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The Immune System Notes.doc The Immune System Notes.doc Document Transcript

  • PCOL 582 Immune System Jan 11, 2006 OBJECTIVES: 1. Understand the difference between the innate and adaptive immune response. 2. Know the cells that provide immune coverage for the innate immune response. 3. Understand the differences between antibody and T-cell responses. 4. Understand the role of cytokines in the immune response. 5. Know the difference between Th1 and Th2 immune responses. 6. Understand the specific role of natural killer cells in immune responses. 1. OVERVIEW The immune system is a network of interacting cellular and soluble components. Its function is to distinguish entities within the body as "self" or "nonself" and to eliminate those that are non-self. Microorganisms are the principal non-self entities, but neoplasms, transplants, and certain foreign substances (eg, some toxins) are also important. To accomplish its tasks, the immune system has evolved two mechanisms: nonspecific immunity and specific immunity, which are linked to and influence each other. 2. NONSPECIFIC (INNATE) IMMUNITY – HOURS FOR RESPONSE This type of immunity is older phylogenetically, is present at birth, does not require a previous encounter with the offending substance, and does not develop memory. Innate immunity includes barriers, such as the skin, and chemical protection, such as gastric acid. There are two cellular components: (1) the phagocytic system (neutrophils and macrophages), whose function is to ingest and digest invading microorganisms, and (2) natural killer (NK) cells, whose function is to kill some tumors, microorganisms, and virally infected cells. The soluble components consist of complement proteins, acute phase reactants, and cytokines. Phagocytes include neutrophils and monocytes (in the blood) and macrophages (in the tissues). Widely distributed, macrophages are strategically situated at the interfaces of tissues with blood or cavitary spaces; eg, alveolar macrophages (lungs), Kupffer cells (liver sinusoids), synovial cells (joint cavities), perivascular microglial cells (lining of CNS), mesangial phagocytes (kidneys) and vascular endothelial cells. 2.A. Nonspecific Immune Responses Cytokine production, principally by macrophages and activated lymphocytes, serves as a prelude to specific immune responses. These pro-inflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α, interferon-γ) mediate an acute- phase response in the host that is not antigen-specific but remarkably consistent, developing regardless of the local and systemic nature of the inciting microorganism. Fever is the most obvious sign of the acute-phase response; in addition, the total number of neutrophils and the number of immature circulating neutrophils increase as a result of the effects of cytokines on the bone marrow; replication and differentiation of bone marrow cells toward mature neutrophils are augmented by granulocyte- macrophage colony-stimulating factor and granulocyte colony-stimulating factor. Endothelial cells produce large amounts of interleukin-8, an important mediator of neutrophil chemotaxis. 2.B. Inflammatory response directs immune system components to injury or infection sites and is manifested by increased blood supply and vascular permeability, which 1
  • PCOL 582 Immune System Jan 11, 2006 allows chemotactic peptides, neutrophils, and mononuclear cells to leave the intravascular compartment. Micro-organisms are engulfed by phagocytic cells (eg, neutrophils and macrophages) in an attempt to contain the infection in a small-tissue space. The response includes attraction of phagocytes in a chemotactic gradient of microbial products, movement of the phagocyte to the inflammatory site and contact with the organism, phagocytosis (ingestion) of the organism, development of an oxidative burst directed toward the organism, fusion of the phagosome and lysosome with degranulation of lysosomal contents, and death and degradation of the organism. When quantitative or qualitative defects in neutrophil function result in infection, the infection usually is prolonged and recurrent and responds slowly to antimicrobial agents. Staphylococci, gram-negative organisms, and fungi are the usual pathogens responsible for these infections. 3. SPECIFIC (ADAPTIVE) IMMUNE RESPONSES – DAYS FOR A RESPONSE Specific immunity has the hallmarks of learning, adaptability, and memory. The cellular component is the lymphocyte, and immunoglobulins (Igs) are the soluble component. Once infected, the host can produce a variety of antibodies or T-lymphocytes in response to specific microbial antigens. Antibodies--complex glycoproteins known as immunoglobulins--bind to specific antigenic targets and elicit a biologic response from the host. After binding to antigens, antibodies can enlist the host's effector cells, activate the complement system, or do both to help eradicate the infecting microorganism. 