Immunologic mechanisms of tissue damage. Although the immune system generally is protective, the same mechanisms that protect the host may at times cause tissue damage so severe that death results. Gell and Coombs have classified these damaging immune reactions into four-types (these reaction sometimes are referred to as hypersensitivity reactions). A, Type I reaction: immediate hypersensitivity. This local or generalized response occurs within minutes of reexposure to an antigen to which the host has been pre- viously sensitized. 1. Pathogenetic mechanism. Type I reactions are initiated by antigens reacting with cell-bound antibody-usually IgE. a. The first step is initial exposure to the antigen, which stimulates IgE produc- tion. Mast cells and basophils are strongly attracted to IgE and bind the antibody through Fc receptors. This cytotropic antibody persists for weeks. b. Upon reexposure, the antigen binds to the cell-bound IgE at its Fab portion. When adjacent IgE molecules become bound (bridged) by the antigen, the mast cells and basophils are activated to release a variety of substances that mediate the hypersensitivity response. Mast cells also can be activated directly by C3a and C5a. c. The mediators of immediate hypersensitivity include histamine, chemotactic factors for eosinophils (ECF) and neutrophils (NSF), platelet activating factor, enzymes, leukotrienes, and prostaglandins. These effects include smooth muscle contract ion, vasodilatation , increased vascular permeability, and proteolytic destruction. 2. Clinical features. Immediate hypersensitivity reactions can manifest in many ways, depending on the target tissue. Type I reactions range frome life-threatening systemic anaphylaxis to the more minor conditions of allergic rhinitis (hay fever), and food allergies. a. Local signs include swelling, erythema, edema. pruritus, and urticaria; scal- ing, papular, or lichenoid lesions may be seen in atopic dermatitis. b. Generalised symptoms may include bronchoconstriction (which may be se- vere and progress to asphyxia), nausea and vomiting, hypotension, and circulatory collapse. B. Type II reaction: antibody-mediated cytotoxicity. In this type, antibody reacts with a normal or altered "cell-surface component, leading to subsequent destruc- tion or inactivation of the target cell, 1. Pathogenetic mechanism. Type II reactions are initiated by cytotoxic antibodies- usually IgM or IgG. When such antibody binds to antigen on a cell surface or in connective tissue, one of two antibody-mediated cytotoxic reactions occurs. a. Complement-mediated cytotoxicitv. In this reaction the binding the anti- body with cell-surface antigen causes complement to be activated via the classic pathway. This results in activation of the terminal complement compo- nents (the membrane attack complex) which can directly lyse cell membranes. C3b also enhances cytotoxicity by functioning as an opsonin. b. Antibody-dependent cell-mediated cytotoxicity (ADSS). Antibody also may affect cytotoxicity through complement independent mechanisms. In this reac- tion, target cells coated, with antibody are lysed by K cells, which possess Fc re- ceptors. 2.Clinical features. Examples of antibody-mediated cytotoxic reactions include: a. Transfusion reactions, in which transfusion of mismatched blood type re- sults in an immediate antibody reaction to nonself blood-group antigens, with resultant intravascular hemolysis. b. Antoimmune hemolytic anemia, in which patients produce antibodies to their own red cell antigens, with resultant intravascular hemolysis. C. Type III reaction: immune complex disease, In this type of reaction, circulating antigen-antibody (immune) complexes (which normally are removed by the reticu- loendothelial system) are deposited in tissues, leading to complement activation and further tissue injury, Immune complexes also may develop in situ (i.e., antibo- dies are directed against antigens that are endogenous to the tissues or have been planted there), thus triggering localized tissue damage. 1. Pathogenetic mechanism. a. Immune complex formation. Immune complexes are formed in the presence of antigen which may be exogenous (e.g., drugs, hormones, infectious agents) or endogenous (e.g., tumors, rheumatoid factor, altered DNA) - and antibody. The concentration and duration of exposure to the antigen as well as the quantity and type of antibody are important in determining the quantity and chronicity of com- plex formation and deposition. b. Inflammatory mechanisms. Once formed, immune complexes incite a varie- ty of inflammatory processes. (1) They can interact with complement, leading to the activation of C3a and C5a, with resultant release of vasoactive amines, increase in vascular permeability, and attraction of neutrophils. Neutrophils, through release of lysosomal enzymes, pro- duced local tissue injury. (2) Immune complexes also interact with pletelets, lea-ding to the formation of mi- crothrombi and further increase in vascular permeability due to the release of va- soactive amines from the activated platelets, 2. Clinical features. Immune complex diseases typically are characterized by mul- tisystem involvement reflecting that immune complexes are deposited in various tissues (e.g., the vessels, kidneys, joints, skin, muscle). Two important example of type III reactions-systemic lupus erythematosus (SLE) and polymyositis - are de- scribed in IVB a I\/E. D. Tvpe IV reaction: cell-mediated hypersensitivity. Cell-mediated hyper- sensitivity reactions do not require the presence of antibody and, characteristically, are delayed anywhere from about 24 hours to 2 weeks. Three interrelated mechan- isms are recognized, all of which involve activated T-cells. 1. Delayed-type hypersensitivity may be of the tuberculin or granulomatous type, a. Tuberculin-type hvpersensitivity. A subcutaneous infection of soluble protein antigen (tuberculin) will elicit an inflammatory reaction composed of lymphocvtes and mononuclear phagocytes. This reaction, characterized by induration and swel- ling at the infection site, becomes most intense within 1 to 2-days. (1) In this reaction. protein antigen is taken UP and processed by macrophages, then presented in the cell membrane of the macrophage in conduction with class II MHC antigen. Antigen-specific T cells recognize this complex and become acti- vated. (2) Through lymphokin and monokin signals, requitment and proliferation of addi- tional T cells, macrophages, and fibroblasts yield an amplified inflammatory reac- tion. If antigen is not cleared, the reaction may present as granulomatous inflam- mation. b. Granulomatous hvpersesitivity is clinically the most significant form of type IV reaction; sarcoidosis is an example of this type of reaction. (1) Granulomatous hypersensitivity results from the presence of a persistent antigen within macrophages. Usually, this antigen is the infectious agent, although granulomas may form in the presence of immune complexes or particulate matter (e.g.,talc) or for no apparent reason (e.g., in sarcoidosis, which is ofidiopathic ori- gin. (2) The characteristic morphologic pattern of granulomatous inflammation is dis- cussed in Chapter 1 VB.2b. 2. Cell-mediated cytotoxicity. The target of cytotoxic T cells may include MHC antigen, as is the case in organ transplantation rejection as well as in immunity to viral antigens in certain tumors. Cytotoxic T cells may kill by disrupting ionic flux in target cells. a. In cell-mediated cytotoxic reactions, helper (CD4+) T cells recognize target cell antigen in the context of class II MHC antigen. Cells naturally expressing class II MHC molecules (e.g., mononuclear phagocytes, endothelial cells, dendritic cells), thus, are important in the initiation of this inflammatory pathway, CD4+ T cells become activated, proliferate, and release lymphokines (YL-2), which amplify the pro1iferation. b. Cytotoxoc (CD8+ T cells recognise target cell antigen in the context of class I MHC glvcoprotein. Antigen-specific CDS-4- T cell population are expanded un- der the influence of YL-2. 3. NK-cell cytotoxicity . NC cells recognize a variety of cellular targets and are not restricted by MHC molecules. NK activity is thought to be important in immune reactions aimed at viral—or tumor targets.