Porth's Essentials of Pathophysiology, 4e

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Disorders of the Immune Response

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prior bacterial infection, combined with the inherited HLA-B27 antigens. Superantigens. Superantigens are a family of related substances, including staphylococcal and streptococcal exotoxins, that can short-circuit the normal sequence of events in an immune response, leading to inappropriate activation of CD4 + helper T cells. Superantigens do not require the typical processing and presentation of anti- gen by APCs to induce a T-cell response. 31 Instead, they are able to interact with a T-cell receptor outside the normal antigen-binding site. This distinctive mode of activation, combined with the ability of superantigens to bind to a wide variety of MHC class II molecules, can lead to the activation of large numbers of T cells regard- less of their MHC/peptide specificity. Superantigens are involved in several diseases, including food poisoning and toxic shock syndrome. Release of Sequestered Antigens Normally the body does not produce antibodies against self-antigens. Thus, any self-antigen that was completely sequestered during development and then reintroduced to the immune system is likely to be regarded as foreign. Among the sequestered tissues that could be regarded as foreign are spermatozoa and ocular antigens such as those found in uveal tissue. Posttraumatic uveitis and orchiditis after vasectomy may fall into this category. Changes in antigen structure or release of hidden antigens may also account for the persistence of auto- immune disorders. Once an autoimmune disorder has been induced, it tends to be progressive, sometimes with sporadic relapses and remissions. A possible mechanism for the persistence and evolution of auto- immunity is the phenomenon called epitope spreading . 2 Infections, and even the initial autoimmune episode, may expose self-antigens that have been hidden from the immune system, resulting in continued activation of new lymphocytes that recognize the previously hid- den epitopes. Suggested criteria for determining whether a disor- der is an autoimmune disease include the following: evidence of an autoimmune reaction, determination that the immunologic findings are not secondary to another condition, and no other identifiable causes for the disorder. Currently, the diagnosis of autoim- mune disease is based primarily on clinical findings and serologic testing. The basis for most serologic assays is the demon- stration of antibodies directed against tissue antigens or cellular components. For example, an individual with a history of fever, arthritis, and a macular rash and who has high levels of antinuclear antibody has a probable diagnosis of SLE. The detection of Diagnosis andTreatment of Autoimmune Disease

autoantibodies in the laboratory usually is accom- plished by one of three methods: indirect fluorescent antibody assay (IFA), enzyme-linked immunosorbent assay (ELISA), or particle agglutination of some kind. The rationale behind each of these methods is similar: the patient’s serum is diluted and allowed to react with an antigen-coated surface (e.g., whole, fixed cells for the detection of antinuclear antibodies). In the case of IFA and ELISA, a second “labeled” antibody is added, which binds to the patient’s antibody and can induce a visible reaction. Particle agglutination assays are much simpler—the binding of the patient’s antibody to antigen-coated particles causes a visible agglutination reaction. For most serologic assays, the patient’s serum is serially diluted until it no longer produces a visible reaction (e.g., 1:100 dilution). This is called a posi- tive titer. Healthy persons sometimes have low titers of antibody against cellular and tissue antigens, but their titers usually are far lower than in patients with autoimmune disease. Treatment of autoimmune disease is based on the tissue or organ that is involved, the effector mecha- nism involved, and the magnitude and chronicity of the effector processes. Ideally, treatment should focus on the mechanism underlying the autoimmune disor- der. Corticosteroids and immunosuppressive drugs may be used to arrest or reverse the downhill course of some autoimmune disorders. Purging autoreactive cells from the immune repertoire through the use of plas- mapheresis is also an option in some severe cases of autoimmunity. Recent research has focused on the cytokines involved in the inflammatory response that accom- panies many of the autoimmune disorders (e.g., interferon- β for multiple sclerosis and tumor necrosis factor- α [TNF- α ] antibodies for rheumatoid arthritis and Crohn disease). ■■ Autoimmune diseases represent a disruption in self-tolerance that results in damage to body tissues by the immune system. ■■ Self-tolerance is maintained through central and peripheral mechanisms that delete autoreactive B or T cells or otherwise suppress or inactivate immune responses that would be destructive to host tissues. Defects in any of these mechanisms could impair self-tolerance and predispose to the development of autoimmune disease. ■■ Autoimmunity results from a failure of tolerance. Autoimmune disorders may be triggered by environmental stimuli, such as infections, in a genetically predisposed individual. SUMMARY CONCEPTS