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Mediators of immediate hypersensitivity are chemicals generated or released by effector cells following activation. They have various biological activities and normally function in host defense, but they play a pathologic role in immune hypersensitivity. Mediators may exist in a preformed state in the granules of mast cells and basophils, or are newly synthesized at the time of activation of these and some other nucleated cells (Tables 17–1 and 17–2). Increased awareness of the immunologic and physiologic effects of mediators has led to a better understanding of immunopathology and provides potential targets for future pharmacotherapies.
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Preformed mediators include histamine, eosinophil and neutrophil chemoattractants, proteoglycans (heparin, chondroitin sulfate), and various proteolytic enzymes. Histamine is a bioactive amine, packaged in dense intracellular granules, that when released binds to membrane-bound H1, H2, and H3 receptors resulting in significant physiologic effects. Binding to H1 receptors causes smooth muscle contraction, vasodilatation, increased vascular permeability, and stimulation of nasal mucous glands. Stimulation of H2 receptors causes enhanced gastric acid secretion, mucus secretion, and leukocyte chemotaxis. Histamine is important in the pathogenesis of allergic rhinitis, allergic asthma, and anaphylaxis.
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Newly generated mediators include kinins, platelet-activating factor, and arachidonic acid metabolites, including leukotrienes and prostaglandins. In many immune cells, arachidonic acid, liberated from membrane phospholipid bilayers, is metabolized either by the lipoxygenase pathway to form leukotrienes (LT) or by the cyclooxygenase pathway to form prostaglandins (PG) and thromboxanes A2 and B2 (TXA2 and TXB2). LTB4 is a potent chemoattractant for neutrophils. LTC4, LTD4, and LTE4 constitute slow-reacting substance of anaphylaxis, which has bronchial smooth muscle spasmogenic potency 100–1000 times that of histamine and which also causes vascular dilation and vascular permeability.
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Almost all nucleated cells generate prostaglandins. The most important members are PGD2, PGE2, PGF2, and PGI2 (prostacyclin). Human mast cells produce large amounts of PGD2, which causes vasodilatation, vascular permeability, and airway constriction. Activated polymorphonuclear neutrophils and macrophages generate PGF2a, a bronchoconstrictor, and PGE2, a bronchodilator. PGI2 causes platelet disaggregation. TXA2 causes platelet aggregation, bronchial constriction, and vasoconstriction.
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Macrophages, neutrophils, eosinophils, and mast cells generate PAF, which causes platelet aggregation, vasodilatation, increased vascular permeability, and bronchial smooth-muscle contraction. PAF is the most potent eosinophil chemoattractant described and also plays a role in anaphylaxis. The kinins are vasoactive peptides formed in plasma when kallikrein, released by basophils and mast cells, digests plasma kininogen. Kinins, including bradykinin cause slow, sustained contraction of bronchial and vascular smooth muscle, vascular permeability, secretion of mucus, stimulation of pain fibers contributing to human angioedema and anaphylaxis.
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The union of antigen with IgG or IgM antibody initiates activation of the classic complement pathway. Complement-fixing sites on these immune complexes are exposed, allowing binding of the first component of the complement sequence, C1q. Other components of the complement sequence are subsequently bound, activated, and cleaved, eventually leading to cell lysis. Important by-products of the classic pathway include activated cleavage products, the anaphylatoxins C3a, C5a, and less-potent C4a. C5a is a potent leukocyte chemotactic factor, and also causes mediator release from mast cells and basophils. C4b and C3b mediate binding of immune complexes to phagocytic cells, facilitating opsonization.
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Activation of the complement sequence by the alternative pathway is initiated by a number of agents, including lipopolysaccharides (LPS), trypsin-like molecules, aggregated IgA and IgG, and cobra venom. Activation of the alternative pathway does not require the presence of antigen-antibody complexes, nor does it use the early components of the complement sequence, C1, C4, and C2. Ultimately, as a result of activation of the classic or alternative pathway, activation of the terminal complement sequence occurs, resulting in cell lysis and/or tissue inflammation.
