Immune Response Summary PDF

Chapter 1. Properties and Overview of Immune Responses Protective immunity against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity. Innate immune responses are stimulated by molecular structures shared by groups of microbes and by molecul...

Chapter 1. Properties and Overview of Immune Responses Protective immunity against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity. Innate immune responses are stimulated by molecular structures shared by groups of microbes and by molecules expressed by damaged host cells. Adaptive immunity is specific for different microbial and nonmicrobial antigens and is increased by repeated exposures to antigen (immunologic memory). Many features of adaptive immunity are of fundamental importance for its normal functions. These include specificity for different antigens, a diverse repertoire capable of recognizing a wide variety of antigens, memory of antigen exposure, and the ability to discriminate between foreign antigens and self antigens. Immunity may be acquired by a response to antigens (active immunity) or conferred by transfer of antibodies or effector cells (passive immunity). Lymphocytes are the only cells capable of specifically recognizing antigens and are thus the principal cells of adaptive immunity. The total population of lymphocytes consists of many clones, each with a unique antigen receptor and specificity. The two major subsets of lymphocytes are B cells and T cells, and they differ in their antigen receptors and functions. The adaptive immune response is initiated by the recognition of foreign antigens by specific lymphocytes. Specialized antigen-presenting cells capture microbial antigens and display these antigens for recognition by lymphocytes. Lymphocytes respond by proliferating and by differentiating into effector cells, whose function is to eliminate the antigen, and into memory cells, which show enhanced responses on subsequent encounters with the antigen. The elimination of antigens often requires the participation of various effector cells. Humoral immunity is mediated by antibodies secreted by B lymphocytes and their differentiated progeny, plasma cells, and is the mechanism of defense against extracellular microbes. Antibodies neutralize the infectivity of microbes and promote the elimination of microbes by phagocytes and by activation of the complement system. Cell-mediated immunity is mediated by T lymphocytes and their products, such as cytokines, and is important for defense against intracellular microbes. CD4+ helper T lymphocytes help macrophages to eliminate ingested microbes and help B cells to produce antibodies. CD8+ cytotoxic T lymphocytes kill cells harboring intracellular pathogens, thus eliminating reservoirs of infection. Chapter 2. Cells and Tissues of the Immune System The anatomic organization of the cells and tissues of the immune system is of critical importance for the generation of effective innate and adaptive immune responses. This organization permits the rapid delivery of innate immune cells, including neutrophils and monocytes, to sites of infection and permits a small number of lymphocytes specific for any antigen to locate and respond effectively to that antigen regardless of where in the body the antigen is introduced. The cells that perform the majority of effector functions of innate and adaptive immunity are phagocytes (including neutrophils and macrophages), mast cells, basophils, eosinophils, dendritic cells, innate lymphoid cells (ILCs), and natural killer (NK) cells, and lymphocytes. Many surface molecules are differentially expressed on distinct types and subsets of immune cells, and these are named according to the CD nomenclature. Neutrophils, the most abundant blood leukocyte with a distinctive multilobed segmented nucleus and abundant cytoplasmic lysosomal granules, are rapidly recruited to sites of infection and tissue injury, where they perform phagocytic and microbial killing functions.  Tissue resident–macrophages are sentinel cells that detect microbes and alert the immune system and may perform other specialized functions in different tissues, such as lung, spleen, and liver. Monocytes are circulating phagocytes that are recruited to sites of tissue infection and injury, where they rapidly differentiate into macrophages that ingest and kill microbes and dead host cells and secrete cytokines and chemokines that promote the recruitment of leukocytes from the blood and initiate the repair of damaged tissues. Dendritic cells (DCs) are bone marrow–derived cells with extended cytoplasmic processes that are present in most tissues of the body and function as innate sentinel cells and as antigen-presenting cells (APCs) uniquely capable of activating naive T lymphocytes. There are different subsets of DCs with different functions in innate and adaptive immunity. Innate lymphoid cells (ILCs) are cytokine-producing cells of the innate immune system with a lymphocyte-like morphology. They perform functions similar to those of CD4+ or CD8+ effector T cells. ILCs, which include NK cells, do not express highly diverse, clonally distributed antigen receptors. B and T lymphocytes express highly diverse and specific antigen receptors and are the cells responsible for the specificity and memory of adaptive immune responses. Both B and T lymphocytes arise from a common precursor in the bone marrow. B cell development proceeds in the bone marrow, whereas T cell precursors migrate to and mature in the thymus. After maturing, B and T cells leave the bone marrow or thymus, enter the circulation, and populate peripheral lymphoid organs. Naive B and T cells are mature lymphocytes that have not been previously stimulated by antigen. When they encounter antigen, they proliferate and differentiate into effector lymphocytes that have functions in protective immune responses. Effector B lymphocytes are antibody-secreting plasma cells. Effector T cells include cytokine-secreting CD4+ helper T cells and CD8+ CTLs. Some of the progeny of antigen-activated B and T lymphocytes differentiate into memory cells that survive for long periods in a quiescent state. These memory cells are responsible for the rapid and enhanced responses to subsequent exposures to antigen. The organs of the immune system may be divided into the primary, or generative, lymphoid organs (bone marrow and thymus), where lymphocytes mature, and the secondary, or peripheral, lymphoid organs (lymph nodes, spleen, and the mucosal and cutaneous immune systems), where lymphocytes are activated by antigens. Bone marrow contains the stem cells for all blood cells, including lymphocytes, and is the site of maturation of all of these cell types except T cells, which mature in the thymus. Extracellular fluid (lymph) is constantly drained from tissues through lymphatics into lymph nodes and eventually into the blood. Microbial antigens are carried in soluble form and within DCs in the lymph to lymph nodes, where they are recognized by lymphocytes. Lymph nodes are encapsulated secondary lymphoid organs located throughout the body along lymphatics, where naive B and T cells respond to antigens that are collected by the lymph from peripheral tissues. The spleen is an encapsulated organ in the abdominal cavity where senescent or opsonized blood cells are removed from the circulation, and in which lymphocytes respond to blood borne antigens. Lymph nodes and the white pulp of the spleen are organized into B cell zones (the follicles) and T cell zones. The T cell areas are also the sites of residence of mature DCs, which are APCs specialized for the activation of naive T cells.  Fibroblastic reticular cells (FRCs) are specialized myofibroblasts found in secondary lymphoid organs, which are essential for the structural organization and function of these organs. FRCs produce chemokines and form FRC-conduits, both of which are required for the directed movement of lymphocytes and DCs within the organs, and the separation of B and T cells. Follicular dendritic cells are related to FRCs and are required for B cell follicle structure and function. The development of secondary lymphoid tissues depends on cytokines and lymphoid tissue inducer cells. Chapter 3. Leukocyte Circulation and Migration Into Tissues Leukocyte migration from blood into tissues occurs through postcapillary venules and depends on chemokines and adhesion molecules expressed on the leukocytes and vascular endothelial cells. Selectins are carbohydrate-binding adhesion molecules that mediate low-affinity interaction of leukocytes with endothelial cells, the first step in leukocyte migration from blood into tissues. E-selectin and P-selectin are expressed on activated endothelial cells and bind to selectin ligands on leukocytes, and L-selectin is expressed on leukocytes and binds ligands on endothelial cells. Integrins are a large family of adhesion molecules, some of which mediate tight adhesion of leukocytes with activated endothelium, a critical step in leukocyte migration from blood into tissues. The important leukocyte integrins include LFA-1 and VLA-4, which bind to ICAM-1 and VCAM-1, respectively, on endothelial cells. Chemokines and other signals at sites of infection increase the affinity of integrins on leukocytes, and various cytokines (tumor necrosis factor, interleukin-1) increase the expression of integrin ligands on endothelium. Chemokines are a family of proteins that regulate when and how leukocytes migrate into and within tissues, and they organize the functional locations of lymphocytes and dendritic cells (DCs) in lymphoid organs. Chemokines bind to chemokine receptors on leukocytes, which signal to increase leukocyte integrin affinity and stimulate leukocyte chemokinesis along a concentration gradient of chemokines. Different types of leukocytes and leukocytes at different stages of differentiation express distinct sets of chemokine receptors, and the types of chemokines present in tissues or on endothelial cells varies with different inflammatory states and tissue types. Migration of leukocytes from blood into tissues involves a series of sequential interactions with endothelial cells, starting with low-affinity leukocyte binding to and rolling along the endothelial surface (mediated by selectins and selectin ligands). Next, chemokines displayed on endothelial cells bind to chemokine receptors on the rolling leukocytes, which generates signals that increase the affinity of leukocyte integrins. Then the leukocytes become firmly bound to the endothelium through interactions of the integrins binding to Ig superfamily ligands on the endothelium. Finally, the leukocytes move through cell junctions between endothelial cells into the tissues. Lymphocyte recirculation is the process by which naive lymphocytes continuously migrate from the blood into the secondary lymphoid organs, back into the blood through lymphatics, and into other secondary lymphoid organs. This process maximizes