3.A. Lymphocytes are divided into two subsets: thymus-derived (T cell) and bone marrow-derived (B cell). Lymphocytes are clonally distributed; each clone specializes in recognizing a specific antigen (Ag) by means of its Ag receptor. Because the number of Ags is potentially limitless, this specialization would seem to place an undue burden on the immune system. The dilemma of providing an infinite number of unique clones is solved by the ability of the lymphocyte's Ag-receptor genes to combine in potentially limitless arrangements. 3.A.1. B-cells The function of the Ag receptor on B cells is mediated by surface immunoglobulins (sIgs). After B cells bind soluble Ag through their sIg, a series of events (eg, proliferation, differentiation) culminates in secretion of Ig that is the specific antibody (Ab) for that Ag. The current belief is that the Ab repertoire of an organism before exposure to Ag is due to Abs generated during B-cell maturation through Ig gene rearrangements. 3.A.2. T-cells T cells do not have sIg but recognize Ag by their principal recognition tool, the T-cell receptor (TCR), and other accessory adhesion molecules. Genes that encode the TCR belong to the Ig-gene superfamily; similar to the Ig genes, they are subject to recombination, thus giving rise to a large number of T-cell clones, each with a specific Ag responsiveness. The Ag-binding portion of the TCR consists of two chains (either αβ or γδ); each has a constant and a variable domain. Unlike Ig, which exists independently on the B-cell surface, the TCR is associated with the CD3 molecule; the whole unit is called the TCR/ CD3 complex. Although TCR chains are subject to gene rearrangement and are variable, CD3 chains (consisting of at least five chains) are invariable and are not Ag- specific. Some anti-CD3 Abs activate T cells directly, thus bypassing the requirement for 2
  • PCOL 582 Immune System Jan 11, 2006 Ag. Thus, CD3 is important for the transduction of the activation signal through the lymphocyte membrane. Lymphocytes can be further divided into subsets either by function or by surface markers. Lymphocyte subsets have been identified by combinations of certain molecules on their surfaces. These surface markers have been designated clusters of differentiation (CD). To date, 166 CD have been identified. Up-to-date information on CD antigens can be found on the worldwide web ( 3.A.3. Major Histocompatibility Complex The ability of the immune system to differentiate self from nonself is determined largely by products of the major histocompatibility complex (MHC) whose genes are on chromosome 6, belong to the Ig gene superfamily, and are subject to recombination (see Figure 2). Class I MHC products consist of HLA-A, -B, and -C; they have a wide distribution and are present on the surface of all nucleated cells and on platelets.Class II MHC products consist of HLA- D, -DR, -DP, and -DQ; they have a more limited distribution on B cells, macrophages, dendritic cells, Langerhans' cells, and activated (but not resting) T cells. B cells can respond to soluble Ag, but T cells rarely do so and recognize Ag only when embedded within the MHC; T cells therefore recognize MHC/Ag complex. The mechanism by which Ag is processed and associated with MHC before it is presented to the T cells is accomplished by antigen-presenting cells (APCs)--eg, Langerhans' cells, monocytes, macrophages, follicular dendritic cells, endothelial cells, and B cells. Although the nuances are not fully understood, it appears that to be processed, Ag must be unfolded, degraded, and fragmented. By exogenous processing, Ag undergoes endocytosis and degradation in lysosomes, is associated with class II MHC products, and is transported to the cell surface. By endogenous processing, Ag is produced intracellularly (eg, by viral infection) and undergoes degradation outside the lysosomes in organelles called proteosomes. The resulting peptides are transported to the rough endoplasmic reticulum (RER) by transporter proteins. Once in the RER, these peptides are associated with class I MHC products before transport to the cell surface. It is important to know whether Ag is associated with class I or II MHC, because the CD4 and CD8 molecules act as accessory adhesion molecules by binding to class II or I, respectively. Engagement of the TCR with the MHC/Ag complex may not be sufficient for induction of T-cell activation. A co-activation signal needs to be present; this second signal is mediated by engaging CD28 on the T-cell surface with CD80 or CD86 on the APC. Absence of the CD28/CD80-CD86 interaction may render the T cell anergic or tolerant. 3
