Porth's Essentials of Pathophysiology, 4e

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Infection and Immunity

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with genetic predisposition, it appears that other factors—such as a “trigger event”—interact to precipi- tate the altered immune state. The event or events that trigger the development of an autoimmune response are unknown. It has been suggested that the “trig- ger” may be a virus or other microorganism, a chemi- cal substance, or a self-antigen from a body tissue that has been hidden from the immune system during development. Role of Infections Viral and bacterial infections may contribute to the development and exacerbations of autoimmunity. In many persons, the onset of autoimmunity is associ- ated with or preceded by infection. In most of these cases, the infectious microorganisms are not present in lesions or detectable when autoimmunity develops. 1–3 Therefore, the lesions of autoimmunity are not due to the infectious agent itself, but to the immune process that was triggered by the microbe. There are three pro- posed mechanisms through which infections can trigger autoimmunity: breakdown of T-cell anergy, molecular mimicry, and superantigens. Breakdown of T-Cell Anergy. Infections of particu- lar tissues may induce local innate immune responses that attract leukocytes into the tissue and result in the activation of antigen-presenting cells. These antigen- presenting cells begin to express costimulators and secrete T cell–activating cytokines, resulting in the breakdown of self-tolerance. 1,2 Most normal tissues do not express the costimulatory molecules and thus are protected from autoreactive T cells. However, this protection can be lost if the cells that do not normally express the costimulatory molecules are induced to do so. Molecular Mimicry. One proposed link between infections and autoimmunity is molecular mimicry, in which a microbe shares an immunologic epitope with the host. 29,30 In rheumatic fever and acute glo- merulonephritis, a protein in the cell wall of group A β -hemolytic streptococci has considerable similarity with antigens in heart and kidney tissue, respectively. After infection, antibodies directed against the micro- organism cause a classic case of mistaken identity, which leads to inflammation of the heart or kidney. Not everyone exposed to group A β -hemolytic strep- tococci develops an autoimmune reaction. The reason that only certain persons are targeted for autoimmune reactions to a particular self-mimicry molecule may be determined by differences in HLA types. The HLA type determines exactly which fragments of a pathogen are displayed on the cell surface for presentation to T cells. One individual’s HLA may bind self-mimicry molecules for presentation to T cells, whereas anoth- er’s HLA type may not. In the spondyloarthropathies, particularly Reiter syndrome and reactive arthritis, there is a clear relationship between arthritis and a

the costimulatory signals that are necessary for its acti- vation. The peripheral activation of T cells requires two signals: recognition of the peptide antigen in associa- tion with the MHC molecules on the APCs, and a set of secondary costimulatory signals. Because costimula- tory signals are not strongly expressed on most nor- mal tissues, the encounter of the autoreactive T cells and their specific target antigens frequently results in anergy. 1,2 Another self-tolerance mechanism involves the apop- totic death of autoreactive T cells. 20,21,24 This type of apoptosis is mediated by an apoptotic cell surface recep- tor (called Fas) that is present on the T cell and a soluble membrane messenger molecule (Fas ligand) that binds to the apoptotic receptor and activates the death pro- gram (see Chapter 2). The expression of the apoptotic Fas receptor is markedly increased in activated T cells; thus, coexpression of the Fas messenger molecule by the same cohort of activated autoreactive T cells may serve to induce their death. Suppressor T cells with the ability to down-regulate the function of autoreactive T cells are also thought to play an essential role in peripheral T-cell tolerance. These cells are believed to be a distinct subset of CD4 + and CD8 + T cells. 25,26 The mechanism by which these T cells exert their suppressor function is unclear. They may secrete cytokines that suppress the activity of self-reactive immune cells, or they may delete the self-reactive T-cell clones. Mechanisms of Autoimmune Disease It is not known what triggers autoimmunity, but both genetic susceptibility and environmental factors, such as infectious agents, appear to play a role. Moreover, a number of autoimmune disorders such as SLE occur more commonly in women than men, suggest- ing that estrogens may play a role in their develop- ment. Evidence suggests that estrogens stimulate the immune response and androgens suppress it. 27,28 For example, estrogen stimulates a DNA sequence that promotes the production of interferon- γ , which is thought to assist in the induction of an autoimmune response. Genetic Susceptibility Genetic factors can increase the incidence and sever- ity of autoimmune diseases, as shown by the famil- ial clustering of several autoimmune diseases and the observation that certain inherited HLA types occur more frequently in persons with a variety of immu- nologic disorders. 2,22,23 For example, 90% of persons with ankylosing spondylitis carry the HLA-B27 anti- gen, compared with 7% of persons without the dis- ease. 2 Other HLA-associated diseases include Reiter syndrome with HLA-B27, rheumatoid arthritis with HLA-DR4, and SLE with HLA-DR3 (see Chapter 44). The molecular basis for these associations is unknown. Because autoimmunity does not develop in all persons