the chance of naive T or B cell encounter with the antigen it recognizes and is critical for the initiation of immune responses. Naive B and T cells migrate preferentially to secondary lymphoid organs. In lymph nodes and Peyer’s patches, this process is mediated by binding of L-selectin on lymphocytes to peripheral lymph node addressin on high endothelial venules in lymph nodes and by binding of the CCR7 receptor on lymphocytes to the chemokines CCL19 and CCL21, which are produced in lymph nodes. There are no HEVs in splenic white pulp, and naive T and B cell migration into the spleen is not well understood. Within the T cell zones of the lymph nodes and spleen, naive T cells constantly move along an FRC network, interacting with DCs bound to the FRCs. If a naive T cell interacts with a DC displaying the antigen it can recognize, the T cell becomes activated to generate effector and memory T cells. If a naive T cell does not find its antigen within several hours, it will leave the lymph node via efferent lymphatics by a process dependent on the S1PR on the lymphocytes and a gradient of S1P. Naive B cells that enter secondary lymphoid tissues migrate into follicles in response to a gradient of the chemokine CXCL13 chemokine binding to the CXCR5 receptors on the B cell. Within the follicle, B cells move on a reticular network made of follicular dendritic cells and may bind antigens displayed by other cell types in the follicle. The effector and memory lymphocytes that are generated by antigen stimulation of naive cells exit the lymph node by the S1P pathway. Effector T cells have decreased expression of L-selectin and CCR7 but increased expression of integrins and E-selectin and P-selectin ligands, and these molecules mediate binding to endothelium at peripheral inflammatory sites. Effector and memory lymphocytes also express receptors for chemokines that are produced in infected peripheral tissues Naive follicular B cells that are activated by antigen in lymph node, spleen, or mucosal-associated lymphoid tissue may differentiate into short-lived antibody-secreting plasma cells that may stay in the secondary lymphoid organs. With help from T cells, some B cells may differentiate into plasmablasts that migrate through the blood to bone marrow or mucosal sites, where they differentiate into long-lived plasma cells that secrete antibodies for long periods. Chapter 4. Innate Immunity The innate immune system provides the first line of host defense against microbes, before adaptive immune responses have had sufficient time to develop. The mechanisms of innate immunity exist before exposure to microbes. The cellular components of the innate immune system include epithelial barriers and leukocytes (neutrophils, macrophages, natural killer [NK] cells, lymphocytes with invariant antigen receptors, and mast cells). The innate immune system uses cell-associated pattern recognition receptors, present on plasma and endosomal membranes and in the cytosol, to recognize structures called pathogen-associated molecular patterns (PAMPs), which are shared by microbes, are not present on mammalian cells, and are often essential for survival of the microbes, thus limiting the capacity of microbes to evade detection by mutating or losing expression of these molecules. In addition, these receptors recognize molecules made by the host but whose expression or location indicates cellular damage; these are called damage associated molecular patterns (DAMPs). Toll-like receptors (TLRs), present on the cell surface and in endosomes, are an important family of pattern recognition receptors, recognizing a wide variety of ligands, including bacterial cell wall components and microbial nucleic acids. Cytosolic pattern recognition receptors exist that recognize microbial molecules. These receptors include the retinoic acid–inducible gene (RIG)-like receptors (RLRs), which recognize viral RNA; cytosolic DNA sensors (CDSs), which recognize microbial DNA; and NOD-like receptors (NLRs), which recognize bacterial cell wall constituents and also serve as recognition components of many inflammasomes.  Pattern recognition receptors, including TLRs, NLRs, and RLRs, signal to activate the transcription factor NF-κB, which stimulates expression of cytokines, costimulators, and other molecules involved in inflammation, and the interferon response factor (IRF) transcription factors, which stimulate expression of the antiviral type I interferon (IFN) genes. The inflammasome, a specialized caspase-1–containing enzyme complex that forms in response to a wide variety of PAMPs and DAMPs, includes recognition structures, which are often NLR family proteins, an adaptor, and the enzyme caspase-1, the main function of which is to produce active forms of the inflammatory cytokines interleukin 1 (IL-1) and IL-18. Inflammasome-mediated proteolytic processing of the cytosolic protein gasdermin generates membrane pores, which are a conduit for release of IL-1 from the cell and also cause osmotic cell death, called pyroptosis. Soluble effector molecules of innate immunity are found in the plasma and include pentraxins (e.g., C-reactive protein [CRP]), collectins (e.g., mannose-binding lectin [MBL]), and ficolins. These molecules bind microbial ligands and enhance clearance by complement-dependent and complement-independent mechanisms. Innate lymphoid cells are cells with lymphocyte morphology and functions similar to those of T lymphocytes, but they do not express clonally distributed T cell antigen receptors. Three helper subsets of ILCs secrete the same cytokines as Th1, Th2, and Th17 helper T cells. NK cells have cytotoxic functions and secrete interferon-γ (IFN-γ), similar to cytotoxic T lymphocytes (CTLs). NK cells defend against intracellular microbes by killing infected cells and providing a source of the macrophage-activating cytokine IFN-γ. NK cell recognition of infected cells is regulated by a combination of activating and inhibitory receptors. Inhibitory receptors recognize class I major histocompatibility complex (MHC) molecules, because of which NK cells do not kill normal host cells but do kill cells in which class I MHC expression is reduced, such as virus infected cells. The complement system includes several plasma proteins that become activated in sequence by proteolytic cleavage to generate fragments of the C3 and C5 proteins, which promote inflammation, or opsonize and promote phagocytosis of microbes. Complement activation also generates membrane pores that kill some types of bacteria. The complement system is activated on microbial surfaces and not on normal host cells, because microbes lack regulatory proteins that inhibit complement. In innate immune responses, complement is activated mainly spontaneously on microbial cell surfaces and by MBL to initiate the alternative and lectin pathways, respectively. The two major effector functions of innate immunity are to induce inflammation, which involves the delivery of microbe-killing leukocytes and soluble effector molecules from blood into tissues, and to block viral infection of cells mainly by the antiviral actions of type I IFNs. Both types of effector mechanisms are induced by PAMPs and DAMPs. Several cytokines produced mainly by macrophages, dendritic cells (DCs), and other innate immune cells mediate inflammation. Tumor necrosis factor (TNF) and IL1 activate endothelial cells, stimulate chemokine production, and increase neutrophil production in the bone marrow. IL-1 and TNF both induce IL-6 production, and all three cytokines mediate systemic effects, including fever and acute-phase protein synthesis by the liver. IL-12 and IL18 stimulate production of the macrophage-activating cytokine IFN-γ by NK cells and T cells. These cytokines function in innate immune responses to different classes of microbes, and some (IL-1, IL-6, IL-12, IL-18) modify adaptive immune responses that follow the innate immune response.  Neutrophils and monocytes (the precursors of tissue macrophages) migrate from blood into inflammatory sites during innate immune responses because of the effects of cytokines and chemokines produced by PAMP- and DAMPstimulated tissue cells. Neutrophils and macrophages phagocytose microbes and kill them by producing reactive oxygen species, nitric oxide, and enzymes in phagolysosomes. Macrophages also produce cytokines that stimulate inflammation and promote tissue repair at sites of infection. Phagocytes recognize and respond to microbial products by several different types of receptors, including TLRs, C-type lectins, scavenger receptors, and N-formyl met-leu-phe receptors. Molecules produced during innate immune responses stimulate adaptive immunity and influence the nature of adaptive immune responses. DCs activated by microbes produce cytokines and costimulators that enhance T cell activation and differentiation into effector T cells. Complement fragments generated by the alternative pathway provide second signals for B cell activation and antibody production. Innate immune responses are regulated by negative feedback mechanisms that limit potential damage to tissues. IL-10 is a cytokine that is produced by and inhibits activation of macrophages and DCs. Inflammatory cytokine secretion is regulated by autophagy gene products. Negative signaling pathways block the activating signals generated by pattern recognition receptors and inflammatory cytokines. Chapter 5. Antibodies and Antigens Antibodies, or immunoglobulins (Igs), are a family of glycoproteins produced in membrane-bound or secreted form by B lymphocytes. Membrane-bound antibodies serve as receptors that mediate the antigen-triggered activation of B cells. Secreted antibodies function as mediators of specific humoral immunity by neutralizing microbes and toxins and by engaging various effector mechanisms that serve to eliminate the bound antigens. The antigen-binding regions of antibody molecules are highly variable, and any one individual has the potential to produce millions of different antibodies, each with distinct antigen specificity. All antibodies have a common symmetric core structure of two identical covalently linked heavy chains and two identical light chains, each linked to one of the heavy chains. Each chain consists of two or more independently folded Ig domains of about 110 amino acids containing conserved sequences and intrachain disulfide bonds. The N-terminal domains of heavy and light chains form the V regions of antibody molecules, which differ among antibodies of different specificities. The V regions of heavy and light chains each contain three separate hypervariable regions of about 10 amino acids that are spatially assembled to form the antigen-combining site of the antibody molecule. Antibodies are classified into different isotypes and subtypes on the basis of differences in the heavy chain C regions, which consist of three or four Ig C domains, and these classes and subclasses have different functional properties. The antibody classes are called IgM, IgD, IgG, IgE, and IgA. Both light chains of a single Ig molecule are of the same isotype, either κ or λ, which differ in their single C domains. Most of the effector functions of antibodies are mediated by the C regions of the heavy chains, but these functions are triggered by binding of antigens to the combining site in the V region.  