Mannose Mannosebinding lectin C3b C3a C3a C3b Bb C3b C4b 2a C3b C4b 2a C3b C5 C5 C5 C5 convertase C5 convertase C5b C5a C5b C5 convertase C5a C5b C5a Late steps of complement activation FIGURE 8–7 Early steps of complement activation A, Table illustrates the steps in the activation of the alternative, classical, and lectin pathways Although the sequence of events is similar, the three pathways differ in their requirement for antibody and the proteins used Continued 160 Chapter – Effector Mechanisms of Humoral Immunity B Protein Serum conc Function (µg/mL) C3 1000-1200 C3b binds to the surface of a microbe, where it functions as an opsonin and as a component of C3 and C5 convertases C3a stimulates inflammation Factor B 200 Bb is a serine protease and the active enzyme of C3 and C5 convertases Factor D 1-2 Plasma serine protease that cleaves factor B when it is bound to C3b Properdin 25 C Protein Stabilizes the C3 convertase (C3bBb) on microbial surfaces Serum conc Function (µg/mL) Initiates the classical pathway; C1q binds to Fc portion of antibody; C1r and C1s are proteases that lead to C4 and C2 activation C1 (C1qr2s2) C4 300-600 C4b covalently binds to surface of microbe or cell where antibody is bound and complement is activated C4b binds to C2 for cleavage by C1s C4a stimulates inflammation C2 20 C2a is a serine protease functioning as an active enzyme of C3 and C5 convertases Mannose- 0.8-1 binding lectin (MBL) Initiates the lectin pathway; MBL binds to terminal mannose residues of microbial carbohydrates An MBLassociated protease activates C4 and C2, as in the classical pathway FIGURE 8–7, cont’d B, Table summarizes the important properties of the proteins involved in the early steps of the alternative pathway of complement activation C, Table summarizes the important properties of the proteins involved in the early steps of the classical and lectin pathways Note that C3, which is listed among the alternative pathway proteins (B), also is the central component of the classical and lectin pathways microbe-bound C3b binds another protein called factor B, which is then broken down by a plasma protease to generate the Bb fragment This fragment remains attached to C3b, and the C3bBb complex enzymatically breaks down more C3, functioning as the alternative pathway C3 convertase As a result of this convertase activity, many more C3b and C3bBb molecules are produced and become attached to the microbe Some of the C3bBb molecules bind an additional C3b molecule, and the C3bBb3b complex functions as a C5 convertase, to break down the complement protein C5 and initiate the late steps of complement activation e10 Answers to Review Questions and wasting The infections are caused by a profound loss of T cell–mediated and Tdependent antibody-mediated immunity, mainly due to death of infected CD4+ T cells The increased in tumors reflects reduced T cell–mediated immune surveillance against oncogenic viruses The dementia reflects loss of microglial function, perhaps from HIV infection The wasting syndrome is caused by altered metabolism and reduced caloric intake, possibly a result of cytokines produced during repeated and chronic infections INDEX A ABO blood group antigens, 202-203, 203f, 247 See also Antigens Acquired immunodeficiency, 225-240 See also Immunodeficiencies Acquired immunodeficiency syndrome (AIDS), 234-239 clinical features of, 237-239, 237f-238f definition of, 1-2, 225, 247, 260-261 epidemiology of, 234 human immunodeficiency virus (HIV) and, 234, 235f-236f immune response to, 238-239 pathogenesis of, 234-237 therapy strategies for, 239 Activation protein (AP-1), 104-105, 247 See also Proteins Activation-induced cell death (AICD), 247 Activation-induced deaminase (AID), 142-143, 143f, 247 Active immunity, 247 Acute graft rejection, 201 See also Grafts Acute rejection, 247 See also Rejection Acute-phase reactants, 248 Note: Page number followed by “f” indicate figures Acute-phase responses, 38-40, 248 Adaptive immunity, 71-91 antigen recognition in, 71-91 See also Antigens antibodies, 73f, 74-78, 75f diversity (D), 82-87 See also Diversity (D) features of, 82f immune repertoire development, 80-90, 81f complement system and, 158-164, 159f-160f See also Complement system definition of, 71, 248 vs innate immunity, 23-24 See also Innate immunity overviews of, 71-72, 90-91 Adaptor proteins, 248 See also Proteins ADCC See Antibody-dependent cell-mediated cytotoxicity (ADCC) Adenosine triphosphate (ATP), 27 Adhesion molecules cell-mediated immunity and, 99-100 definition of, 248 Adjuvants, 45-46, 101, 248 Adoptive transfer, 248 Affinity antigen recognition and, 76 See also Antigens definition of, 248 maturation definition of, 21, 76, 145, 248 humoral immunity and, 132, 132f, 145-146, 146f Agammaglobulinemia, X-linked, 227-229, 281 AICD See Activation-induced cell death (AICD) AID See Activation-induced deaminase (AID) AIDS See Acquired immunodeficiency syndrome (AIDS) AIREs See Autoimmune regulators (AIREs) Alleles definition of, 248 exclusion, 88, 248 Allergens, 248 Allergies, 249 Alloantibodies, 249 See also Antibodies Alloantigens, 249 See also Antigens Alloantiserum, 249 See also Antiserum Allogenic grafts, 196, 249 See also Grafts Allografts See Allogenic grafts Alloreactivity, 249 See also Reactivity ALPS See Autoimmune lymphoproliferative syndrome (ALPS) Alternative macrophage activation, 33, 125, 249, 267 Alternative pathways, 36-38, 37f, 249 See also Complement activation Amines, biogenic, 251 Anaphylactic shock, 249 Anaphylatoxins, 249 Anaphylaxis, 249 Anchor residues, 249 307 308 Index Anergy clonal, 253 definition of, 175-177, 249 Antibodies See also Immunoglobulins (Igs) affinity of, 133-135, 134f alloantibodies, 249 antibody-dependent cellular cytotoxicity (ADCC), 35, 249 antibody-secreting cells, 249-250 autoantibodies, 250 definition of, 72, 249 downregulation of, 249 effector mechanisms of, 151 features of, 77f feedback of, 249 maternal, 166-167 monoclonal, 76-78, 79f, 269 natural, 269-270 properties of, 72, 73f repertoire of, 249 Antibody-dependent cellular cytotoxicity (ADCC), 35, 249 Antigen-presenting cells (APCs) definition of, 250, functions of, 13, 50-51 professional, 273 Antigens, ABO blood group, 