Autoimmune diseases mechanisms

Immunosuppression induced by sirolimus (36) appears to be mediated by a mechanism distincdy different from that of either cyclosporin or FK-506. Sirolimus markedly suppresses IL-2 or IL-4-driven T-ceU proliferation. The preclinical studies suggest that sirolimus is a potent immunosuppressive agent in transplantation and autoimmune disease models. The clinical potential of this agent depends on its toxicity profile (80). 

Autoimmune Disease. Figure 1 Mechanisms of self tolerance. DC, dendritic (antigen presenting) cell T, T-lymphocyte Th, T helper lymphocyte Treg, T regulatory lymphocyte. For details see text. 

Immune defense mechanisms can become deleterious for an individual when they are not controlled properly. Then they can cause disease. In such situations therapy is aimed to dampen immune reactions. Important examples are sqttic shock, allergy, autoimmune diseases, and chronic inflammatory diseases such as rheumatoid arthritis. Also, the success of organ transplantation... 

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown aetiology with some autoimmune features. Current thinking favours the hypothesis that interplay between genetic factors, sex hormones, and possibly an infectious agent or another immune activating agent initiates an autoimmune pathogenic mechanism that culminates in a disease with inflammatory and destructive features. 

During differentiation of T- or B-lymphocytes antigen recqrtors are generated which react to self or autoantigens. These are generally eliminated by the mechanisms of central tolerance or kept silent by the mechanisms of peripheral tolerance ( autoimmune disease). 

Breakdown of tolerance mechanisms. There are at least two mechanisms for maintaining unresponsiveness to self The first is by specific deletion of self-reactive clones and the second by suppression. A failure of either of these two may result in an autoimmune disease. In normal, healthy individuals, antigen-binding, self-reactive B cells and the resultant low litres of autoantibodies are not uncommon. The origin of the self-reactive B cells is not clear, but there are four ways in which they may become activated. 

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

Sakaguchi, S. et al., Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases, J. Immunol. 155, 1151-1164, 1995. 

The mechanism most commonly invoked to explain the association of infection with autoimmune disease is molecular mimicry that is, the concept that antigens (or more properly, epitopes) of the microorganism closely resemble self-antigens.50 The induction of an immune response to the microbial antigen thus results in cross-reactivity with selfantigens and the induction of autoimmunity. Although epitope specific cross-reactivity has been shown in some animal models,48,51 53 molecular mimicry is clearly demonstrated to be the causative mechanism in few, if any, human diseases.3 54,55... 

Rao, T. and Richardson, B., Environmentally induced autoimmune diseases Potential mechanisms, Environ. Health Perspect., 107(Suppl. 5), 737, 1999. 

There is considerable interest in the role of infectious agents in the development of autoimmune diseases. Some of this interest is based on the concept of molecular mimicry as a causal mechanism. Molecular mimicry refers to the possible pathologic role of cross-reactive antibodies or T cells to a self-antigen that is structurally similar to, and thus shares epitopes with, a viral or other infectious agent. For most autoimmune diseases, however, evidence of molecular mimicry leading to disease is not conclusive.1819 Viruses and other infections also have a less-specific immune effect, stimulating toll-like receptors and proinflammatory cytokine secretion, which is another mechanism that has been postulated to influence autoimmune disease risk.20... 

Few epidemiologic studies of pesticide use in general, or specific pesticides, in relation to any autoimmune disease. Mechanistic research primarily for hexachlorobenzene and malathion. Mechanisms other than endocrine-disruption should be considered, even for pesticides with endocrine-disrupting properties. 

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