Monoclonal antibodies are produced from a single clone of B cells and recognize a single antigenic determinant. Monoclonal antibodies can be generated in the laboratory and are widely used in research, diagnosis, and therapy. Antigens are substances specifically bound by antibodies or T lymphocyte antigen receptors. Antigens that bind to antibodies include a wide variety of biologic molecules, including sugars, lipids, carbohydrates, proteins, and nucleic acids. This is in contrast to most T cell antigen receptors, which recognize only peptide antigens. Macromolecular antigens contain multiple epitopes, or determinants, each of which may be recognized by an antibody. Linear epitopes of protein antigens consist of a sequence of adjacent amino acids, and conformational determinants are formed by folding of a polypeptide chain. The affinity of the interaction between the combining site of a single antibody molecule and a single epitope is generally represented by the Kd calculated from binding data. Polyvalent antigens contain multiple identical epitopes to which identical antibody molecules can bind. Antibodies can bind to 2 or, in the case of IgM, up to 10 identical epitopes simultaneously, leading to enhanced avidity of the antibody-antigen interaction. The relative concentrations of polyvalent antigens and antibodies may favor the formation of immune complexes that may deposit in tissues and cause damage. Antibody binding to antigen can be highly specific, distinguishing small differences in chemical structures, but cross-reactions may also occur in which two or more antigens may be bound by the same antibody. Several changes in the structure of antibodies made by one clone of B cells may occur in the course of an immune response. B cells initially produce only membrane-bound Ig, but in activated B cells and plasma cells, Ig with the same antigen-binding specificity as the original membrane bound Ig receptor is secreted. Changes in the use of C region gene segments without changes in V regions are the basis of isotype switching, which leads to changes in effector function without a change in specificity. Point mutations in the V regions of an antibody specific for an antigen lead to increased affinity for that antigen (affinity maturation). Chapter 6. Antigen Presentation to T Lymphocytes and the Function of Major Histocompatibility Complex Molecules The antigen receptors of most T cells recognize only peptides displayed by major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). CD4 + helper T lymphocytes recognize antigens in association with class II MHC molecules, and CD8 + CTLs recognize antigens in association with class I MHC molecules. APCs capture protein antigens, process them, and display MHC-associated peptides to T cells. Dendritic cells (DCs) are the most efficient APCs for initiating primary responses by activating naive T cells, and macrophages and B lymphocytes present antigens to helper T cells in the effector phase of cell-mediated immunity and in humoral immune responses, respectively. All nucleated cells can present class I–associated peptides, derived from cytosolic proteins, such as viral and tumor antigens, to CD8 + T cells. DCs capture antigens from their sites of entry (usually through epithelia) or production (in tissues) and transport these antigens to secondary (peripheral) lymphoid organs. Naive T cells that recirculate through these organs recognize the antigens, and primary immune responses are induced in these organs. The MHC is a large genetic region coding for highly polymorphic, codominantly expressed class I and class II MHC molecules.  Class I MHC molecules are composed of an α (or heavy) chain in a noncovalent complex with a nonpolymorphic polypeptide called β2-microglobulin. Class II MHC molecules contain two MHC-encoded polymorphic chains, an α chain and a β chain. Both classes of MHC molecules consist of an extracellular peptide-binding cleft, a nonpolymorphic immunoglobulin (Ig)-like region, a transmembrane region, and a cytoplasmic region. The peptide-binding cleft of MHC molecules has α-helical sides and an eight-stranded antiparallel β-pleated sheet floor. The polymorphic residues of MHC molecules are localized to the peptide-binding domain. The Ig-like domains of class I and class II MHC molecules contain the binding sites for the T cell coreceptors CD8 and CD4, respectively. The function of class I and class II MHC molecules is to bind peptide antigens and display them for recognition by antigen-specific T lymphocytes. Peptide antigens associated with class I MHC molecules are recognized by CD8 + T cells, whereas class II MHC–associated peptide antigens are recognized by CD4 + T cells. MHC molecules bind only one peptide at a time. Every MHC molecule has a broad specificity for peptides and can bind multiple peptides that have common structural features, such as anchor residues. The peptide-binding cleft of class I MHC molecules can accommodate peptides that are 6 to 16 amino acid residues in length, whereas the cleft of class II MHC molecules allows larger peptides (up to 30 amino acid residues in length or more) to bind. Some polymorphic MHC residues determine the binding specificities for peptides by forming structures called pockets that interact with complementary residues of the bound peptide, called anchor residues. Other polymorphic MHC residues and some residues of the peptide are not involved in peptide binding to MHC molecules but instead form the structure recognized by T cells. Class I MHC molecules are expressed on all nucleated cells, whereas class II MHC molecules are expressed mainly on specialized APCs, such as DCs, macrophages, and B lymphocytes, and a few other cell types, including endothelial cells and thymic epithelial cells. The expression of MHC gene products is enhanced by inflammatory and immune stimuli, particularly cytokines such as IFN-γ, which stimulate the transcription of MHC genes. Antigen processing is the conversion of native proteins into MHC-associated peptides. This process consists of the introduction of exogenous protein antigens into vesicles of APCs or the synthesis of antigens in the cytosol, the proteolytic degradation of these proteins into peptides, the binding of peptides to MHC molecules, and the display of the peptide-MHC complexes on the APC surface for recognition by T cells. Thus, both extracellular and intracellular proteins are sampled by these antigenprocessing pathways, and peptides derived from both normal self proteins and foreign proteins are displayed by MHC molecules for surveillance by T lymphocytes. For the class I MHC pathway, protein antigens are degraded in the proteasome, generating peptides that bind to class I MHC molecules. Most of these antigens are synthesized in the cytosol or introduced into the cytosol from microbes or vesicles. These peptides are delivered from the cytosol to the endoplasmic reticulum (ER) by an ATP-dependent transporter called transporter associated with antigen processing (TAP). Newly synthesized class I MHC–β2 - microglobulin dimers in the ER are associated with the TAP-containing peptide-loading complex and receive peptides transported into the ER. Stable complexes of class I MHC molecules with bound peptides move out of the ER, through the Golgi complex, to the cell surface. Specialized APCs, mainly DCs, can ingest virus-infected or tumor cells and transport their antigens into the cytosol for presentation by class I MHC molecules. This process, called cross-presentation, enables DCs to initiate CD8 + T cell responses to the antigens of ingested cells. For the class II MHC pathway, protein antigens are internalized into endosomes, and these proteins are proteolytically cleaved by enzymes in lysosomes and late endosomes. Newly synthesized class II MHC molecules associated with the invariant chain (Ii ) are transported from the ER to the endosomal vesicles. Here the Ii is proteolytically cleaved, and a small peptide remnant of the Ii , called CLIP, is removed from the peptide-binding cleft of the MHC molecule by the DM molecules. The peptides that were generated from extracellular proteins then bind to the available cleft of the class II MHC molecule, and the trimeric complex (class II MHC α and β chains and peptide) moves to and is displayed on the surface of the cell. These pathways of MHC-restricted antigen presentation ensure that most of the body’s cells are screened for the possible presence of foreign antigens. The pathways also ensure that proteins from extracellular microbes preferentially generate peptides bound to class II MHC molecules for recognition by CD4 + helper T cells, which activate effector mechanisms that eliminate extracellular antigens. Conversely, proteins synthesized by intracellular (cytosolic) microbes generate peptides bound to class I MHC molecules for recognition by CD8 + CTLs, which function to eliminate cells harboring intracellular infections. The immunogenicity of foreign protein antigens depends on the ability of antigen-processing pathways to generate peptides from the proteins that bind to self MHC molecules. Chapter 7. Immune Receptors and Signal Transduction Signaling receptors, typically located on the cell surface, generally initiate signaling in the cytosol, followed by a nuclear phase during which gene expression is altered. Many different types of signaling receptors contribute to innate and adaptive immunity, the most prominent category being immune receptors that belong to a receptor family in which non-receptor tyrosine kinases phosphorylate tyrosine-containing immunoreceptor tyrosine-based activation motif (ITAM) on the cytoplasmic tails of proteins in the receptor complex. Some of the other types of receptors of interest in immunology include those of the receptor tyrosine kinase family, nuclear receptors, heterotrimeric G protein–coupled serpentine receptors, and receptors of the Notch family. Antigen receptors on T and B cells, as well as immunoglobulin (Ig) Fc receptors, are members of the immune receptor family. Antigen receptors can produce widely varying outputs, depending on the affinity and valency of the antigen that can recruit different numbers of ITAMs. Coreceptors, such as CD4 or CD8 on T cells and CD21 (CR2) on B cells, enhance signaling from antigen receptors. Coreceptors bind to the same antigen complex that is being recognized by the antigen receptor. Signaling from antigen receptors can be aenuated by inhibitory receptors such as CD22 and PD-1, which contain cytosolic immunoreceptor tyrosine-based inhibition motifs (ITIMs) and sometimes immunoreceptor