202-203, 203f, 247 in adaptive immunity, 71-91 See also Adaptive immunity affinity and, 76 alloantigens, 249 antigen A, 250 antigen-presenting cells (APCs) See Antigen-presenting cells (APCs) blood group ABO, 202-203, 203f, 247 Rh, 275 capture of, 49-69 clustering, antigen-induced, 135 definition of, 250 endocytose protein, 137 nonprotein, 133 oncofetal, 270-271 presentation of, 49-69 definition of, 250 direct, 256 Antigens (Continued) processing of, 250 purified, vaccines, 274 See also Vaccines recognition of, 71-91 self, 177-178, 180 superantigens, 99, 277 T-dependent, 278 T-independent, 278-279 tolerogenic, 279 transplant immune responses and, 196-198 See also Transplant immune responses transporter-associated antigen processing (TAP), 280 tumor, 190-191, 191f, 280 See also Tumor immune responses xenoantigens, 281 Antiretroviral therapy (ART), 239, 250 Antiserum alloantiserum, 249 definition of, 250 Antiviral states, 44 AP-1 See Activation protein (AP-1) APCs See Antigen-presenting cells (APCs) Apoptosis, 115, 250 APS-1 See Autoimmune polyendocrine syndrome (APS-1) ART See Antiretroviral therapy (ART) Arteriosclerosis, graft, 259 See also Grafts Arthus reaction, 250 Asthma, bronchial, 251 Ataxia-telangiectasia, 233 Atherosclerosis, 27-28 Atopy, 250 ATP See Adenosine triphosphate (ATP) Attenuated microbes, 168-169 Autoantibodies, 250 See also Antibodies Autocrine factor, 250 Autoimmune diseases, 183, 250 Autoimmune lymphoproliferative syndrome (ALPS), 185f Autoimmune polyendocrine syndrome (APS-1), 185f Autoimmune regulators (AIREs), 250 Autoimmunity, 250 Autoinflammatory syndromes, 27-28 Autologous grafts, 250 See also Grafts Autophagy, 250 Autosomal severe combined immunodeficiency (SCID), 227, 227f-228f Avidity antigen recognition and, 76 definition of, 250 B B cells antigen receptors in, 72-80 B cell receptor (BCR) complex, 135 definition of, 251 functions of, 72 B cell-activating factor (BAFF), 283t-286t B-1, 36, 133, 133f, 251 definition of, 251 follicular, 133, 133f marginal-zone, 133, 133f receptors (BCRs), 251 subsets of, 133, 133f BAFF See B cells Bare lymphocyte syndrome, 229-230, 251 Basophils, 251 Bcl-2 family proteins, 251 BCR complex See B cells BCRs See B cells Beta2 (β2)-microglobulin, 268-269 Biogenic amines, 251 Biologic response modifiers, 251 Blot, Western, 281 Bone marrow B lymphocyte maturation/ selection in, 87-88 definition of, 251 transplantation, 251, 260 Bronchial asthma, 251 Bruton tyrosine kinase (BTK), 227-229, 251 Bruton’s agammaglobulinemia, 281 BTK See Bruton tyrosine kinase (BTK) Burkitt’s lymphoma, 251 Burst, respiratory, 275 C C regions See Constant (C) regions C1, 159f-160f, 251 C1 inhibitors (C1 INH), 251-252 C3, 136-137, 252 C3 convertase, 159f-160f, 252 C3 protein, 36-38 C5 convertase, 252 Calcineurin, 103, 252 Calmodulin, 103 Cancer therapies, 194-196, 195f Capture, antigen, 49-69 See also Antigens Cascades definition of, 104-105 enzymatic, 36-38 mitogen-activated protein (MAP)-kinase, 269 Caspases caspase-1, 27-28 definition of, 126, 252 immunological tolerance and, 178-179 Cathelicidins, 29-30, 252 Cathepsins, 252 CCR7, 17, 140 CD molecules, 252 See also Cluster of differentiation (CD) molecules CD40L-mediated signaling, 142 CDRs See Complementaritydetermining regions (CDRs) Cell-mediated immunity (CMI) definition of, 4, 5f, 117, 252 effector mechanisms of, 117-130 cytotoxic T lymphocytes (CTLs), 117-118 macrophages, activation of, 122-124, 123f overviews of, 117, 129-130 pathogenic microbes, resistance of, 127-129, 128f reaction types, 117-118, 118f T lymphocytes, migration of, 118-121, 120f-121f immune responses of, 93-116 adhesion molecules and, 99-100 antigens, costimulation of, 97-102, 100f antigens, recognition of, 97-102 clonal expansion, 107-108, 108f Index Cell-mediated immunity (CMI) (Continued) decline of, 115 effector cells, 108-114, 109f functional, 105-115 signal transduction, 104f T cells, differentiation of, 108-114 T cells, response phases of, 94-97, 94f-96f Central tolerance, 252 See also Tolerance CGD See Chronic granulomatous disease (CGD) Chains class II-associated invariant chain peptides (CLIPs), 253 heavy-chain class switching, 21, 76, 132, 152-154 invariant (Ii), 265 joining (J), 265 light, surrogate, 87-88, 277 polypeptide, 74 zeta (ζ), 97-99, 282 Chédiak-Higashi syndrome, 232, 232f, 252 Chemoattractants, 41 Chemokine receptors, 15-16, 252 Chemokines, 15-16, 41, 252 Chemotaxis, 252 Chemotherapy effects, 233f Chronic graft rejection, 201 See also Grafts Chronic granulomatous disease (CGD), 44, 230-231, 232f, 252-253 Chronic rejection, 199-201, 200f201f, 253 See also Rejection c-Jun amino (N)-terminal kinase (JNK), 104-105 c-Kit ligand, 253 Class II-associated invariant chain peptides (CLIPs), 253 Class switching, 76, 142-145, 143f, 152-154 Classical macrophage activation, 33, 125, 253, 267 Classical pathways, 36-38, 37f, 253 See also Complement activation Cleft, peptide-binding, 271 CLIPs See Class II-associated invariant chain peptides (CLIPs) Clonal anergy, 253 See also Anergy 309 Clonal deletion, 253 Clonal distribution, 71-72 Clonal expansion, 96, 132, 253 Clonal ignorance, 253 Clonal selection hypothesis, 253 Clones, 72, 253 Cluster of differentiation (CD) molecules, 287-294 CD1, 36, 287t-294t CD3, 73f, 287t-294t CD4, 25, 287t-294t CD5, 287t-294t CD8, 25, 287t-294t CD16, 35, 156f, 287t-294t CD18, 232f, 287t-294t CD19, 137f, 287t-294t CD20, 194, 216-218, 287t-294t CD21, 136-137, 287t-294t CD25, 177-178, 185f, 287t-294t CD28, 98f-99f, 100-101, 287t-294t CD32, 156f, 287t-294t CD35, 161, 164f-165f, 287t-294t CD40, 55f, 101, 287t-294t CD46, 164f-165f, 287t-294t CD59, 164f-165f, 287t-294t CD62L (L-selectin), 119, 287t-294t CD64, 156f, 287t-294t CD69, 103f, 287t-294t CD80, 100-101, 287t-294t CD81, 137f, 287t-294t CD86, 100-101, 287t-294t CD94, 35-36, 287t-294t CD95, 126, 178, 287t-294t CD152, 175-176, 287t-294t CD154, 101, 122-124, 287t-294t complete listing of, 287-294 definition of, 252 features of, 287-294 lymphocyte function-associated antigen-2 (LFA-2), 287t-294t overviews of, 287-294 Clustering, antigen-induced, 135 CMI See Cell-mediated immunity (CMI) Collectins, 38, 253 Colony-stimulating factors (CSFs) definition of, 253-254 innate immunity and, 31 