  • PCOL 582 Immune System Jan 11, 2006 4. CYTOKINES Cytokines are potent molecules which can cause changes in cellular proliferation, differentiation, and movement at nanomolar to picomolar concentrations. It is clear that there are no circumstances in vivo in which cytokines are produced individually. Rather they are produced together with other cytokines in patterns characteristic of the particular stimulus or disease. The potency of cytokines, and the potential for amplification and damage which excessive cytokine carry, has resulted in elaborate controls on cytokine production and action. The current view of cytokine biology reflecting these concepts is of a network of positive and negative cytokines, and cytokine inhibitors and inducers, which combine to give an overall biological or clinical response. An important example of the cytokine network concept is the differential affect achieved in the description of TH1 and TH2 cytokine patterns. 4.A. COLONY STIMULATING FACTORS (CSF) are cytokines that stimulate individual pluripotent stem cells or committed progeny to produce RBCs, lymphocytes, neutrophils, monocytes, eosinophils, and basophils. G-CSF and GM-CSF are produce by recombinant DNA technology and have been approved by the FDA for use in patients with bone marrow depression such as cancer patients and patients who receive bone marrow transplants. In these patients the bone marrow is depressed due to intensive chemotherapy, or irradiation, and the use of colony stimulating factors avoids the profound and prolonged neutropenia. 4.B. INTERFERONS are produced by CD4+ cells and NK cells and have a wide range of effect. The important effect of interferons is the inhibition of viral replication in uninfected host cells. IFN-α and IFN-β bind to a common receptor on cells. The second effect of interferons in host defense is to increase expression of MHC class I molecules, TAP transporter proteins, and the Lmp2 and Lmp7 components of the proteasome, enhancing the ability of virus-infected cells to present viral peptides to CD8 T cells 4.C. CHEMOKINES are chemotactic cytokines. Chemokines are produced by a variety of cell types during the initial phase of host response to injury, allergens, antigens, or 4
  • PCOL 582 Immune System Jan 11, 2006 invading microorganisms. They selectively attract leukocytes to inflammatory foci, inducing both cell migration and activation. 4.D. GROWTH FACTORS support immune functions and wound healing. Transforming growth factor, for example, promotes fibroblast growth and wound healing and has potent antiproliferative activity as it acts as an negative regulator of immunity and hematopoiesis.. 4.E. CYTOKINE REGULATION. Regulation of cytokine expression follows a logical pattern. There is evidence for constitutive expression of hematopoietic cytokines such as M-CSF, G-CSF, CSF, IL-6 and EPO. Other cytokines are pre-synthesized and stored in cytoplasmic granules such as GM-CSF, TGFβ, PF-4, PDGF and membrane proteins TNFα, IL-1β, EGF, TGFβ or complexed with surface binding proteins. 4.F. Virokines. Pathogenic organisms, particularly pox viruses, have subverted the cytokine network to their own ends. For example, vaccina and cowpox viruses encode a secreted IL-1o binding protein. The Shope fibroma virus encodes a secreted TNF binding protein, and myxoma virus contains a secreted protein related to the IFNo receptor. The Epstein-Barr virus contains a homologue of IL-10 and the cytomegalovirus a homologue of MIP-1α receptor. The expression of these genes is thought to confer an immunological advantage to the viruses. 4.G. Cytokine receptors belong to four families of receptor proteins, each with a distinctive structure. Cytokines act on receptors that can be grouped into five families of structures with genetic, structural, and functional similarity. Some cytokine receptors are members of the: (1) immunoglobulin superfamily, (2) members of the hematopoietin receptor family, (3) members of the tumor necrosis factor (TNF) receptor family, (4) some are members of the chemokine receptor family, and (5) the Type I IFN family. Each family member is a variant with a distinct specificity, performing a particular function on the cell that expresses it. 5. INTERLEUKINS Interleukins are molecules made by leukocytes that act upon leukocytes. IL-1 (known as endogenous pyrogen, lymphocyte activating factor). IL-1 is a factor in osteoporosis, via the CNS induced fever, in the liver it causes production of acute phase proteins, virtually all cells of the body have receptors for IL-1, and it is key for T-cell activation. There are two forms of IL-1 (IL-1α and IL-1β). IL-1α is mostly cell associated and IL-1β is the