tyrosine-based switch motifs (ITSMs). The T cell receptor (TCR) complex is made up of the TCR α and β chains that contribute to antigen recognition and the ITAM-containing signaling chains CD3 γ, δ, and ε and the ζ homodimer. The CD3 chains each contain one ITAM, whereas each ζ chain contains three ITAMs. TCR ligation results in tyrosine phosphorylation of CD3 and ζ ITAMs by SRC family kinases and the recruitment of ZAP70 to the phospho-ITAMs, with each SH2 domain of ZAP70 binding to one phosphorylated tyrosine of the ITAM. Activated ZAP70 phosphorylates tyrosine residues on adaptors, and downstream enzymes are recruited to the signalosome. Enzymes that mediate the exchange of GTP for GDP on small G proteins such as RAS and RAC help initiate mitogen-activated protein (MAP) kinase pathways. These pathways lead to the induction or activation of transcription factors such as JUN and FOS, components of the AP1 transcription factor. Activation of PLCγ1 leads to the release of IP3 from PIP2, and IP3 induces release of calcium from intracellular stores. Depletion of calcium from intracellular stores facilitates the opening of the calcium release–activated calcium (CRAC) channel, a store-operated channel on the cell surface that maintains the raised intracellular calcium levels. Calcium binds to calmodulin and activates downstream proteins, including calcineurin, a phosphatase that facilitates the entry of the nuclear factor of activated T cell (NFAT) transcription factor into the nucleus. DAG is generated in the membrane when PLCγ1 releases IP3 from PIP2. DAG can activate PKCθ, which, among other things, can contribute to NF-κB activation. A lipid kinase called PI3-kinase converts PIP2 to PIP3. PIP3 can recruit and activate pleckstrin homology (PH) domain– containing proteins to the plasma membrane. PIP3 activates ITK in T cells and BTK in B cells. It activates PDK1, a kinase that can phosphorylate a downstream kinase called AKT that mediates cell survival. Costimulatory receptors initiate signaling separately from antigen receptors, and signaling outputs from antigen receptors and costimulatory receptors synergize in the nucleus. The major costimulatory receptor in T cells is CD28. The BCR is made up of membrane-bound Ig and an associated disulfide-linked Igα and Igβ heterodimer. Both Igα and Igβ contain ITAMs in their cytoplasmic tails. Signaling pathways linked to the BCR are broadly similar to signaling pathways downstream of the TCR. Aenuation of immune receptor signaling in B cells, T cells, and NK cells, among others, is mediated by inhibitory receptors that frequently contain inhibitory tyrosinecontaining motifs or ITIMs in their cytoplasmic tails and recruit phosphatases. Another important mechanism of signal aenuation involves the ubiquitination of signaling proteins by E3 ubiquitin ligases, which tags these proteins for intracellular degradation. Cytokine receptors can be divided into categories based on structural features and mechanisms of signaling. Many cytokine receptors use non-receptor tyrosine kinases called JAKs to phosphorylate transcription factors called p p y p STATs, which dimerize after phosphorylation, translocate to the nucleus, and induce transcription of target genes. Some cytokine receptors such as those of the interleukin-1 (IL-1), IL-17, and tumor necrosis factor (TNF) receptor families activate either canonical or noncanonical NF-κB signaling. Canonical NF-κB signaling is activated downstream of many receptors, including TNF receptor family cytokine receptors, Toll-like receptors (TLRs) and IL-1R family members, and antigen receptors. The pathway involves activation of IKKβ in the IKK complex, phosphorylation of the IκBα inhibitor by activated IKKβ, ubiquitination and proteasomal degradation of IκBα, and transport of NF-κB to the nucleus. Transforming growth factor-β (TGF-β) binds to TGF-βRII, which phosphorylates and activates TGF-βRI, which in turn phosphorylates and activates an R-SMAD. The phosphorylated R-SMAD then dimerizes with a co-SMAD, and this dimer enters the nucleus and stimulates transcription of target genes. Chapter 8. Lymphocyte Development and Antigen Receptor Gene Rearrangement B and T lymphocytes arise from a common bone marrow– derived precursor that becomes commied to the lymphocyte lineage. Early maturation is characterized by cell proliferation induced by cytokines, mainly interleukin 7. Transcription factors induce the expression of lineagespecific genes and open up specific antigen receptor gene loci. The initial expression of pre-antigen receptors and the subsequent expression of antigen receptors are essential for the survival, expansion, and maturation of developing lymphocytes and for selection processes that lead to a diverse repertoire of useful antigen specificities. The antigen receptors of B and T cells are encoded by a limited number of gene segments that are spatially segregated in the germline loci but are somatically recombined in developing B and T cells. Separate loci encode the immunoglobulin (Ig) heavy chain, Ig κ light chain, Ig λ light chain, T cell receptor (TCR) β chain, TCR α and δ chains, and TCR γ chain. These loci contain V, J, and in the Ig heavy chain and TCR β and δ loci only, D gene segments. Somatic rearrangement of both Ig and TCR loci involves the joining of D and J segments in the loci that contain D segments followed by the joining of the V segment to the recombined DJ segments in these loci, or direct V-to-J joining in the other loci. This process of somatic gene recombination is mediated by a recombinase enzyme complex made up of the lymphocyte-specific components RAG-1 and RAG-2. The diversity of the antibody and TCR repertoires is generated by the combinatorial associations of multiple germline V, D, and J gene segments and junctional diversity generated by the addition or removal of random nucleotides at the sites of recombination. These mechanisms generate the most diversity at the junctions of the segments that form the third hypervariable regions of both antibody and TCR polypeptides. B cell maturation occurs in stages characterized by different paerns of Ig gene rearrangement and expression. In the earliest B cell precursors, called pro-B cells, Ig genes are initially in the germline configuration, and D to J rearrangement occurs at the Ig heavy chain locus. At the pro-B to pre-B cell transition, V-D-J recombination is completed at the Ig H chain locus, and the VDJ exon is spliced to the µ C region exons of the heavy chain RNA to generate a mature mRNA that is translated into the µ heavy chain protein. The pre-B cell receptor is formed by pairing of the µ chain with surrogate light chains and by association with the signaling molecules Igα and Igβ. This receptor delivers survival and proliferation signals and also signals to inhibit rearrangement on the other heavy chain allele (allelic exclusion). As cells differentiate into immature B cells, V-J recombination occurs initially at the Ig κ locus, and light chain proteins are expressed. Heavy and light chains are then assembled into intact IgM molecules and expressed on the cell surface. Immature B cells leave the bone marrow to populate peripheral lymphoid tissues, where they complete their maturation. At the mature B cell stage, synthesis of µ and δ heavy chains occurs in parallel mediated by alternative splicing of primary heavy chain RNA transcripts, and membrane IgM and IgD are expressed. During B lymphocyte maturation, immature B cells that express high-affinity antigen receptors specific for self antigens present in the bone marrow are induced to edit their receptor genes, or these cells are eliminated.  T cell maturation in the thymus progresses in stages distinguished by the paern of expression of the antigen receptor and CD4 and CD8 coreceptor molecules. The earliest T lineage immigrants to the thymus do not express T cell receptors (TCRs) or CD4 or CD8 molecules. The developing thymocytes initially populate the outer cortex, where they undergo proliferation and rearrangement of TCR genes, and express CD3, TCR, CD4, and CD8 molecules. At the pre-T stage, thymocytes remain double-negative, but V-D-J recombination is completed at the TCR β chain locus, and TCR β chain polypeptides are produced. The TCR β chain associates with the invariant pre-Tα protein to form a pre-TCR, which transduces signals that inhibit rearrangement on the other β chain allele (allelic exclusion) and promote dual CD4 and CD8 expression. At the CD4 +CD8 + (double-positive) stage, V-J recombination occurs at the TCR α locus, α chain polypeptides are produced, and low levels of TCR are expressed on the cell surface. Positive selection of CD4 +CD8 + TCR αβ thymocytes requires low-avidity recognition of peptide–major histocompatibility complex (MHC) complexes. As TCR αβ thymocytes mature, they move into the medulla and become either CD4 +CD8 − or CD8 +CD4 −. Lineage commitment accompanying positive selection results in the matching of TCRs that recognize MHC class I with CD8 expression and the silencing of CD4; TCRs that recognize MHC class II molecules are matched with CD4 expression and the loss of CD8 expression. Negative selection of CD4 +CD8 + TCR αβ double-positive thymocytes occurs when these cells recognize, with high avidity, antigens that are present in the thymus. This process is responsible for tolerance to many self antigens. Chapter 9. Activation of T Lymphocytes T cell responses are initiated by signals that are generated by T cell receptor (TCR) recognition of peptide–major histocompatibility complex (MCH) complexes on the surface of antigen-presenting cells (APCs) and through signals provided at the same time by costimulators expressed on APCs. The best-defined costimulators are members of the B7 family, which are recognized by receptors of the CD28 family expressed on T cells. The expression of B7 costimulators on APCs is increased by encounter with microbes, providing a mechanism for generating optimal responses against infectious pathogens. Some members of the CD28 family inhibit T cell responses, and the outcome of T cell antigen recognition is determined by the balance between engagement of activating and inhibitory receptors of this family. T cell responses to antigen and costimulators include changes in the expression of surface molecules, synthesis of cytokines and cytokine receptors, cellular proliferation, and differentiation into effector and memory cells. The surface molecules whose expression is induced on T cell activation include proteins that are involved in retention of T cells in lymphoid organs, cytokines and cytokine receptors, effector and regulatory molecules, and molecules that influence migration of the T cells. Shortly after activation, T cells produce the cytokine interleukin-2 (IL-2) and express high levels of the functional IL-2 receptor. IL-2 drives the proliferation of the cells, which can result in marked expansion of antigen-specific clones. Some activated T cells may differentiate into memory cells, which survive for long periods and respond rapidly to antigen challenge. The maintenance of memory cells is dependent on cytokines such as IL-7, which may promote the expression of anti-apoptotic proteins and stimulate lowlevel cycling. Memory T cells are heterogeneous and consist of populations that differ in migration properties and functional responses.  