Combinatorial diversity (D), 83-84, 253-254 See also Diversity (D) Common variable immunodeficiency (CVID), 229 310 Index Complement, 158, 254 Complement activation, 158-161 See also Complement system definition of, 158 pathways of, 158-161 alternative, 36-38, 37f, 158-160, 249 classical, 36-38, 37f, 161, 253 comparisons of, 158, 159f-160f definition of, 249 lectin, 36-38, 37f, 161 regulation of, 163-164 Complement receptors (CRs) definition of, 254 type (CR1), 254 type (CR2), 254 Complement system, 136-137 activation pathways, 158-161 See also Complement activation alternative, 36-38, 37f, 158-160 classical, 36-38, 37f, 161, 253 comparisons of, 158, 159f-160f lectin, 36-38, 37f, 161 regulation of, 163-164 results of, 161 adaptive immunity and, 158, 159f-160f See also Adaptive immunity definition of, 158 functions of, 161-162, 162f-163f pathways, 158-161 Complementarity-determining regions (CDRs), 72, 254, 261 Congenic mouse strains, 254 See also Mouse strains Congenital immunodeficiency causes of, 226 definition of, 254, 262, 273 innate immunity defects, 230-233, 232f lymphocytes See also Lymphocytes abnormalities of, 233 activation defects of, 229-230, 230f-231f function defects of, 229-230 maturation defects of, 226-229, 227f Conjugate vaccines, 141, 254 See also Vaccines Constant (C) regions antigen recognition and, 72, 78 definition of, 254 gene segments of, 251 Contact sensitivity, 254 Controllers, elite, 239 Coreceptors, 254 Costimulation, 280 Costimulators, 46, 100-101, 254-255 CpG nucleotides, 255 C-reactive proteins (CRPs), 38, 252 Crohn’s disease, 185f Cross-linking, receptor, 135, 136f Crossmatching, 255 Cross-presentation, 65-66, 255 Cross-priming, 255 Cross-reactions, 76 CRPs See C-reactive proteins (CRPs) CRs See Complement receptors (CRs) CSFs See Colony-stimulating factors (CSFs) CTLs See Cytotoxic/cytolytic T lymphocytes (CTLs) C-type lectin, 255 Cutaneous immune system, 15, 255 CVID See Common variable immunodeficiency (CVID) CXCR5, 15-17, 140 Cyclosporine, 255 Cytidine, 247 Cytokines abbreviations for, 283t-286t definition of, 255 interleukin-1 (IL-1) family, 283t-286t major, 283-286 overviews of, 283-286 transforming growth factor-β (TGF-β), 283t-286t tumor necrosis factor superfamily (TNFSF), 283t-286t type family, 283t-286t type family, 283t-286t Cytomegalovirus, 128f Cytotoxic/cytolytic T lymphocytes (CTLs), 190-191, 192f, 255 D D See Diversity (D) DAG See Diacylglycerol (DAG) Damage-associated molecular patterns (DAMPs), 25-26, 27f, 41, 255 Damaged cells, 25 DAMPs See Damage-associated molecular patterns (DAMPs) DCs See Dendritic cells (DCs) Dectins, 27, 255 Defective immune responses, 225-240 See also Immunodeficiencies Defensins, 29-30, 122, 255 Definitions, 247-282 Delayed-type hypersensitivity (DTH), 124, 255 Dendritic cells (DCs), 255-256 Deoxyribonucleic acid (DNA) vaccines, 256 See also Vaccines Desensitization, 256 Determinants antigen recognition and, 76 definition of, 256-257 Deviation, immune, 262 Diabetes mellitus type 1, 184f-185f, 280-281 definition of, 280-281 type 2, 27-28 Diacylglycerol (DAG), 256 Differentiation, 96 DiGeorge syndrome, 228f, 256 Direct allorecognition, 256 Direct antigen presentation, 256 Direct recognition, 198, 199f Discrimination, self-nonself, 171-187 See also Immunological tolerance Diversity (D) adaptive immunity and, 82-87 in antibodies vs T cell receptors (TCRs), 72, 73f antigen receptor production and, 82-87 combinatorial, 83-84, 254 definition of, 256 junctional, 83-84, 265 mechanisms of, 83-84, 86f segments, 256 DNA vaccines See Deoxyribonucleic acid (DNA) vaccines Domains, 72 Donors, 196 Double-negative T cells, 88-90, 256 Double-negative thymocytes, 256 Double-positive T cells, 88-90, 256 Double-positive thymocytes, 256 Double-stranded ribonucleic acid (dsRNA), 25, 38-40 Downregulation, 249 See also Antibodies Drosophila protein, 26 dsRNA See Double-stranded ribonucleic acid (dsRNA) DTH See Delayed-type hypersensitivity (DTH) E EAE See Experimental autoimmune encephalomyelitis (EAE) EBV See Epstein-Barr virus (EBV) Effector cells, 256 Effector functions, 72, 73f Effector mechanisms of cell-mediated immunity (CMI), 117-130 of humoral immune immunity, 151-170 Effector phase, 256 ELISA See Enzyme-linked immunosorbent assay (ELISA) Elite controllers, 239 Endocytose protein antigens, 137 See also Antigens Endosomes, 26, 27f, 256-257 Endotoxins, 25, 257, 266 Enhancers, 257 Entry portals, 13, 26 Environmental triggers, 182-183 Enzymatic cascades, 36-38 Enzyme-linked immunosorbent assay (ELISA), 257 Eosinophils, 43, 257 Epitopes, 20-21, 76, 78, 257 Epstein-Barr virus (EBV), 128f, 257 ERK See Extracellular signalregulated kinase (ERK) E-selectin, 41, 120f-121f, 287t-294t Exclusion, allelic, 88, 248 Experimental autoimmune encephalomyelitis (EAE), 257 Extracellular signal-regulated kinase (ERK), 104-105 Extrafollicular reactions, 141-142 Index F Fab (fragment, antigen-binding), 74 FACS See Fluorescence-activated cell sorter (FACS) FAS, 185f Fas (CD95) ligand, 126, 184, 257 Fc receptors, 258 FcεR1 receptors, 258 Fcγ receptors (Fcγr), 157, 258 FcγRIIB receptors, 157 FDCs See Follicular dendritic cells (FDCs) Feedback, antibodies, 249 Fetal tissues, maternal tolerance to, 204 Ficolins, 258 First-set rejection, 258 Flagellin, 26 Flow cytometry, 258 Fluorescence-activated cell sorter (FACS), 258 Follicles, 15, 258 Follicular dendritic cells (FDCs), 145, 258 Follicular helper T (TFH) cells, 142, 258 Foreign cell immunity, 189-205 FOXP3, 184, 185f, 258 Fungal glycans, 27 G G protein-coupled receptor family, 259 G proteins, 259 GALT See Gut-associated lymphoid tissue (GALT) GATA-3 cell-mediated immunity and, 112-113 definition of, 259 G-CSF See Granulocyte-colony stimulating factor (G-CSF) GDP See Guanosine diphosphate (GDP) Generative lymphoid organ, 259 Genetically complex autoimmune diseases, 185f Germinal center, 15, 139, 142, 259 Germinal center reactions, 139, 141-142, 259 311 Germline encoding, 25-26 organization, 80f, 259 pattern recognition, encoded, 25-26 Glomerulonephritis, 259 Glossary, 247-282 GM-CSF See Granulocyte monocytecolony stimulating factor (GM-CSF) Gout, 27-28 Grafts allogenic, 196, 249 arteriosclerosis, 259 autologous, 250 definition of, 259 