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Many immune functions are regulated or mediated by cytokines, which are soluble factors secreted by activated immune cells. Cytokines can be organized functionally into groups according to their major activities: (1) those that promote inflammation and mediate natural immunity, such as IL-1, IL-6, IL-8, TNF, and interferon (IFN)-γ; (2) those that support allergic inflammation, such as IL-4, IL-5, and IL-13; (3) those that control lymphocyte regulatory activity, such as IL-10, IL-12, and IFN-γ; and (4) those that act as hematopoietic growth factors, such as IL-3, IL-7, and GM-CSF (Table 17–3). This complicated network of interacting cytokines functions to modulate cellular function and immunologic responses. Many ongoing research investigations are focused on modulating cytokine responses as a way to control or treat disease processes.
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The major immunologic responses to antigen include the elimination of antigen through antibody-mediated events (humoral response) and the direct killing of target cells by a subset of T lymphocytes called cytotoxic T lymphocytes (CTLs) (cellular response). The series of events that embody the immune response include antigen processing and presentation, lymphocyte recognition and activation, cellular and/or humoral immune responses, and antigenic destruction or elimination (Figure 17–2).
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Immune responses may have both positive and deleterious effects. Tight control of inflammatory mechanisms promotes efficient elimination of foreign substances and prevents uncontrolled lymphocyte activation and unregulated antibody production. Inappropriate activation or dysregulation of the system, however, can perpetuate inflammatory processes leading to tissue damage and organ dysfunction. Inflammation is responsible for hypersensitivity reactions and for many of the clinical effects of autoimmunity.
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A. Antigen Processing and Presentation
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Most foreign immunogens are not recognized by the immune system in their native form and require capture and processing by specialized antigen-presenting cells. Antigen-presenting cells include macrophages, dendritic cells in lymphoid tissue, Langerhans cells in the skin, Kupffer cells in the liver, microglial cells in the nervous system, and B lymphocytes. Following encounter with immunogens, the antigen-presenting cells internalize the foreign substance by phagocytosis or pinocytosis, modify its parent structure, and display antigenic fragments of the native protein on its surface.
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B. T-Lymphocyte Recognition and Activation
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The recognition of processed antigen by specialized T lymphocytes known as “helper” T (CD4+) lymphocytes constitutes the critical event in the immune response. The helper T lymphocytes orchestrate the many cells and biological signals that are necessary to carry out the immune response. Helper T lymphocytes recognize processed antigen displayed by antigen-presenting cells only in association with polymorphic cell surface proteins encoded by the major histocompatibility gene complex. MHC genes are highly polymorphic and determine immune responsiveness. They are known as HLA or human leukocyte antigen, with certain HLA genotypes conferring genetic susceptibility to or resistance against a range of specific autoimmune, environmental, and occupational diseases.
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Endogenously synthesized viral proteins are processed in association with MHC class I molecules, while exogenous foreign antigens that require an antibody-mediated response are expressed in association with MHC class II structures. All somatic cells express MHC class I, whereas only the specialized antigen-presenting cells can express MHC class II. Helper T lymphocytes expressing the CD4 antigen recognizeantigen in the context of MHC class II, while cytotoxic T lymphocytes (CD8+) recognize target cells bearing MHC class I complexed to antigen.
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Two signals are required for activation of these T lymphocytes: (1) binding of the antigen-specific T-cell receptor (CD3) to the antigen-MHC complex, and (2) costimulation through CD28(on T cells)-B7(on antigen presenting cell) interactions. These two signals induce the expression of IL-2 receptors on the surface of the CD4+ lymphocytes, as well as the production of various cell growth and differentiation factors (cytokines). Activated CD4+ T helper lymphocytes subsequently trigger the effector cells that mediate the cellular and humoral arms of the immune response.
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Cytotoxic T lymphocytes (CTLs) eliminate target cells (virally infected cells, tumor cells, or foreign tissues), constituting the cellular immune response. These “killer” T lymphocytes release substances called cytotoxins, which lead to cytolysis or destruction of infected target cells. CTLs arise from the antigen-driven activation and differentiation of resting mature small lymphocyte precursors. Activated CTLs manufacture a membrane pore-forming protein (perforin or cytolysin), IFN-γ. Killing of target cells by CTLs requires direct cell-to-cell contact and proceeds sequentially by (1) adhesive interactions between CTLs and target cell, (2) activation of CTLs by antigen engagement of CTL receptors, (3) delivery of the lethal hit to target cells by poorly characterized mechanisms, and (4) programmed cell death of target cells.