secreted form. There also is an IL-1 receptor antagonist termed IL-1Ra which is related to the IL-1β. The IL-1Ra is made by the same cells that secrete IL-1β and may be an important physiological regulator. Sources of IL-1 include monocytes, endothelial cells, macrophages, Langerhans cells, T and B lymphocytes, smooth muscle cells, fibroblasts, thymic epithelium, astrocytes, glioma cells chondrocytes, and keratinocytes. IL-1 receptor is found on T and B lymphocytes, NK cells, neutrophils, eosinophils, dendritic cells, endothelial cells, and neural cells. IL-2 (Known as T-cell growth factor). IL-2 is produced by CD4+ TH and CD8+ cells. It is the most potent of growth factors and activators. IL-2 is used in experimental cancer 5
  • PCOL 582 Immune System Jan 11, 2006 therapy - especially renal cancer. IL-2 effects the target cells via the IL-2 receptor (IL-2r). The IL-2r consists of two chains, each of which can bind IL-2 with low affinity, and following stimulation the high affinity receptor is expressed with up to 50,000/cell. IL-3 (known as multispecific hemopoietin). IL-3 stimulates growth of precursors of all the hemopoietic lineage (RBC, Granulocytes, lymphocytes). IL-4 (known as B-cell activating or differentiating factor-1). IL-4 acts to induce B cell activation and differentiation. IL-4 is particularly important to the production of IgG1 and IgE. Induces MHC Class II in macrophages but inhibits cytokine production. IL-5 is chiefly a growth and activation factor for eosinophils. IL-5 is responsible for eosinophilia of parasitic disease. IL-6 (Known as B-cell differentiating factor) IL-6 is produced by T-cells, macrophages, B-cells, fibroblasts, and endothelial cells. It is very important in differentiation of B-cells into antibody-forming cells. IL-7 is made by thymic stroma and acts on thymocytes. IL-7 is a T-cell activation factor and a macrophage activation factor. It was reported at the 1996 International Cell Biology Society meeting that most blood IL-7 is in platelets and is secreted upon platelet activation. This adds to the list of cytokines (e.g., PDGF, TGF-beta, RANTES) also secreted by activated platelets. It is likely that IL-7 is stored and secreted from platelet alpha-granules, the granules that contain most of the proteins secreted by activated platelets. At a minimum, these observations raise questions about the role of IL-7 released at a site of injury, the usual activation site for platelets, and they raise intriguing questions about the possibility of a role specifically related to the co-release of other factors. In this regard, regulatory interactions between TGF-beta 1 and IL-7 are known. IL-8 belongs to a family of low molecular weight cytokines. They are produced by endothelial cells and macrophages. IL-8 is involved in inflammation and chemotaxis. IL-9 (known as P40, T cell growth factor III, mast cell growth-enhancing) IL-9 enhances proliferation of T-cells. It is produced by IL-2 activated lymphocytes. IL-10 (known as cytokine synthesis inhibitory factor) IL-10 inhibits production of IFNs , inhibits antigen presentation, and macrophage production of IL-6, IL-1, and TNFI . IL-11 (Adipogenesis inhibitory factor) IL-11 is a hematopoietic stimulator. IL-12 (natural killer stimulatory factor, cytotoxic lymphocyte maturation factor) Source is B cells, macrophage, and monocytes. It induces IFNB , by T cells and NK cells, enhances NNK and ADCC activity, and induces differentiation of the TH1 subset of T lymphocytes. IL-13 is secreted by activated T cells and inhibits production of inflammatory mediators: IL-1β, IL-6 TNFα and IL-8. IL-13 induces the expression of CD23 on B cells to promote proliferation and Ab secretion. IL-14 enhances B cell proliferation and inhibits Ig synthesis. 6
  • PCOL 582 Immune System Jan 11, 2006 IL-15 was isolated in the kidney epithelium and shares many of the properties of IL-2. It is found in many cell types including monocytes, placenta, skeletal muscle, kidney liver, heart, and bone marrow. 6. INTERFERONS: Interferons were first characterized by their antiviral activities. IFNα and IFNβ possess antiviral activities. IFN-α and IFN-β bind to a common receptor on cells. The interferon receptor is coupled to the promoters of several genes that induce the synthesis of host-cell proteins that contribute to the inhibition of viral replication IFNγ is produced by T cells and natural killer cells and has much less antiviral activity. IFNγ is a potent stimulator of MHC Class II expression and IFNα but IFNβ blocks this effect. In general IFNγ is a potent stimulator of APC. 7. TUMOR NECROSIS FACTORS: TNF (Tumor Necrosis Factor, cachectin) is an important mediator of inflammation and immune functions. TNFα is selectively cytotoxic for transformed cells especially in combination with IFNγ. (1) TNFα enhances macrophage and neutrophil anti-microbicidal activity. (2) TNFα enhances IFNγ release by NK. (3) TNFα enhances adhesion by endothelial cells. Sources: TNFα is secreted by activated macrophages, monocytes, T and B cells, and fibroblasts. TNFβ (Lymphotoxin) also induces death in tumor cells and is important as a mediator of inflammation and immune function. The sources are activated T and B lymphocytes. TNF Receptors There are two types of TNF receptors and they both bind TNFα and TNFβ. These receptors are located on all cells except for RBCs and resting T-  lymphocytes. 