graft-versus-host disease (GVHD), 203-204, 259 rejection of, 259 acute, 201 chronic, 201 hyperacute, 199-201 mechanisms of, 199-201, 200f-201f prevention of, 201-202 treatment of, 201-202, 202f syngeneic, 196, 278 xenografts, 196, 281 Graft-versus-host disease (GVHD), 203-204, 259 See also Grafts Granulocyte monocyte-colony stimulating factor (GM-CSF), 259, 283t-286t Granulocyte-colony stimulating factor (G-CSF), 259, 283t-286t Granulomas, 259 Granzyme, 259 Granzymes, 126 GTP See Guanosine triphosphate (GTP) Guanosine diphosphate (GDP), 104-105 Guanosine triphosphate (GTP), 104-105 Gut-associated lymphoid tissue (GALT), 260 GVHD See Graft-versus-host disease (GVHD) H H-2 molecules, 260 HAART See Highly reactive antiretroviral therapy (HAART) 312 Index Haemophilus influenzae, 141, 254, 274 Haplotypes, 260 Haptens, 141, 260 Heavy-chain class switching, 21, 76, 132, 152-154, 260 Heavy-chain isotype switching, 142-145, 143f Helminths definition of, 260 diseases, 157-158 parasites, 111, 111f Helper T cells, 260 activation of, 139-140 functions of, 138-146, 139f mechanisms of, 141, 141f migration of, 139-140 Hematopoiesis, 260 Hematopoietic stem cells definitions of, 260 transplantation of, 260 Hereditary angioneurotic edema, 164 Herpes simplex virus (HSV), 128f, 232f HEVs See High endothelial venules (HEVs) High endothelial venules (HEVs), 17, 260 High-affinity B cells, 146-148, 147f Highly reactive antiretroviral therapy (HAART), 239, 250 High-mobility group box (HMGB1), 252 Hinge regions, 74, 260, 268 See also Regions Histamines, 260 HIV See Human immunodeficiency virus (HIV) HLAs See Human leukocyte antigens (HLAs) HMGB1 See High-mobility group box (HMGB1) Homeostasis, 21, 115, 260 Homing, lymphocyte, 121, 267 Hosts, 196 HSV See Herpes simplex virus (HSV) Human immunodeficiency virus (HIV), 167-168, 167f, 234, 235f-236f, 247, 260-261 Human leukocyte antigens (HLAs) definition of, 55, 196-197, 261 HLA-DM peptide exchange molecule, 260 Human leukocyte antigens (HLAs) (Continued) transplantation and, 196-197 typing of, 279 Humanized antibodies, 261 Humoral immunity definition of, 131, 151, 261 effector mechanisms of, 151-170 antibody functions, 152-154, 153f-154f, 164-167 antibody-dependent cellular cytotoxicity (ADCC), 157, 157f complement system, 158-164, 159f-160f See also Complement system eosinophil-mediated reactions, 157-158, 158f immunoglobulin-E (IgE) reactions, 0, 157-158, 158f mast cell-mediated reactions, 157-158 microbe evasion, 167-168, 167f microbe neutralization, 154-156, 155f mucosal immunity, 166, 166f neonatal immunity, 166-167 opsonization, antibodymediated, 156f, 157 overviews of, 151 phagocytosis, 156f, 157 secretory immunity, 166 toxin neutralization, 154-156, 155f vaccines and, 168-169 See also Vaccines immune responses of, 131-150 affinity maturation, 145-146, 146f antibody responses, 146-148 antigens, presentation of, 140-141, 140f antigens, recognition of, 132-135, 132f B lymphocyte activation, 132-138, 132f feedback, antibody, 148-149, 149f heavy-chain isotype switching, 142-145, 143f-144f Humoral immunity (Continued) helper T lymphocytes, activation of, 139-140 helper T lymphocytes, functions of, 138-146, 139f helper T lymphocytes, mechanisms of, 141, 141f helper T lymphocytes, migration of, 139-140 overviews of, 131-132, 149-150 phases of, 132-135, 132f primary, 133-135, 134f regulation of, 148-149 reviews of, 150 secondary, 133-135, 134f signaling, antigen-induced, 135, 136f T-independent antigens, 146-148 types of, 132-135 Hybridomas, 76, 79f, 261 Hyperacute rejection, 199-201, 200f-201f, 261 Hypersensitivity, 207-223 autoimmune diseases and, 207 autoimmunity and, 207 definition of, 207 delayed-type (DTH), 255 features of, 207 reaction types classification of, 207-209, 208f definition of, 207 type (immediate hypersensitivity), 209-215 definition of, 208f, 209 event sequences of, 209, 210f-211f IgE antibodies, activation of, 209-211 TH2 cells, activation of, 209-211 Hypersensitivity diseases, 261 Hypervariable loops, 261 Hypervariable regions, 72, 261 I IBD See Inflammatory bowel disease (IBD) ICAM-1 See Intercellular adhesion molecule (ICAM-1) IFNs See Interferons (IFNs) IFRs See Interferon regulatory factors (IFRs) Ignorance, clonal, 253 Igs See Immunoglobulins (Igs) ILs See Interleukins (ILs) Immature B lymphocytes, 88, 261 Immediate hypersensitivity, 261 Immune complex, 262 Immune complex disease, 262 Immune deviation, 262 Immune inflammation, 262 Immune repertoire development, 80-90, 81f Immune response antigen capture/presentation, 49-69 antigen recognition, 71-91 cell-mediated immunity (CMI) effector mechanisms of, 117-130 immune responses of, 93-116 cluster of differentiation (CD) molecules, 287-294 cytokines, major, 283-286 defective, 225-240 humoral immune immunity effector mechanisms of, 151-170 immune responses of, 131-150 hypersensitivity, 207-223 immune system, 1-22 immunodeficiencies, acquired vs congenital, 225-240 immunological tolerance, 171-187 innate immunity, 23-48 nomenclature, 247-282 tumor/transplant immune responses, 189-205 Immune response (Ir) genes, 262 Immune surveillance, 190, 262 Immune system, 1-22 adaptive immunity See also Adaptive immunity properties of, 5-7, 6f types of, 4-5, 5f cells of, 7-13 antigen-presenting cells (APCs), 9f, 13 comparisons of, 7-8, 9f effector cells, 9f, 13 lymphocytes, 8-13, 9f-12f Index Immune system (Continued) definition of, 1, 262 fundamentals of, 1-3, 21-22 immune responses, 18-21 adaptive immune response, 19-21, 20f antigen capture, 19 antigen display, 19 cell-mediated immunity, 19-20 comparisons of, 1, 18 costimulators, 19 decline of, 21 early innate response, 18-19 humoral immunity, 20-21 immunologic memory and, 21 major histocompatibility complex (MHC) molecules and, 19 immunity and, immunology and, importance of, 1-2, 2f innate immunity and, 3-4, 3f See also Innate immunity physiologic functions of, tissues of, 13-18 comparisons of, 13 cutaneous immune system, 15 lymph, 14 lymph nodes, 14, 14f lymphocyte recirculation/ migration and, 17-18, 18f mucosal immune system, 15, 16f peripheral lymphoid organs, 13-16 spleen, 14-15, 15f vaccine effectiveness and, 1-2, 2f See also Vaccines Immune-mediated inflammatory disease, 262 Immunity, 262 