T cell responses decline after elimination of the antigen, thus returning the system to rest. The decline is because the g y signals for continued lymphocyte activation are eliminated and because of various inhibitory mechanisms Chapter 10. Differentiation and Functions of CD4+ Effector T Cells Cell-mediated immunity is the adaptive immune response stimulated by microbes inside host cells. It is mediated by T lymphocytes and can be transferred from immunized to naive individuals by T cells and not by antibodies. Naive CD4 + T lymphocytes may differentiate into different types of specialized effector T cells, including: Th1 cells that secrete interferon-γ (IFN-γ), which mediate defense against intracellular microbes; Th2 cells that secrete interleukin-4 (IL-4) and IL-5, which favor IgE- and eosinophil/mast cell– mediated immune reactions against helminths; or Th17 cells, which promote inflammation and mediate defense against extracellular fungi and bacteria. The differentiation of naive CD4 + T cells into subsets of helper T cells is induced by cytokines produced by antigenpresenting cells, by the T cells themselves, and by other cells. The differentiation program is governed by transcription factors that promote cytokine gene expression in the T cells and epigenetic changes in cytokine gene loci, which may be associated with stable commitment to a particular subset. Each subset produces cytokines that p p y increase its own development and inhibit the development of the other subsets, thus leading to increasing polarization of the response. Th1 cells recognize antigens of microbes that have been ingested by phagocytes and activate the phagocytes to kill the microbes. The activation of macrophages by Th1 cells is mediated by IFN-γ and CD40L-CD40 interactions. Activated macrophages kill phagocytosed microbes ingested into phagolysosomes by the actions of reactive oxygen and nitrogen species and enzymes (called classical macrophage activation). Activated macrophages also stimulate inflammation and can damage tissues. Th2 cells recognize antigens produced by helminths and other microbes, as well as environmental antigens associated with allergies. IL-4 promotes B cell isotype switching and production of IgE, which may cause mast cell degranulation and inflammation. IL-5 secreted by activated Th2 cells activates eosinophils to release granule contents that destroy helminths but may also damage host tissues. IL-4 and IL-13 together provide protection at epithelial barriers and induce an alternative form of macrophage activation that generates macrophages that control inflammation and mediate tissue repair and fibrosis. Th17 cells stimulate neutrophil-rich inflammatory responses that eradicate extracellular bacteria and fungi and maintain the integrity of epithelia. Th17 cells also may be important in mediating tissue damage in autoimmune diseases. γδ T cells, natural killer T cells, and mucosa-associated invariant T cells are T cells that express receptors of limited diversity and recognize various antigens without a requirement for major histocompatibility complex– associated presentation. These cells produce cytokines and may contribute to host defense and inflammatory diseases. Chapter 11. Differentiation and Functions of CD8+ Effector T Cells T cells of the CD8 + subset proliferate and differentiate into cytotoxic T lymphocytes (CTLs), which express cytotoxic granules and can kill infected cells. The differentiation of CD8 + T cells into functional CTLs and memory cells requires recognition of antigen presented by dendritic cells, signals from CD4 + helper T cells in some situations, costimulation, and cytokines. Differentiation to CTLs involves the acquisition of the machinery to kill target cells and is driven by various transcription factors.  In some situations of chronic antigen exposure (such as tumors and chronic viral infections), CD8 + T cells initiate a response but begin to express inhibitory receptors that suppress the response, a process called exhaustion. CD8 + CTLs kill cells that express peptides derived from cytosolic antigens (e.g., viral antigens) that are presented in association with class I MHC molecules. CTL-mediated killing is mainly the result of exocytosis of secretory granules that contain granzymes and perforin. Perforin facilitates granzyme entry into the cytoplasm of target cells, and granzymes initiate the process of apoptosis. Another granule protein, granulysin, destroys some intracellular bacteria and fungi. CD8 + T cells also secrete interferon-γ and thus may participate in defense against phagocytosed microbes and in delayed-type hypersensitivity reactions. Chapter 12. B Cell Activation and Antibody Production In humoral immune responses, B lymphocytes are activated by antigen and secrete antibodies that act to eliminate the antigen. Both protein and nonprotein antigens can stimulate antibody responses. B cell responses to protein antigens require the contribution of CD4 + helper T cells specific for the antigen. Helper T cell–dependent B cell responses to protein antigens require initial independent activation of naive T cells in the T cell zones and of B cells in lymphoid follicles in lymphoid organs, each specific for a different part of the same protein antigen. A B cell that recognizes a conformational epitope of a native protein antigen internalizes the protein, processes it, and displays a peptide derived from the protein on its class II major histocompatibility (MHC) molecules for recognition by helper T cells. The activated lymphocytes migrate toward one another and interact at the edges of follicles, where the B cells present the peptide antigen to antigen-specific helper T cells. Activated helper T cells express CD40 ligand (CD40L), which engages CD40 on the B cells, and the T cells secrete cytokines that bind to cytokine receptors on the B cells. The combination of CD40 and cytokine signals stimulates B cell proliferation and differentiation. Stimulation of activated B cells at extrafollicular sites by helper T cells leads to the formation of extrafollicular foci where isotype switching occurs and short-lived plasma cells are generated. Some activated helper T cells differentiate into specialized T follicular helper (T) cells that express high levels of inducible costimulator (ICOS) and CXCR5 and secrete interleukin-21 (IL-21). T cells and antigen-activated B cells migrate into the follicle, and T cells activate these specific B cells to initiate the formation of germinal centers. The late events in T cell–dependent antibody responses, including additional isotype switching, somatic mutation, affinity maturation, generation of memory B cells, and induction of long-lived plasma cells, take place within germinal centers. Helper T cell–derived signals, including CD40L and cytokines, induce isotype switching in B cells by a process of switch recombination, leading to the production of various immunoglobulin (Ig) isotypes. Isotype switching requires the induction of activation-induced deaminase (AID), a cytidine deaminase that converts cytosine to uracil in single-stranded DNA, and different cytokines allow AID to access distinct downstream heavy chain loci. Affinity maturation occurs in germinal centers and leads to increased affinity of antibodies during the course of a T cell–dependent humoral response. Affinity maturation is a result of somatic mutation of Ig heavy and light chain genes induced by AID, followed by selective survival of the B cells that produce high-affinity antibodies and bind to antigen displayed by follicular dendritic cells in the germinal centers. The high-affinity B cells are best able to present antigens to T cells, which promote survival of the B cells. Some of the progeny of germinal center B cells differentiate into antibody-secreting plasma cells that migrate to the bone marrow. Other progeny become memory B cells that live for long periods, recirculate between lymphoid organs and peripheral tissues, and respond rapidly to subsequent exposures to antigen by differentiating into high-affinity antibody secretors. The expression of various transcription factors controls the differentiation of activated B cells into plasma cells or memory cells. T-independent (TI) antigens are generally nonprotein antigens that induce humoral immune responses without the involvement of helper T cells. Many TI antigens, including polysaccharides, membrane glycolipids, and nucleic acids, are multivalent, can cross-link multiple membrane Ig molecules on a B cell, and activate complement, thereby activating the B cells without T cell help. Toll-like receptor (TLR) activation on B cells by microbial products may facilitate T-independent B cell activation. TI antigens stimulate antibody responses in which there is limited heavy chain class switching, affinity maturation, or memory B cell generation because these features are largely dependent on helper T cells, which are not activated by nonprotein antigens. However, some T-independent isotype switching can be induced by TLR stimulation by microbes, g y y which may lead to the production of cytokines of the TNF family that activate B cells to induce AID. Antibody feedback is a mechanism by which humoral immune responses are downregulated when enough antibody has been produced and soluble antibody–antigen complexes are present. B cell membrane Ig and the receptor on B cells for the Fc portions of IgG, called FcγRIIB, are clustered together by antibody-antigen complexes. This activates an inhibitory signaling cascade through the cytoplasmic tail of FcγRIIB that terminates the activation of the B cell. Chapter 13. Effector Mechanisms of Humoral Immunity Humoral immunity is mediated by antibodies and is the effector arm of the adaptive immune system responsible for defense against extracellular microbes and microbial toxins. The antibodies that provide protection against infection may be produced by long-lived plasma cells generated by the first exposure to microbial antigen or by reactivation of memory B cells by the antigen. Antibodies block, or neutralize, the infectivity of microbes by binding to the microbes and sterically hindering interactions of the microbes with cellular receptors. Antibodies similarly block the pathologic actions of toxins by preventing binding of the toxins to host cells. Antibody-coated (opsonized) particles are phagocytosed by binding of the Fc portions of the antibodies to phagocyte Fc receptors. There are several types of Fc receptors specific for different subclasses of IgG and for IgA and IgE antibodies, and