Mechanisms of Autoimmunity

Lymphocytes that recognize self-antigens with high affinity undergo negative selection in the bone marrow (B cells) and thymus (T cells) and are eliminated via 

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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. 

The mechanisms of autoimmunity may also entail interaction with MHC structures determined by the HLA alleles. Individuals carrying certain HLA alleles have been shown to be predisposed to certain autoimmune diseases, which may account in part for the genetic variability of autoimmunity. In addition, metabolites of a particular drug may vary between individuals to confound the development of drug-induced autoimmunity. Dendritic cells, such as the Langerhans cells of the skin and B lymphocytes that function to present antigens to Th cells, express class-II... 

Adamus G. Autoantibody-induced apoptosis as a possible mechanism of autoimmune retinopathy. Autoimmun Rev 2003 2(2) 63-68. 

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. 

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). 

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Xu W, Fazekas G, Hara H, et al. Mechanism of natural killer (NK) cell regulatory role in experimental autoimmune encephalomyelitis. J Neuroimmunol 2005 163 24-30. 

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. 

Rowley, B. and Monestier, M. Mechanisms of heavy metal-induced autoimmunity, Mol. Immunol., 42, 833, 2005. 

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