Immunoblots, 262 Immunodeficiencies acquired vs congenital, 225-240 definition of, 262 diseases, 225, 226f Immunodominant epitopes, 78, 262 Immunofluorescence, 262 Immunogens, 262-263 Immunoglobulins (Igs) See also Antibodies A (IgA), 77f chains See also Chains 313 Immunoglobulins (Igs) (Continued) heavy, 263 light, 263 D (IgD), 73f, 74-78, 75f, 77f, 132 definition of, 72, 263 domains of, 74, 263 E (IgE), 77f expression of, 83-84, 85f, 87f features of, 77f G (IgG), 77f M (IgM), 73f, 74-78, 75f, 77f, 132 recombination of, 83-84, 85f superfamily, 74, 263 Immunohistochemistry, 263 Immunologic memory, 25, 263 Immunologic synapse, 102 Immunological tolerance, 171-187 autoimmunity and, 171, 182-186 definition of, 171, 182 environmental influences, 184-186 genetic factors, 183-184 mechanisms of, 182-183, 182f pathogenesis, 182-183 B lymphocyte, 179-181 central B cells, 180, 181f peripheral, 181, 181f central lymphocyte, 172-174, 173f-174f definition of, 171-172, 263 mechanisms of, 172 overviews of, 171, 186-187 peripheral T lymphocyte, 172, 173f, 174-179 anergy, 175-177, 176f antigen recognition, 174-175 apoptosis, 178-179, 179f definition of, 174 deletion, 178-179 immune suppression, 177-178 significance of, 172 Immunologically privileged sites, 263 Immunology fundamentals antigen capture/presentation, 49-69 antigen recognition, 71-91 cell-mediated immunity (CMI) effector mechanisms of, 117-130 immune responses of, 93-116 314 Index Immunology fundamentals (Continued) cluster of differentiation (CD) molecules, 287-294 cytokines, major, 283-286 humoral immune immunity effector mechanisms of, 151-170 immune responses of, 131-150 hypersensitivity, 207-223 immune system, 1-22 immunodeficiencies, acquired vs congenital, 225-240 immunological tolerance, 171-187 innate immunity, 23-48 nomenclature, 247-282 tumor/transplant immune responses, 189-205 Immunoperoxidase technique, 263 Immunoprecipitation, 263 Immunoreceptor tyrosine-based activation motifs (ITAMs), 35-36, 102, 135, 263 Immunoreceptor tyrosine-based inhibition motifs (ITIMs), 263 Immunosuppression, 264 Immunotherapy, 264 Inbred mouse strains, 264 See also Mouse strains Indirect antigen presentation, 264 Indirect recognition, 198, 199f Inducible nitric oxide synthase (iNOS), 43-44, 264 Inflammasomes, 27-28, 264 Inflammation, 124, 264 Inflammatory bowel disease (IBD), 264 Inherited factors, 183-184 Innate immunity, 23-48 vs adaptive immunity, 23-25 See also Adaptive immunity cellular receptors for, 26-29, 27f dectins, 29 mannose receptors, 29 NOD-like receptors (NLRs), 27-29 toll-like receptors (TLRs), 26-27, 28f-29f components of, 25, 29-40 complement system, 36-38, 37f cytokines, 38-40, 38f-39f dendritic cells, 34 epithelial barriers, 29-30, 31f Innate immunity (Continued) lymphocytes, 36 macrophages, 31-34, 31f-33f mast cells, 34 monocytes, 31-34, 31f natural killer (NK) cells, 34-36, 34f-35f neutrophils, 31-34, 31f phagocytes, 31-34, 32f plasma proteins, 38 definition of, 23, 264 features of, 24-26, 24f fundamentals of, 0, 23-24, 47 microbial evasion of, 44-45, 46f reactions of, 40-44 antiviral defense, 24-25, 44 immune response regulation, 44, 45f inflammation, 24-25, 41-44, 41f microbial destruction, 43-44, 43f phagocytosis, 43-44, 43f recruitment, 41-43, 42f specificity of, 24-26, 24f iNOS See Inducible nitric oxide synthase (iNOS) Inositol 1,4,5-triphosphate (IP-3), 264 Integrins, 41-42, 99, 264 Intercellular adhesion molecule (ICAM-1), 99 Interferon regulatory factors (IFRs), 26-27, 264-265 Interferons (IFNs), 24-25 See also Cytokines definition of, 265 interferon-α (IFN-α), 38f-39f, 44, 283t-286t interferon-β (IFN-β), 38f-39f, 44, 283t-286t interferon-γ (IFN-γ), 32f, 33-35, 38f-39f, 106f, 110-111, 122-124, Interleukins (ILs) definition of, 265 interleukin-1 (IL-1), 38f-39f, 40, 114, 123f interleukin-1β (IL-1β), 27-28, 30f, 283t-286t interleukin-2 (IL-2), 96f, 103, 105-107, 177-178, 283t-286t interleukin-4 (IL-4), 33, 33f, 106f, 111, 125, 283t-286t interleukin-5 (IL-5), 106f, 125, 158f, 283t-286t Interleukins (ILs) (Continued) interleukin-6 (IL-6), 38f-39f, 46, 53f, 114, 283t-286t interleukin-7 (IL-7), 81, 88-90, 283t-286t interleukin-10 (IL-10), 44, 111 interleukin-12 (IL-12), 34-35, 34f, 38f-39f, 113, 123f, 283t-286t interleukin-13 (IL-13), 33, 33f, 111, 125, 211, 283t-286t interleukin-15 (IL-15), 34-35, 38f-39f, 283t-286t interleukin-17 (IL-17), 106f, 110-112, 283t-286t interleukin-18 (IL-18), 38f-39f, 44 interleukin-21 (IL-21), 142, 283t-286t interleukin-22 (IL-22), 111-112, 113f, 283t-286t interleukin-23 (IL-23), 114, 283t-286t interleukin-27B (IL-27B), 283t-286t Intraepithelial lymphocytes definition of, 265 T lymphocytes, 29-30, 265 Intravenous immune globulin (IVIG), 157 Invariant chain (Ii), 265 IP-3 See Inositol 1,4,5-triphosphate (IP-3) IPEX See X-linked disorders Ir genes See Immune response (Ir) genes Irradiation effects, 233f Isotypes definition of, 265 switching, 21, 76, 142-145, 143f, 152-154, 260 ITAMs See Immunoreceptor tyrosine-based activation motifs (ITAMs) ITIMs See Immunoreceptor tyrosinebased inhibition motifs (ITIMs) IVIG See Intravenous immune globulin (IVIG) J J See Joining (J) JAK-STAT signaling pathways See Janus kinase-signal transducers/ activators of transcription (JAK-STAT) signaling pathways Janus kinase-signal transducers/ activators of transcription (JAK-STAT) signaling pathways, 265 Joining (J) chains, 265 definition of, 82-87 segments, 82-83, 86f, 265 Junctional diversity (D), 83-84, 265 See also Diversity (D) K Kaposi’s sarcoma, 265 Killer immunoglobulin-like receptors (KIRs), 35-36, 265-266 KIRs See Killer immunoglobulin-like receptors (KIRs) Knockout mice, 266 See also Mouse strains L LADs See Leukocyte adhesion deficiencies (LADs) LAK cells See Lymphokine-activated killer (LAK) cells Lamina propria, 166, 266 Langerhans cells, 266 Large granular lymphocytes, 266 Late-phase reactions, 266 Lck, 102, 266 Lectin, 26-27 Lectin pathway, 36-38, 37f, 266 See also Complement activation Legionella pneumophila, 127-129 Leishmania, 266 Leishmania major, 125 Leukemia, 266 Leukocyte adhesion deficiencies (LADs), 42, 230-231, 232f, 266 Leukocyte function-associated antigen (LFA-1), 99-100 Leukotrienes, 266 LFA-1 See Leukocyte functionassociated