Various studies over the last 25 years in Man and animal models have revealed many steps in the pathogenesis of myasthenia gravis (MG) which is now considered the classical organ specific, autoantibody mediated and T cell dependent human autoimmune disease. Though not a disease entity, MG is associated with pathological alterations of the thymus in about 80% of cases. These are described here with reference to distinct models of autoimmunization against the acetylcholine receptor (AChR). In MG with thymitis, intrathymic production of AChR-specific autoantibodies is the result of a classical antigen-driven immune reaction that occurs completely inside the thymus and probably involves AChR on myoid cells as the triggering (myasthenogenic) antigen. Genetic factors contribute essentially to the pathogenesis of this form of MG. In thymoma-associated MG genetic factors are probably of marginal significance. Neither intratumour autoantibody production nor T cell activation seem to occur and the AChR is not the myasthenogenic antigen. Instead, abnormal neurofilaments that share epitopes with the AChR and other autoantigen targets in paraneoplastic MG are expressed in thymomas and may trigger autoantigen-specific, non-tolerogenic T cell selection by molecular mimicry. These data support the hypothesis that initial steps in the pathogenesis of most MG cases take place within abnormal thymic microenvironments, be they inflammatory or neoplastic. Where these initial steps occur in MG cases without thymic pathology is not known. Likewise, the factors involved in the initial triggering of MG remain enigmatic in all MG subtypes.& k w d : Key words Autoimmunity · Thymus · Thymoma · Acetylcholine receptor · Aetiology& b d y :Myasthenia gravis as a prototypic model autoimmune diseaseThe triggering of a autoimmune disease is incompletely understood. In experimental models molecular alterations of autoantigens in an otherwise intact immune system may elicit autoimmunity [27], however, defects of the immune system facing an intact antigen repertoire may also lead to autoimmunity [75]. In addition, microenvironmental factors such as abnormal interleukin levels may change the interaction between a normal T cell repertoire and normal autoantigens [including the acetylcholine receptor (AChR)] as shown in mice [30,77]. In mice, the loss of an established tolerance [65,92,93] or the recruitment of ignorant T cells [32,76] have been described as mechanisms in the induction of autoimmunity but whether or not these mechanisms are involved in human autoimmune diseases has not been resolved.In fact, myasthenia gravis (MG) may be an ideal model to investigate the role of T cell tolerance in humans. The target autoantigens in MG (the AChR and striational autoantigens) are well characterized [52] as are the autoreactive T cells that play a pivotal role in MG by providing B cell help [36,61,62,82,111]. Since the late steps in the pathogenesis are well defined, MG should be an ideal disease in which to investigate those early steps in pathogenesis t...

Autoimmune phenomena are more frequent in thymic epithelial tumors (TET) than in any other human tumor. Mysthenia gravis (MG) is by far the most common autoimmune disease in thymoma patients. MG is characterized by muscle weakness due to autoantibodies against the acetylcholine receptor (AChR), and CD4 AChR-specific T cells play a pivotal role for the production of these autoantibodies. About 10% of MG patients have a thymoma and, interestingly, only such thymomas exhibit an MG association that maintains thymuslike morphological and functional features with respect to the homing and differentiation of immature T cells. Since AChR protein is not expressed in thymomas, the specificity of the autoimmunity in thymoma-associated MG is thought to be determined by nonreceptor proteins with AChR epitopes. Such proteins are overexpressed in cortical-type MG-associated thymomas, and medullary thymomas express these proteins at barely detectable levels. Aside from this quantitative difference, the pathogenesis of anti-AChR autoimmunity might be qualitatively different in these thymoma subtypes. Our findings suggest that an antigen-specific abnormal Tcell selection,by cortical-type TET may contribute to the pathogenesis of paraneoplastic MG. In contrast, an abnormal (intratumorous) activation of autoreactive T cells may be operative in medullary thymomas.

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