8. CHEMOKINES: During the late 1960’s and 1970’s, supernatants from cultures of stimulated leukocytes were shown to contain chemoattractants for monocytes and granulocytes. Over the past twelve years, many of these chemoattractants and their receptors have been purified and/or molecularly cloned. Chemokines are a large family of cytokines that control the trafficking of leukocytes. They participate in virtually all immune responses, from the sniffles to AIDS. There is great complexity to the action of chemokines because of the large number of factors and because of the overlapping specificities for the seven known chemokine receptors. The mechanism of chemokine action involves initial binding to specific seven transmembrane spanning G protein-linked receptors on target cells. To date, four different such receptors have been identified for the alpha chemokines (CXCR1-4) and five for the beta chemokines (CCR1-5). The interaction of chemokines with these G protein-linked receptors causes a rapid reconfiguration of adhesion proteins, such as β integrins, on the surface of the responding cells, facilitating their adhesion to endothelial cells (EC) lining blood vessel walls. This adhesion is followed by leukocyte transmigration between the EC into the tissues. Once there, the inflammatory leukocytes migrate along a gradient of increasing concentration of the chemokine to the site of 7
  • PCOL 582 Immune System Jan 11, 2006 origin. In response to the higher chemokine concentration at the site of injury or microbial invasion, the leukocytes are activated to perform effector functions such as release of their granule contents and increased production of cytokines. 10. T CELLS AND CELLULAR IMMUNITY T cells mature, acquire functional repertoires, and learn the concept of self in the thymus. The thymus accomplishes dual tasks of positive selection (clones that recognize Ag/MHC are allowed to proliferate, mature, and emigrate to the periphery) and negative selection (clones that react to self as if foreign are eliminated). The exact cellular and molecular mechanisms of this selection are not fully known. During fetal development, the T-stem cell, derived from bone marrow, moves to the thymus, where it matures and learns the concept of self. The process of thymic selection occurs, and mature lymphocytes are allowed to leave the thymus; they are found in peripheral blood and in lymphoid tissues. All mature T cells express CD4 or CD8 in a mutually exclusive fashion. 10.A. T-Helper Cells T cells that express CD4 are generally referred to as T-helper (TH) lymphocytes. These cells can be subdivided into two major categories, depending on their function, response to various cytokines, and ability to secrete cytokines. The current thinking is that TH cells start as precursor cells that make IL-2. On initial stimulation, these cells develop into THO cells, which can secrete several cytokines, including IFN- , IL-2, IL-4, IL-5, and IL-10. Depending on the cytokine available, THO cells can develop into either TH1 or TH2 cells, with IFN-γ and IL-12 favoring the development of TH1 and IL-4 and IL-10 favoring the development of TH2. TH1 and TH2 differ in the profile of the cytokines they secrete: TH1 cells secrete IFN-γ, whereas TH2 cells secrete IL-4, although both secrete several other cytokines (eg, IL-3, GM-CSF, TNF- ) equally well. In general, TH1 favors the promotion of cellular immunity, whereas TH2 favors the promotion of humoral immunity. 10.B. T-Suppressor/Cytotoxic Cells T cells that express CD8 are less well characterized than TH subsets, although it appears that they too can be divided into two types depending on the cytokines they secrete, with the segregation being identical to CD4 subsets. Cytotoxic T cells (TC) refer to Ag-specific MHC-restricted cytotoxic T lymphocytes. Both CD4 and CD8 cells can function as CTL, depending on whether class II or class I MHC is recognized, respectively. Several kinds of cytotoxic or killer cells are also recognized; only some of them express CD8 or CD4 markers. 10.C. Killer Cells Identification of each kind (of several) depends on MHC restriction, requirements for sensitization, target specificities, and responses to cytokines. Although macrophages can be cytotoxic, such toxicity is nonspecific and results from activation by some cytokines. The various types of killer cells can be simplified into MHC-restricted (eg, CTL) and MHC-nonrestricted (eg, NK cells). Neither kind requires Ab, complement, or phagocytosis to kill the target cell; instead, they deliver the lytic signal through the target cell membrane after establishing intimate cell-to-cell contact. MHC-restricted killers: Cytotoxic T lymphocytes (CTL) are killer cells generated only on specific sensitization either against cells that express foreign MHC products 8