antigen (LFA-1) Lipopolysaccharide (LPS), 25, 266 See also Endotoxins Listeria monocytogenes, 44, 121, 122f, 127-129 Live virus vaccines, 266-267 See also Vaccines Long-term nonprogressors, 239 LPS See Lipopolysaccharide (LPS) L-selectin, 287t-294t Index LTs See Lymphotoxins (LTs) Lupus See Systemic lupus erythematosus (SLE) Lymph, 267 Lymph nodes, 120f-121f, 267 Lymphatic system, 267 Lymphocytes abnormalities of, 233 activation defects of, 229-230, 230f-231f antigen capture and, 49-69 antigen recognition, 50-51, 50f overviews of, 49-50, 68-69 B See B cells cluster of differentiation (CD) molecules See Cluster of differentiation (CD) molecules definition of, 267 function defects of, 229-230 homing, 267 innate immunity and, 36 See also Innate immunity intraepithelial, 29-30, 265 large granular, 266 maturation, 267 maturation defects of, 226-229, 227f migration, 267 recirculation, 267 repertoire, 267 Lymphoid follicles, 258, 267 Lymphoid tissue inducer cells, 267 Lymphokine-activated killer (LAK) cells, 267 Lymphokines, 267 Lymphomas, 267 Lymphotoxin-α (LTα), 283t-286t Lymphotoxin-αβ (LTαβ), 283t-286t Lymphotoxins (LTs), 267 Lysomal proteases, 43-44 Lysomes, 267 M M cells, 267 M1 macrophages, 267 M2 macrophages, 267 MAC See Membrane attack complex (MAC) Macrophage activation alternative, 125 classical, 125, 253 definition of, 267-268 315 Major cytokines, 283-286 abbreviations for, 283t-286t definition of, 255 interleukin-1 (IL-1) family, 283t-286t overviews of, 283-286 transforming growth factor-β (TGF-β), 283t-286t tumor necrosis factor superfamily (TNFSF), 283t-286t type family, 283t-286t type family, 283t-286t Major histocompatibility complex (MHC) antigen recognition and, 50-51, 50f definition of, 268 molecules class I, 253 class II, 252 definition of, 268 restriction, 268 tetramer, 268 MALT See Mucosa-associated lymphoid tissue (MALT) Mammalian target of rapamycin (mTOR), 105 Mannose receptors, 27, 268 terminal residues, 25 Mannose-binding lectin (MBL), 38, 268 MAP-kinase cascades See Mitogenactivated protein (MAP)-kinase cascades Marginal zones B cells, 36, 268 definition of, 268 Marrow See Bone marrow Mast cells, 268 Master transcription factors, 112-113 Maternal antibodies, 166-167 See also Antibodies Mature B cells, 88, 268 MBL See Mannose-binding lectin (MBL) M-CSF See Monocyte-colony stimulating factor (M-CSF) Mechanisms, effector of cell-mediated immunity (CMI), 117-130 of humoral immune immunity, 151-170 316 Index Membrane attack complex (MAC) definition of, 268 humoral immunity and, 161 Membrane proteins, 164f-165f, 166 See also Proteins Membrane-bound antigen receptors, 72-74 Memory, 268 Memory cells, 18 See also Memory lymphocytes B cells, 131, 132f, 146 definition of, 268 humoral immunity and, 152 T cells, 96 Memory lymphocytes, 268 MHC See Major histocompatibility complex (MHC) Microglobulin β2, 268-269 Mitogen-activated protein (MAP)kinase cascades, 104-105, 269 Mixed leukocyte reactions (MLRs), 269 MLRs See Mixed leukocyte reactions (MLRs) Molecular mimicry, 184-185, 269 Molecular patterns damage-associated (DAMPs), 255 pathogen-associated (PAMPs), 25-26, 27f, 41, 271 Monoclonal antibodies, 76-78, 79f, 269 See also Antibodies Monocyte-colony stimulating factor (M-CSF), 269, 283t-286t Monocytes, 269 Mononuclear phagocyte system, 31, 32f Mononuclear phagocytes, 269 Mouse strains congenic, 254 inbred, 264 knockout, 266 nude, 270 T cell receptor (TCR) transgenic, 278 transgenic, 279-280 MS See Multiple sclerosis (MS) mTOR See Mammalian target of rapamycin (mTOR) Mucosa-associated lymphoid tissue (MALT), 269 Mucosal immune system, 15, 269 Multiple myeloma, 269 Multiple sclerosis (MS), 185f Multivalency, 269, 272 See also Polyvalency Mycobacterium spp., 128f, 269 M leprosy, 125 M tuberculosis, 127-129, 259, 269 N N nucleotides, 269 Naive lymphocytes B, 45-46, 132 definition of, 269 T, 45-46 Native immunity, 3-4, 23 See also Innate immunity Natural antibodies, 36, 269-270 See also Antibodies Natural immunity, 3-4, 23 See also Innate immunity Natural killer (NK) cells, 36 definition of, 270 humoral immunity and, 157, 157f Natural killer T cells (NK-T cells), 78, 270 Negative selection, 172-173 definition of, 270 immunological tolerance and, 180 Neisseria meningitidis, 46f Neonatal Fc receptors (FcRns), 142, 154, 154f, 270 Neonatal immunity, 270 Neutrophils, 270 NFAT cells See Nuclear factor of activated T (NFAT) cells NF-κB family See Nuclear factor κB (NF-κB) family N-Formylmethionine, 258 Nitric oxide (NO), 43-44, 270 Nitric oxide synthase (NOS), 264 NK cells See Natural killer (NK) cells NK-T cells See Natural killer T cells (NK-T cells) NLRPs See Prototypic NOD-like receptors (NLRPs) NLRs See NOD-like receptors (NLRs) NO See Nitric oxide (NO) NOD See Nucleotide oligomerization domain (NOD) NOD-like receptors (NLRs), 270 Nomenclature, 247-282 Noninfectious cell immunity, 189-205 Nonprotein antigens, 133 See also Antigens NOS See Nitric oxide synthase (NOS) Nuclear factor κB (NF-κB) family, 26-27, 105, 270 Nuclear factor of activated T (NFAT) cells, 103, 270 Nucleotide oligomerization domain (NOD), 27 Nude mice, 270 See also Mouse strains O Oncofetal antigens, 270-271 See also Antigens Opsonins, 157, 271 Opsonization, 38, 156f, 157, 271 Oral tolerance, 271 See also Tolerance P P nucleotides, 271 PALS See Periarteriolar lymphoid sheath (PALS) PAMPs See Pathogen-associated molecular patterns (PAMPs) Paracrine factor, 271 Parafollicular areas, 139-140 Paroxysmal nocturnal hemoglobinuria, 164 Passive immunity, 271 Pathogen-associated molecular patterns (PAMPs), 25-26, 27f, 41, 271 Pathogenicity, 271 Pattern recognition receptors, 25 cell-mediated immunity and, 101 definition of, 271 PCRs See Polymerase chain reactions (PCRs) Pentraxins, 271 Peptides exchange molecules, 260 peptide-binding cleft, 271 Peptidoglycan receptors, 25 Perforin, 126, 271 Periarteriolar lymphoid sheath (PALS), 271 Peripheral lymphoid organs/tissues, 139-140, 140f, 271 Peripheral tolerance, 271 See also Tolerance Peyer’s patches, 271-272 PHA See Phytohemagglutinin (PHA) Phagocyte oxidase, 43-44 Phagocytosis, 272 Phagolysomes, 43-44 Phagosomes, 43-44, 122-124, 157, 272 Phosphatase, 272 Phosphatidylinositol-3 (PI-3) kinase, 105 Phospholipase