different Fc receptors bind the antibodies with varying affinities. Aachment of antigen-complexed Ig to phagocyte Fc receptors also delivers signals that stimulate the microbicidal activities of phagocytes. The complement system consists of serum and membrane proteins that interact in a highly regulated manner to produce biologically active products. The three major pathways of complement activation are the alternative pathway, which is activated on microbial surfaces in the absence of antibody; the classical pathway, which is activated by antigen-antibody complexes; and the lectin pathway, which is initiated by circulating lectins binding to carbohydrates on pathogens. These pathways generate enzymes that cleave the C3 protein, and cleaved products of C3 become covalently aached to microbial surfaces or antibodies, so subsequent steps of complement activation are limited to these sites. All pathways converge on the common set of late steps, which involve the proteolytic cleavage of C5 and culminate in the formation of a membrane pore. Complement activation is regulated by various plasma and cell membrane proteins that inhibit different steps in the cascades. The biologic functions of the complement system include opsonization of organisms and immune complexes by proteolytic fragments of C3, followed by binding to phagocyte receptors for complement fragments and phagocytic clearance; activation of inflammatory cells by proteolytic fragments of complement proteins called anaphylatoxins (C3a, C4a, C5a); cytolysis mediated by membrane aack complex formation on cell surfaces; solubilization and clearance of immune complexes; and enhancement of humoral immune responses. Chapter 14. Specialized Immunity at Epithelial Barriers and in Immune Privileged Tissues Regional immune systems, including those in the gastrointestinal tract, respiratory tract, and skin, are specialized collections of innate and adaptive immune cells at particular anatomic locations that perform protective and regulatory functions that are unique to those sites. The gastrointestinal immune system must cope with the presence of trillions of commensal bacteria in the gut lumen by preventing their invasion and tolerating their presence in the lumen, while also identifying and responding to numerically rare pathogenic organisms. Innate immunity in the gastrointestinal system is mediated by mucosal epithelial lining cells, which impede microbial invasion by tight intercellular junctions, secretion of mucus, and production of antimicrobial molecules such as defensins. Innate immune effector cells in the lamina propria include macrophages, DCs, ILCs, and mast cells. Intraepithelial lymphocytes, including γδ T cells, defend against commonly encountered microbes at the intestinal epithelial barrier. The adaptive immune system in the intestinal tract includes subepithelial collections of lymphoid tissues called gutassociated lymphoid tissues (GALT), such as the oropharyngeal tonsils, Peyer’s patches in the ileum, and similar collections in the colon. M cells in the epithelial lining sample lumen antigens and transport them to antigen-presenting cells in the GALT. Lamina propria DCs extend processes through intestinal epithelial lining cells to sample luminal antigens. Effector B and T lymphocytes that differentiate from naive T cells in the GALT or mesenteric lymph nodes enter the circulation, and selectively migrate back to the intestinal lamina propria. Humoral immunity in the gastrointestinal tract is dominated by IgA secretion into the lumen, where the antibodies neutralize potentially invading pathogens. B cells in the GALT and mesenteric lymph nodes differentiate into IgA-secreting plasma cells through both T-dependent and T-independent mechanisms, and the plasma cells migrate to the lamina propria beneath the epithelial barrier and secrete IgA. Dimerized IgA is transported across the epithelium by the poly-Ig receptor and released into the lumen. IgA is also secreted into breast milk and mediates passive immunity in the gut of breast-feeding infants. Th17 cells in the intestinal tract secrete IL-17 interleukin-17 (IL-17) and IL-22, which enhance epithelial barrier function. Th2 cells are important in defense against intestinal parasites. Changes in bacterial flora influence the balance between different helper T cell subset responses, both in the gut and systemically.  Immune responses to commensal organisms and food antigens in the lumen of the intestinal tract are minimized by selective expression of paern recognition receptors on basolateral surfaces of the epithelial lining cells, and the generation of regulatory T cells that suppress adaptive immune responses. TGF-β, IL-10, and IL-2 are essential to maintain immune homeostasis in the bowel wall. Systemic tolerance to some antigens can be induced by feeding the antigens to mice, a phenomenon called oral tolerance. Mucosal immunity in the respiratory system defends against airborne pathogens and is the cause of allergic airway diseases such as asthma. Innate immunity in the bronchial tree depends on the mucus-producing, ciliated epithelial lining, which moves the mucus with entrapped microbes out of the lungs. Defensins, surfactant proteins, and alveolar macrophages provide antimicrobial and antiinflammatory functions. Treg and immunosuppressive cytokines are important for prevention of harmful responses to nonpathogenic organisms or other inhaled antigens. The cutaneous immune system defends against microbial invasion through the skin and suppresses responses against numerous commensal organisms. The epidermis provides a physical barrier to microbial invasion. Keratinocytes secrete defensins and inflammatory cytokines in response to microbial products. The dermis contains a mixed population of mast cells, macrophages, and DCs that respond to microbes and injury and mediate inflammatory responses. Skin DCs mediate innate immune responses and transport microbial and environmental antigens that enter through the skin to draining lymph nodes, where they initiate T cell responses. T cells activated in skin-draining lymph nodes express chemokine receptors and adhesion molecules that favor homing back to the skin. CD4 + or CD8 + effector memory cells generated in response to skin infections or commensals migrate to and stay in the dermis and epidermis for long periods. These resident memory cells have Th1, Th2, Th17, and CTL phenotypes, and are important for defense against different types of skin invading pathogens. Resident memory Tregs are also present in the skin and likely maintains tolerance to commensal skin organisms. Immune-privileged sites, which are tissues where immune responses are not readily initiated, include the brain, anterior chamber of the eye, and testis. The mechanisms of immune privilege include the tight junctions of endothelial cells in blood vessels, local production of immunosuppressive cytokines, and expression of cell surface molecules that inactivate or kill lymphocytes. Maternal immunologic tolerance to the developing mammalian fetus, which expresses allogeneic paternal antigens, depends on mechanisms that act locally at the placental maternal-fetal interface. Possible mechanisms include lack of MHC expression on fetal trophoblasts, the actions of Tregs, and the local IDO-mediated depletion of tryptophan needed for lymphocyte growth and generation of a toxic by-product. Neonatal protection against infections up to about 6 months of age is mediated by maternal IgG antibodies transferred to the fetal circulation through the placenta and in intestines of nursing babies by maternal IgA in ingested breast milk. Chapter 15. Immunologic Tolerance and Autoimmunity Immunologic tolerance is unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen. Tolerance to self antigens is a fundamental property of the normal immune system, and the failure of self-tolerance leads to autoimmune diseases. Antigens may be administered in ways that induce tolerance rather than immunity, and this may be exploited for the prevention and treatment of transplant rejection and autoimmune and allergic diseases. Central tolerance is induced in the generative lymphoid organs (thymus and bone marrow) when immature lymphocytes encounter self antigens present in these organs. Peripheral tolerance occurs when mature lymphocytes recognize self antigens in peripheral tissues under particular conditions. In T lymphocytes, central tolerance occurs when immature thymocytes with high-affinity receptors for self antigens recognize these antigens in the thymus. Some immature T cells that encounter self antigens in the thymus die (negative selection), and others develop into FOXP3 + regulatory T lymphocytes (Tregs) that function to control responses to self antigens in peripheral tissues. Several mechanisms account for peripheral tolerance in mature T cells. In CD4 + T cells, anergy is induced by antigen recognition without adequate costimulation or by engagement of inhibitory receptors such as CTLA-4 (cytotoxic T lymphocyte antigen 4) and PD-1 (programmed cell death protein-1). Tregs inhibit immune responses by multiple mechanisms. T cells that encounter self antigens without other stimuli or that are repeatedly stimulated may die by apoptosis. In B lymphocytes, central tolerance is induced when immature B cells recognize multivalent self antigens in the bone marrow. The result is the acquisition of a new specificity, called receptor editing, or apoptotic death of the immature B cells. Mature B cells that recognize self antigens in the periphery in the absence of T cell help may be rendered anergic and ultimately die by apoptosis or become functionally unresponsive because of the engagement of inhibitory receptors. Autoimmunity results from inadequate self-tolerance or regulation of lymphocytes. Autoimmune reactions may be triggered by environmental stimuli, such as infections, in genetically susceptible individuals. Most autoimmune diseases are polygenic, and numerous susceptibility genes contribute to disease development. The greatest contribution is from major histocompatibility complex (MHC) genes; other genes are thought to influence the selection or regulation of self-reactive lymphocytes. Infections may predispose to autoimmunity by several mechanisms, including enhanced expression of costimulators in tissues and cross reactions between microbial antigens and self antigens. Some infections may protect individuals from autoimmunity, by unknown mechanisms. Chapter 16. Immunity to Microbes The interaction of the immune system with infectious organisms is a dynamic interplay of host mechanisms aimed at eliminating infections and microbial strategies designed to permit survival in the face of powerful defenses. Different types of infectious agents stimulate distinct types of immune responses and have evolved unique mechanisms for evading immunity. In some infections, the immune response is the cause of tissue injury and