  • PCOL 582 Immune System Jan 11, 2006 (allogeneic) or against autologous cells--provided these cells have been modified by viral infection or a chemical hapten (syngeneic). Allogeneic CTL can be readily generated in vitro on culture of normal lymphocytes with irradiated allogeneic stimulator cells that differ across all or part of the MHC barrier. Allogeneic CTL can also be generated in vivo on transplantation of an organ derived from a donor whose MHC products differ from those of the recipient and probably play an important role in organ transplant rejection. Successful generation of CTL requires two signals: the antigenic signal (stimulator cells) and the amplification signal (cytokines). Efficient action of these two signals requires APCs, TH, and TC precursors. The amplification signal is mediated by cytokines that act in tandem; the most important are IL-1, IL-2, and IL-4. Other cytokines (including IL-6, IL-7, IL-10, and IL-12) are believed to be involved in CTL generation, at least in vitro. Another kind of CTL that is important in eliminating certain intracellular pathogens (especially virally infected cells) is the so-called Ag-specific CTL (syngeneic CTL). Syngeneic CTL recognize only target cells that express the Ag used for sensitization in association with MHC. Such CTL are generated against autologous cells provided the cells have been "modified" by viral infection or chemical haptens. Expression of viral products, or haptens, on the cell surface in association with MHC triggers a cascade of cell differentiation and cytokine release and response similar to the allogeneic CTL. Both allogeneic and syngeneic CTL use the TCR/CD3 complex for target cell recognition. 11. MHC-nonrestricted killers: Unlike CTL, natural killer (NK) cells do not require sensitization to express their killer function. NK cells constitute 5 to 30% of normal peripheral blood lymphocytes. NK cells are lymphocytes, but they do not belong to the T- or B-cell lineages. Therefore, NK cells do not express sIg or TCR/CD3 on their surface. The surface markers that best characterize NK cells are CD2+, CD3-, CD4-, and CD56+, with a subset being CD8+. NK cells will kill certain autologous, allogeneic, and even xenogeneic tumor cells regardless of whether these targets express MHC; indeed, they may preferentially kill target cells that express little or no class I MHC. Susceptibility to killing by NK cells can be reduced if the target cell is induced to increase its MHC expression (eg, by transfection or by IFN). This apparent inhibition of NK killing activity by class I MHC expression led to the identification of several class I MHC receptors on the surface of NK cells. These receptors are structurally different from the TCR and are generally referred to as killer cell inhibitory receptors (KIR). NK cells have long been thought to be important in tumor surveillance because they can kill some tumor target cells and because most tumors lack MHC expression. NK cells also kill some virally infected cells and some bacteria (eg, Salmonella typhi). The Ag-recognition structure of NK cells remains elusive. In addition to their killing property, NK cells can secrete several cytokines, IFN- and GM- CSF (granulocyte-macrophage colony-stimulating factor) in particular. NK cells may be the most potent source of IFN- . By secreting IFN- , NK cells can influence the adaptive immune system by favoring the differentiation of TH1 and inhibiting the differentiation of TH2. 9
  • PCOL 582 Immune System Jan 11, 2006 12. Antibody-Dependent Cell-Mediated Cytotoxicity NK cells express CD16, a receptor for IgG-Fc, and can use this receptor to mediate another kind of MHC-nonrestricted killing. Ab-dependent cell-mediated cytotoxicity (ADCC) depends on the presence of Abs that recognize a target cell (ADCC specificity is therefore conferred by the specificity of the Ab). Upon binding its Ag, the Ab's Fc region is exposed and will bind its receptor on the NK cell to form a bridge. Once the bridge is formed, a poorly understood lytic signal is delivered to the target cell, resulting in its demise. 10