Cγ (PLCγ) definition of, 272 Phospholipid sphingosine 1-phosphate (SIP), 119 Phosphorylation, 72 Phytohemagglutinin (PHA), 99 cell-mediated immunity and, 99 definition of, 272 PI-3 kinase See Phosphatidylinositol-3 (PI-3) kinase PKC See Protein kinase C (PKC) Plasma cells, 152 definition of, 272 differentiation of, 132 Plasma proteins, 164f-165f, 166 See also Proteins Plasmablasts, 146, 272 Plasmacytoid dendritic cells, 44 PLCγ See Phospholipase Cγ (PLCγ) PMN leukocytes See Polymorphonuclear (PMN) leukocytes Polyclonal activators, 272 Poly-immunoglobulin (Ig) receptors, 166, 272 Polymerase chain reactions (PCRs), 272 Polymorphisms, 183-184, 272 Polymorphonuclear (PMN) leukocytes, 31, 272 See also Neutrophils Polypeptide chains, 74 Polyvalency, 269, 272 Positive selection, 272 Poxvirus, 128f Pre-B cell receptor (pre-BCR) complex, 87-88 Pre-B cell receptors (Pre-BCRs), 273 Pre-B cells, 87-88, 87f, 272-273 Pre-T cell receptors, 273 Index Pre-T cells, 88-90, 273 Pre-Tα, 273 Primary immune response, 273 Primary immunodeficiency, 225-240, 254, 273 See also Congenital immunodeficiency Pro-B cells, 87-88, 87f, 273 Professional antigen-presenting cells (APCs), 273 Programmed cell death, 273 Promoters, 273 Prostaglandins, 273 Pro-T cells, 88-90, 273 Proteasomes, 273 Protein kinase C (PKC), 105, 273-274 Protein tyrosine kinases (PTKs), 274 Proteins activation protein (AP-1), 104-105, 247 adaptor, 248 antigens, 133 Bcl-2 family, 251 C-reactive (CRPs), 38, 252 Drosophila, 26 endocytose protein antigens, 137 membrane, 164f-165f, 166 phosphatase, 272 plasma, 164f-165f, 166 protein-calorie malnutrition, 233f secreted, 72-74 Prototypic NOD-like receptors (NLRPs), 27-29 Protozoa, 274 Provirus, 274 P-selectin, 41, 120f-121f, 287t-294t Pseudomonas, 46f PTKs See Protein tyrosine kinases (PTKs) Purified antigen vaccines, 274 Pyogenic bacteria, 274 R RA See Rheumatoid arthritis (RA) Rac, 274 Radioimmunoassay, 274 RAGs See Recombinase-activating genes (RAGs) Rapamycin, 274 Ras, 274 Ras/Rac-MAP kinase pathways, 104-105 317 Reactions Arthus, 250 cross-reactions, 76 extrafollicular, 141-142 hypersensitivity, 207 late-phase, 266 mixed leukocyte (MLRs), 269 polymerase chain (PCRs), 272 Shwartzman, 276 Reactive oxygen species (ROS), 43-44, 274 Reactivity alloreactivity, 249 xenoreactivity, 281 Reagins, 274 Receptors chemokine, 15-16, 252 complement (CRs) definition of, 254 type (CR1), 254 type (CR2), 254 cross-linking of, 135, 136f editing of, 88 definition of, 274-275 immunological tolerance and, 180 Fc, 258 FcεR1, 258 Fcγr, 157, 258 killer immunoglobulin-like (KIRs), 265-266 mannose, 268 NOD-like (NLRs), 270 poly-Ig, 272 poly-immunoglobulin (Ig), 166, 272 pre-B cell (Pre-BCRs), 273 pre-T cell, 273 receptor-associated signaling molecules, 135, 136f RIG-like (RLRs), 275 scavenger, 275 Recipients, 196 Recognition, direct vs indirect, 198, 199f Recombinase-activating genes (RAGs) definition of, 275 RAG-1, 83-84, 275 RAG-2, 83-84, 275 Recombination signal sequences, 275 318 Index Recurrent pyogenic bacterial infections, 232f Red pulp, 275 Regions, 72 complementarity-determining regions (CDRs), 72 constant (C), 72, 78 definitions of, 72 hinge, 74, 260, 268 hypervariable, 72 switch, 142-143, 143f, 277-278 variable (V), 72, 78, 281 Regulatory T cells, 275 Rejection acute, 247 chronic, 199-201, 200f-201f, 253 first-set, 258 grafts, 259 See also Grafts mechanisms, 192-193, 192f second-set, 275 Repertoire, antibodies, 249 Residues anchor, 249 terminal mannose, 25 Respiratory burst, 275 Response, immune antigen capture/presentation, 49-69 antigen recognition, 71-91 cell-mediated immunity (CMI) effector mechanisms of, 117-130 immune responses of, 93-116 cluster of differentiation (CD) molecules, 287-294 cytokines, major, 283-286 humoral immune immunity effector mechanisms of, 151-170 immune responses of, 131-150 hypersensitivity, 207-223 immune system, 1-22 immunodeficiencies, acquired vs congenital, 225-240 immunological tolerance, 171-187 innate immunity, 23-48 nomenclature, 247-282 tumor/transplant immune responses, 189-205 Retinoid-related orphan receptor γ T (RORγT), 112-113, 275 Reverse transcriptase, 275 Rh blood group antigens, 275 See also Antigens Rheumatoid arthritis (RA), 185f, 275 RIG-like receptors (RLRs), 27, 275 RLRs See RIG-like receptors (RLRs) Rolling, leukocytes, 41 RORγT See Retinoid-related orphan receptor γ T (RORγT) ROS See Reactive oxygen species (ROS) S SAA See Serum amyloid A (SAA) Scavenger receptors, 275 SCID See Severe combined immunodeficiency (SCID) SCID mice See Severe combined immunodeficiency (SCID) mice Second signals, 45-47, 68 Secondary immune response, 276 Secondary immunodeficiency, 233-234, 247, 276 See also Acquired immunodeficiency Second-set rejection, 275 Secreted proteins, 72-74 See also Proteins Secretory component, 276 Selectins, 41, 276 E-selectin, 287t-294t L-selectin, 287t-294t P-selectin, 287t-294t Selective immunoglobulin (Ig) deficiency, 276 Self antigens, 177-178, 180 See also Antigens Self MHC (major histocompatibility complex) restriction, 276 Self-nonself discrimination, 171-187 See also Immunological tolerance Self-reactive lymphocytes, 184 Self-tolerance, 276 Sensitivity, contact, 254 Septic shock, 40, 276 Seroconversion, 276 Serology, 276 Serotype, 276 Serum, 276 Serum amyloid A (SAA), 276 Serum sickness, 276 Severe combined immunodeficiency (SCID), 226-229, 227f-228f, 276 Severe combined immunodeficiency (SCID) mice, 275 Shock anaphylactic, 249 septic, 40 toxic shock syndrome, 279 Shwartzman reaction, 276 Signal 1, 280 Signal transducer/activator transcription (STAT), 112-113, 277 Signaling in antibodies vs T cell receptors (TCRs), 72, 73f CD40L-mediated, 142 Janus kinase-signal transducers/ activators of transcription (JAK-STAT) signaling pathways, 265 recombination sequences, 275 Single-positive T cells, 90 Single-positive thymocytes, 277 SIP See Phospholipid sphingosine 1-phosphate (SIP) SLE See Systemic lupus erythematosus (SLE) Smallpox, 277 SOCS See Suppressors of cytokine signaling (SOCS) Somatic hypermutation, 145, 277 Somatic rearrangement, 277 Somatic recombination, 25-26, 83-84, 277 Specificity, 277 Spleen, 233f, 277 Src homology domains, 277 Staphylococcus aureus, 279 STAT See Signal