disease. Innate immunity against extracellular bacteria is mediated by phagocytes and the complement system (the alternative and lectin pathways). The principal adaptive immune response against extracellular bacteria consists of specific antibodies that opsonize the bacteria for phagocytosis and activate the complement system. Toxins produced by such bacteria are neutralized by specific antibodies. Some bacterial toxins are powerful inducers of cytokine production, and cytokines account for much of the systemic disease associated with severe, disseminated infections with these microbes. Innate immunity against intracellular bacteria is mediated mainly by macrophages. However, intracellular bacteria are capable of surviving and replicating within host cells, including phagocytes, because they have developed mechanisms for resisting degradation within phagocytes. Adaptive immunity against intracellular bacteria is principally cell-mediated and consists of activation of macrophages by CD4 + T cells, as well as killing of infected cells by CD8 + cytotoxic T lymphocytes (CTLs). The characteristic pathologic response to infection by intracellular bacteria is granulomatous inflammation. Protective responses to fungi consist of innate immunity, mediated by neutrophils and macrophages; adaptive cell mediated immunity, mainly involving Th17 cells; and humoral immunity. Fungi are usually readily eliminated by phagocytes, because of which disseminated fungal infections are seen mostly in immunodeficient persons. Innate immunity against viruses is mediated by type I interferons and natural killer cells. Neutralizing antibodies protect against virus entry into cells early in the course of infection and later if the viruses are released from killed infected cells. The major defense mechanism against established infection is CTL-mediated killing of infected cells. CTLs may contribute to tissue injury even when the infectious virus is not harmful by itself. Viruses evade immune responses involving antigenic variation, blocking type I IFN production or action, inhibition of antigen presentation, inactivation of T cells, and production of immunosuppressive molecules. Parasites such as protozoa and helminths give rise to chronic and persistent infections because innate immunity against them is weak and parasites have evolved multiple mechanisms for evading and resisting specific immunity. The structural and antigenic diversity of pathogenic parasites is reflected in the heterogeneity of the adaptive immune responses that they elicit. Protozoa that live within host cells are destroyed by cell-mediated immunity, whereas helminths are eliminated by eosinophil-mediated killing. Parasites evade the immune system by varying their antigens during residence in vertebrate hosts, by acquiring resistance to immune effector mechanisms, and by masking and shedding their surface antigens. Vaccination is a powerful strategy for preventing infections. The most effective vaccines are those that stimulate the production of high-affinity antibodies and memory cells. Many approaches for vaccination are in clinical use and being tried for various infections. Chapter 17. Transplantation Immunology Allografts are tissues or organs transplanted from one individual to a genetically nonidentical recipient. Allografts stimulate a specific immune response called rejection that can destroy the graft. The major molecular targets in allograft rejection are allogeneic class I and class II major histocompatibility complex (MHC) molecules. Intact allogeneic MHC molecules may be presented on donor antigen-presenting cells (APCs) to recipient T cells (direct recognition), or the allogeneic MHC molecules may be internalized by host APCs that enter the graft or reside in draining lymphoid organs and be processed and presented to T cells as peptides associated with self MHC molecules (indirect recognition). The frequency of T cells capable of recognizing allogeneic MHC molecules is very high, compared with T cells that recognize any microbial peptide bound to self MHC, explaining why the response to alloantigens is much stronger than the response to conventional foreign antigens. Graft rejection is mediated by T cells, including cytotoxic T lymphocytes that kill graft cells and helper T cells that cause cytokine-mediated inflammation resembling delayed type hypersensitivity reactions, and by antibodies. Several effector mechanisms cause rejection of solid organ grafts. Preexisting antibodies specific for donor blood group, MHC, or other antigens cause hyperacute rejection characterized by thrombosis of graft vessels. Alloreactive T cells and antibodies produced in response to the graft cause blood vessel wall damage and parenchymal cell death, called acute rejection. Chronic rejection is characterized by fibrosis and arterial stenosis (graft vasculopathy), which may be due to inflammatory reactions mediated by T cell cytokines. Graft rejection may be prevented by minimizing the immunogenicity of the graft (by limiting MHC allelic differences) and treated by immunosuppression. Most immunosuppression is directed at T cell responses and entails the use of cytotoxic drugs, specific immunosuppressive agents, and anti–T cell antibodies. Widely used immunosuppressive agents target calcineurin, mTOR (mechanistic target of rapamycin), and lymphocyte DNA synthesis. Immunosuppression is often combined with antiinflammatory drugs, such as corticosteroids, that inhibit cytokine synthesis by macrophages and other cells. Patients receiving solid organ transplants may become immunodeficient because of their therapy and are susceptible to viral infections and malignant tumors. Xenogeneic transplantation of solid organs from pigs into humans is limited by the presence of natural antibodies to carbohydrate antigens on the cells of discordant species that cause hyperacute rejection. Other mechanisms of xenograft failure include antibody-mediated acute vascular rejection, T cell–mediated immune response to xenogeneic j p g MHC molecules, and prothrombotic effects of xenogeneic endothelium on human platelets and coagulation proteins. The ABO blood group antigens are polymorphic carbohydrate structures present on blood cells and endothelium that limit transfusions and some solid organ transplantations between individuals. Preexisting natural anti-A or anti-B IgM antibodies are present in individuals who do not express A or B antigens on their cells, respectively, and these antibodies can cause transfusion reactions and hyperacute allograft rejection. Rhesus (Rh) antigens are proteins on red blood cells that can stimulate IgG antibody responses in Rh-negative women carrying Rh-positive fetuses, and these anti-Rh antibodies can cause hemolytic disease in Rh-positive fetuses during subsequent pregnancies. Hematopoietic stem cell (HSC) transplants are performed to treat leukemias and genetic defects restricted to hematopoietic cells. HSC transplants are susceptible to rejection, and recipients require intense preparatory immunosuppression. In addition, T lymphocytes and NK cells in the HSC grafts may respond to alloantigens of the host and cause graft-versus-host disease (GVHD). Acute GVHD is characterized by epithelial cell death in the skin, intestinal tract, and liver; it may be fatal. Chronic GVHD is characterized by fibrosis and atrophy of one or more of these same target organs and the lungs and also may be fatal. HSC transplant recipients also often develop severe immunodeficiency, rendering them susceptible to infections. Chapter 18. Tumor Immunology Tumors express antigens that are recognized by the immune system, but most tumors suppress immune responses or are weakly immunogenic, and immune responses often fail to prevent the growth of tumors. Nonetheless, the immune system can be therapeutically stimulated to effectively kill tumors. Tumor antigens recognized by cytotoxic T lymphocytes (CTLs) are the principal inducers of and targets for antitumor immunity. Tumor-specific neoantigens generated by random mutations of cellular proteins, which can be processed into major histocompatibility complex (MHC) binding mutant peptides, are the most important, but other tumor antigens known to stimulate host T cells include products of mutated oncogenes, normal proteins whose expression is dysregulated or increased in tumors, and antigens of oncogenic viruses. Antibodies specific for tumor cell antigens are used for diagnosis, and the antigens are potential targets for antibody therapy. These antigens include oncofetal antigens, which are expressed normally during fetal life and whose expression is dysregulated in some tumors, altered surface glycoproteins and glycolipids, and molecules that are normally expressed on the cells from which the tumors arise and are thus differentiation antigens for particular cell types. Immune responses that are capable of killing tumor cells are mediated by CTLs, natural killer (NK) cells, and macrophages, possibly activated by tumor antigen–specific helper T cells. Among these immune effector mechanisms, the role of CTLs in protecting individuals from tumors is best defined. Tumors evade immune responses by several mechanisms, including downregulated expression of MHC molecules, selective outgrowth of cells that do not express tumor antigens, production of soluble immunosuppressive substances, the engagement of inhibitory receptors on lymphocytes by their ligands expressed on the tumor cells, and the induction of regulatory T cells. Tumor-associated macrophages and myeloid-derived suppressor cells, found in most solid tumors, can suppress antitumor immunity. Immunotherapy for tumors includes approaches that augment active immune responses against these tumors or provision of tumor-specific immune effectors to provide passive immunity to the patients. Antitumor immunity may be enhanced by blocking mechanisms of immune regulation. Immune responses also may be actively stimulated by vaccination with tumor cells or antigens, and by systemic administration of cytokines that stimulate immune responses. Antitumor antibodies are used widely in tumor immunotherapy. The antibodies bind to molecules on the surface of tumor cells and engage effector mechanisms to kill the tumors, including complement, NK cells, and phagocytes, or the antibodies bind to growth factor receptors, which blocks the signaling needed to sustain tumor cell growth. Tumor antigen–specific antibodies also have been conjugated with chemotherapeutic toxins or radioisotopes, to target these agents specially to tumors. Some genetically engineered bispecific antibodies simultaneously bind tumor antigens and activation receptors on T cells. CAR-T cell therapy is a form of cancer therapy in which a patient’s T cells are engineered ex vivo to express a hybrid antigen receptor (chimeric antigen receptor [CAR]) that recognizes a tumor antigen by antibody V domains and signals via cytoplasmic T cell receptor and costimulatory