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C. Activation of B Lymphocytes (Humoral Immune Response)
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The primary function of mature B lymphocytes is to synthesize antibodies. After proliferation and terminal differentiation, antigen binding to B-cell receptors, that is, surface antibodies, B cells become high-rate antibody-producing cells, called plasma cells. Antibodies are immunoglobulin molecules directed toward specific antigens and mediate humoral immunity. B lymphocytes may also bind and internalize foreign antigen directly, process that antigen, and present it to CD4+ T lymphocytes. A pool of activated B lymphocytes may differentiate to form memory cells, which respond more rapidly and efficiently to subsequent encounters with identical or closely related antigenic structures. These secondary immune responses are more rapid and larger as a consequence of immunologic memory.
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D. Antibody Structure and Function
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It has been estimated that the repertoire of immunoglobulin antigen specificities in the human body is 107. Immunoglobulins serve a variety of secondary biological roles, including complement fixation, transplacental passive immunization of neonates, and facilitation of phagocytosis (opsonization), all of which participate in host defense against disease (Figure 17–3). Circulating immunoglobulins have both a unique specificity for one particular antigenic structure and diversity to encounter a broad range of antigenic materials. This diversity arises from complex DNA rearrangements and RNA processing within B lymphocytes early in their ontogeny. All immunoglobulin molecules share a four-chain polypeptide structure consisting of two heavy and two light chains. Each chain includes an amino-terminal portion, containing the variable (V) region, and a carboxy-terminal portion containing four or five constant (C) regions. V regions are highly variable structures, which form the antigen-binding site, whereas the C domains support effector functions of the molecules. There are five classes (isotypes) of immunoglobulins, which are defined on the basis of differences in the C region of the heavy chains. IgG is the predominant immunoglobulin in serum. IgG antibodies are strong precipitins, and three subclasses—IgG1, IgG2, and IgG3—can activate complement, qualities contributing to the pathogenesis of serum sickness and certain types of hypersensitivity pneumonitis (eg, bird breeder's disease).
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IgA is the predominant immunoglobulin on mucous membrane surfaces. It exists predominantly as a monomer in serum and as a dimer or trimer when secreted on mucous membrane surfaces. When the dimer or trimer passes through the epithelial cells to a mucous membrane surface, it acquires a smaller molecule called a secretory piece that stabilizes the molecule and prevents its degradation by proteolytic enzymes. IgA antibodies protect the host from foreign antigens on mucous membrane surfaces, but they do not fix complement by the classic pathway.
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IgM is a pentamer that is found almost exclusively in the intravascular compartment. IgM antibodies are potent agglutinins and fix complement. They may mediate the trimellitic anhydride pulmonary anemia syndrome. IgD is a monomeric immunoglobulin. Its biological function is unknown.
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IgE is the heaviest immunoglobulin monomer, with a normal concentration in serum varying from 20 to 100 IU, but the concentration may be five times normal or even higher in an atopic individual. The Fc portion of IgE binds to receptors on the surfaces of mast cells and basophils. IgE antibodies play an important role in immediate hypersensitivity reactions such as nasal allergy and allergic asthma in veterinarians, laboratory animal handlers, and enzyme detergent industry workers.
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E. Humoral Mechanisms of Antigen Elimination
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Antibodies can induce the elimination of foreign antigen through a number of different mechanisms. Binding of antibody to bacterial toxins or foreign agents may neutralize or promote elimination of antigen-antibody “immune complexes” through the reticuloendothelial system. Antibodies can also coat bacterial surfaces, allowing clearance by macrophages in a process known as opsonization. Some classes of antibodies can complex with antigen and activate the complement cascade, which culminates in lysis of the target cell. Finally, the major class of antibody, IgG, can bind to natural killer cells that subsequently complex with target cells and release cytotoxins through antibody-dependent cytotoxicity (ADCC).