transducer/activator transcription (STAT) Stem cell factors (c-Kit ligand), 253 Stem cells, 277 Subunit vaccines, 274 See also Vaccines Superantigens, 99, 277 Suppressor T cells, 277 Suppressors of cytokine signaling (SOCS), 44 Surrogate light chains, 87-88, 277 Surveillance, immune, 190 Susceptibility genes, 182-183 Switch recombination, 142-145, 143f, 277-278 Switch regions, 142-143, 143f, 277-278 Syk, 278 Syndromes acquired immunodeficiency (AIDS), 234-239 See also Acquired immunodeficiency syndrome (AIDS) autoimmune lymphoproliferative (ALPS), 185f autoimmune polyendocrine (APS-1), 185f autoinflammatory, 27-28 bare lymphocyte, 229-230, 251 Chédiak-Higashi, 232, 232f, 252 DiGeorge, 228f, 256 toxic shock, 279 Wiskott-Aldrich, 233, 281 X-linked hyper-IgM, 142, 229, 281-282 Syngeneic, 278 Syngeneic grafts, 196, 278 See also Grafts Synthetic vaccines, 278 See also Vaccines Systemic lupus erythematosus (SLE), 185f, 278 T T cell receptor (TCR) transgenic mice, 278 See also Mouse strains T cell receptors (TCRs) alpha-beta (αβ), 247 complex, 72 definitions of, 247, 278 properties of, 72, 73f structures of, 80f T follicular helper (TFH) cells, 258, 278 T lymphocytes, 72-80, 278 Tacrolimus, 278 TAP See Transporter-associated antigen processing (TAP) T-bet, 112-113, 278 TCRs See T cell receptors (TCRs) T-dependent antigens, 278 See also Antigens TdT See Terminal deoxyribonucleotidyl transferase (TdT) Terminal deoxyribonucleotidyl transferase (TdT), 83-84 Terminal mannose residues, 25 Terminology, 247-282 Tertiary lymphoid organs, 278 Index TH1 cells, 110-111, 111f, 122-124, 279 TH2 cells, 110-111, 125, 279 TH17 cells, 110-112, 124-125, 279 Thymic epithelial cells, 279 Thymocytes, 279 Thymus, 279 TILs See Tumor-infiltrating lymphocytes (TILs) T-independent antigens, 278-279 See also Antigens Tissue typing, 279 TLRs See Toll-like receptors (TLRs) TNFs See Tumor necrosis factors (TNFs) Tolerance central, 252 definition of, 279 immunological, 171-187 See also Immunological tolerance oral, 271 peripheral, 271 self-tolerance, 276 Tolerogenic antigens, 279 See also Antigens Tolerogens, 279 Toll, 26 Toll-like receptors (TLRs), 137, 279 Toxic shock syndrome, 279 Transcriptase, reverse, 275 Transfer, adoptive, 248 Transformed cell immunity, 189-205 Transfusions definition of, 202-203, 279 reactions of, 279 Transgenic mouse strains, 279-280 See also Mouse strains Transplant immune responses, 189-205 antigens and, 196-198 See also Antigens comparisons of, 196-204, 196f fetal tissues, maternal tolerance to, 204 graft rejection acute, 201 chronic, 201 graft-versus-host disease (GVHD), 203-204 hyperacute, 199-201 mechanisms of, 199-201, 200f-201f 319 Transplant immune responses (Continued) prevention of, 201-202 treatment of, 201-202, 202f induction of, 198-199 major histocompatibility complex (MHC), 196, 197f overviews of, 189 transplantation blood cell, 202-204 hematopoietic stem cell, 202-204 vs tumor responses See Tumor immune responses xenotransplantation, 202 Transplantation, 280 See also Transplant immune responses Transporter-associated antigen processing (TAP), 280 See also Antigens TSTAs See Tumor-specific transplantation antigens (TSTAs) Tumor immune responses, 189-205 antigens, tumor, 190-191, 191f, 280 See also Antigens cancer therapies, 194-196, 195f evasion of, 193-194, 193f evidence of, 190-191, 190f immune surveillance and, 190 overviews of, 189 rejection mechanisms, 192-193, 192f vs transplant responses See Transplant immune responses Tumor immunity, 280 See also Tumor immune responses Tumor necrosis factors (TNFs) superfamily-1 (TNFSF1), 283t-286t superfamily-13B (TNFSF13B), 283t-286t TNF-α, 283t-286t TNF-β, 283t-286t tumor necrosis factor receptor superfamily (TNFRSF), 280 tumor necrosis factor receptorassociated factors (TRAFs), 279 tumor necrosis factor superfamily (TNFSF), 280 tumor necrosis factor-β (TNF-β), 267 Tumor-infiltrating lymphocytes (TILs), 280 320 Index Tumor-specific transplantation antigens (TSTAs), 280 Two-signal hypothesis, 280 Type diabetes mellitus, 184f-185f, 280-281 Type diabetes mellitus, 27-28 U Ubiquitin, 281 Ubiquitination, 281 Unmethylated CpG oligonucleotides, 25-27 Urticaria, 281 V V gene segments, 281 V regions See Variable (V) regions Vaccines, 168-169 for acquired immunodeficiency syndrome (AIDS), 239 antigen, purified, 168f, 274 comparisons of, 168-169, 168f conjugate, 141, 168-169, 168f, 254 definition of, 281 deoxyribonucleic acid (DNA), 168f, 256 development of, 168, 239 effectiveness of, 1-2, 4-5 Vaccines (Continued) humoral immunity and, 168-169 See also Humoral immunity live virus, 168f, 266-267 strategies for, 168-169, 168f subunit, 168-169, 168f, 274 synthetic, 168f, 278 Variable (V) regions, 72, 78, 281 See also Regions Variola virus, 277 VDJ recombinase, 83-84, 281 Virus cytomegalovirus, 128f definition of, 281 Epstein-Barr virus (EBV), 128f, 257 herpes simplex virus (HSV), 128f human immunodeficiency virus (HIV), 167-168, 167f, 234, 235f-236f, 247, 260-261 poxvirus, 128f variola, 277 W Western blot, 281 Wheal and flare reaction, 281 White pulp, 281 Wiskott-Aldrich syndrome, 233, 281 X Xenoantigens, 281 See also Antigens Xenogenic grafts See Xenografts Xenografts, 196, 281 See also Grafts Xenoreactivity, 281 See also Reactivity Xenotransplantation, 202 X-linked disorders agammaglobulinemia, 227-229, 228f, 281 hyper-IgM syndrome, 142, 229, 281-282 polyendocrinopathy and enteropathy (IPEX), 185f severe combined immunodeficiency (SCID), 226-229, 227f-228f Z ZAP-70 See Zeta (ζ)-associated protein of 70kD (ZAP-70) Zeta (ζ)-associated protein of 70kD (ZAP-70), 102-103, 135, 282 Zeta (ζ) chain, 97-99, 282 ... CD4+ and express high levels of CD25, the α chain of the interleukin -2 (IL -2) receptor The development and function of these cells require a transcription factor called FoxP3 Mutations of the. .. consider the consequences of the failure of self-tolerance, namely, the development of autoimmunity The mechanisms of tissue injury in autoimmune diseases and therapeutic strategies for these disorders. .. across the epithelium into the lumen, where it blocks the ability of microbes to invade the epithelium ✹ Neonates acquire IgG antibodies from their mothers through the placenta and from the milk