receptor motifs. The CAR-T cells are then transferred back to the tumor patient, where they become activated by tumor antigens and kill the tumor cells. CAR-T cell therapy has been effective in treating some hematopoietic tumors. Immune checkpoint blockade is a mode of tumor immunotherapy in which function-blocking antibodies against inhibitory receptors on T cells or their ligands, including PD-1 (programmed cell death protein-1), PD-L1 (PD-ligand 1), and CTLA-4 (cytotoxic T lymphocyte antigen 4), are administered to remove the brakes on lymphocyte activation and thus promote antitumor immunity by previously inhibited host T cells specific for tumor antigens. Checkpoint blockade has been widely adopted to treat many types of cancers. Chapter 19. Hypersensitivity Disorders  Disorders caused by abnormal immune responses are called hypersensitivity diseases. Pathologic immune responses may be autoimmune responses directed against self antigens or uncontrolled and excessive responses to foreign (e.g., microbial) antigens. Hypersensitivity diseases may result from antibodies that bind to cells or tissues (type II hypersensitivity), circulating immune complexes that are deposited in tissues (type III), or T lymphocytes reactive with antigens in tissues (type IV). Immediate hypersensitivity (type I) reactions are the cause of allergic diseases and are described in Chapter 20. The effector mechanisms of antibody-mediated tissue injury are complement activation and Fc receptor–mediated inflammation. Some antibodies cause disease by opsonizing host cells for phagocytosis or by interfering with normal cellular functions without producing tissue injury. The effector mechanisms of T cell–mediated tissue injury are inflammatory reactions induced by cytokines secreted mainly by CD4 + Th1 and Th17 cells and cell lysis by cytotoxic T lymphocytes. The classical T cell–mediated reaction is delayed-type hypersensitivity, induced by activation of previously primed T cells and the production of cytokines that recruit and activate various leukocytes, predominantly macrophages. The current treatment of autoimmune diseases is targeted at reducing immune activation and the injurious consequences of the autoimmune reaction. Agents include those that block inflammation, such as antibodies against cytokines and integrins, and those that block lymphocyte activation or destroy lymphocytes. A future goal of therapy is to inhibit the responses of lymphocytes specific for self antigens and to induce tolerance in these cells. Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, celiac disease, and psoriasis illustrate many of the effector mechanisms that cause tissue injury in hypersensitivity reactions and the roles of susceptibility genes and environmental factors in the development of these disorders. Chapter 20. Allergy Immediate hypersensitivity is an immune reaction triggered by mast cell activation, usually by antigen binding to IgE (immunoglobulin E) attached to mast cells. The steps in the development of immediate hypersensitivity are exposure to an antigen (allergen) that stimulates type 2 responses, characterized by production of the cytokines interleukin-4 (IL-4), IL-5, and IL-13, IgE production, binding of the IgE to Fcε receptors on mast cells, cross-linking of the bound IgE by the allergen, activation of mast cells, and release of mediators. Individuals who are susceptible to immediate hypersensitivity reactions are called atopic and often have more IgE in the blood and more IgE-specific Fc receptors per mast cell than do nonatopic individuals. IgE synthesis by B cells is induced by exposure to antigen and IL-4 and IL-13 secreted by T follicular helper (T) cells. Atopic diseases are characterized by repetitive bouts of type 2 inflammation involving various cell types, including Th2 cells, innate lymphoid cells (ILC2s), mast cells, basophils, and eosinophils. Mast cells are derived from bone marrow precursors that mature in tissues. They express high-affinity receptors for IgE (FcεRI) and contain cytoplasmic granules in which various inflammatory mediators are stored. Basophils are a type of circulating granulocyte that also express high affinity Fcε receptors and contain granules with contents similar to those of mast cells. Eosinophils are a special class of granulocyte; they are recruited into inflammatory reactions by chemokines and IL-4 and are activated by IL-5. Eosinophils are effector cells that are involved in killing parasites. In allergic reactions, eosinophils contribute to tissue injury. On binding of antigen to IgE on the surface of mast cells or basophils, the high-affinity Fcε receptors become crosslinked and activate intracellular signaling pathways that lead to granule exocytosis, releasing histamine and other vasoactive amines and proteases. In response to allergen, mast cells and basophils are also activated to synthesize and secrete lipid mediators, such as prostaglandins, leukotrienes, and platelet-activating factor, and cytokines, such as tumor necrosis factor, IL-4, IL-13, and IL-5. Vasoactive amines and lipid mediators cause the rapid vascular and smooth muscle reactions of immediate hypersensitivity, such as vasodilation, vascular leakage and edema, bronchoconstriction, and gut hypermotility. Cytokines released by mast cells and Th2 cells mediate the y y late-phase reaction, which is an inflammatory reaction involving neutrophil and eosinophil infiltration. Susceptibility to allergic diseases is inherited, and allelic variations of several genes have been associated with allergic asthma. Genetic susceptibility interacts with environmental factors to result in atopy. Various organs show distinct forms of immediate hypersensitivity involving different mediators and target cell types. The most severe and often fatal form is a systemic reaction called anaphylactic shock, characterized by diffuse edema with reduced blood volume, and airway obstruction. Asthma is a chronic airway disease with bronchial inflammation and episodes of reversible bronchial constriction. Most cases of asthma are a manifestation of repetitive immediate hypersensitivity reactions in the lung. Allergic rhinitis (hay fever) is the most common allergic disease of the upper respiratory tract. Food allergens can cause diarrhea and vomiting. In the skin, immediate hypersensitivity is manifested as wheal-and-flare (hives) and late-phase reactions and may lead to chronic atopic dermatitis (eczema). Drug therapy is aimed at inhibiting mast cell mediator production and at blocking or counteracting the effects of released mediators on target organs. Monoclonal antibodies against cytokines, cytokine receptors, and IgE are approved for some allergic diseases, including asthma. Desensitization immunotherapy involves controlled exposure to specific allergens with a goal of preventing or reducing Th2 cell responses and the production of IgE specific for those allergens. Immediate hypersensitivity reactions provide protection against helminthic infections by promoting eosinophil mediated cytotoxicity and gut peristalsis. Mast cells may also play a role in innate immune responses to bacterial infections. Chapter 21. Primary and Acquired Immunodeficiencies Immunodeficiency diseases are caused by congenital or acquired defects in lymphocytes, phagocytes, and other mediators of adaptive and innate immunity. These diseases are associated with an increased susceptibility to infection, the nature and severity of which depend largely on which component of the immune system is abnormal and the extent of the abnormality. Disorders of innate immunity include defects in microbial killing by phagocytes (e.g., chronic granulomatous disease or Chédiak-Higashi syndrome), leukocyte migration and adhesion (e.g., leukocyte adhesion deficiency), Toll-like receptor signaling, and complement. Severe combined immunodeficiencies include defects in lymphocyte development that affect both T and B cells and are caused by defective cytokine signaling, abnormal purine metabolism, defective V(D)J recombination, and mutations that affect T cell maturation.  Antibody immunodeficiencies include diseases caused by defective B cell maturation or activation and defects in T-B cell collaboration (X-linked hyper-IgM syndrome). T cell immunodeficiencies include diseases in which the expression of major histocompatibility complex molecules is defective, T cell signaling disorders, and rare diseases involving cytotoxic T lymphocyte and natural killer cell functions. Treatment of congenital immunodeficiencies involves transfusions of antibodies, stem cell transplantation, or enzyme replacement. Gene therapy may offer improved treatments in the future. Acquired immunodeficiencies are caused by infections, malnutrition, disseminated cancer, and immunosuppressive therapy for transplant rejection or autoimmune diseases. AIDS is a severe immunodeficiency caused by infection with HIV. This retrovirus infects CD4 + T lymphocytes, macrophages, and dendritic cells and causes progressive dysfunction of the immune system. Most of the immunodeficiency in AIDS can be attributed to the depletion of CD4 + T cells. HIV enters cells by binding to both the CD4 molecule and a coreceptor of the chemokine receptor family. After it is inside the cell, the viral genome is reverse-transcribed into DNA and incorporated into the cellular genome. Viral gene transcription and viral reproduction are stimulated by signals that normally activate the host cell. Production of virus is accompanied by death of infected cells. The acute phase of infection is characterized by death of activated and memory CD4 + T cells in mucosal tissues and dissemination of the virus to lymph nodes. In the subsequent latent phase, there is low-level virus replication in lymphoid tissues and slow, progressive loss of T cells. Persistent activation of T cells promotes their death, leading to rapid loss and immune deficiency in the chronic phase of the infection. CD4 + T cell depletion in HIV-infected individuals is largely due to direct cytopathic effects of the virus. Several reservoirs of HIV exist in infected individuals, including short-lived activated CD4 + T cells, longer-lived macrophages, follicular helper T cells and very long-lived, latently infected memory T cells especially in mucosal sites. HIV-induced depletion of CD4 + T cells results in increased susceptibility to infection by a number of opportunistic microorganisms. In addition, HIV-infected patients have an increased incidence of tumors, particularly Kaposi sarcoma and EBV-associated B cell lymphomas, and encephalopathy. The incidence of these complications has been greatly reduced by antiretroviral therapy. HIV has a high mutation rate, which allows the virus to evade host immune responses and become resistant to drug therapies. Genetic variability also poses a problem for the design of an effective vaccine against HIV. HIV infection can be treated by a combination of inhibitors of viral enzymes.