Pathogenesis of myasthenia gravis

Abstract

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...

Increased frequency of thymic T follicular helper cells in myasthenia gravis patients with thymoma

“…A total of 90% patients with MG have thymic aberrant alterations (1) and about 15-20% among which are demonstrated with histological pattern of thymoma (2). The association between pathological changes of the thymus and clinical symptoms of MG demonstrates that thymus is an important focus for initiating or perpetuating the autoimmune response in MG (3,4). Thymectomy results in suppression of both cellular and humoral immunity, and reduction in AChR antibodies,…”

A pathogenetic role for the thymoma in myasthenia gravis. Autosensitization of IL-4- producing T cell clones recognizing extracellular acetylcholine receptor epitopes presented by minority class II isotypes.

“…Nevertheless, mRNAs for individual AChR subunits have been detected in thymoma tissue by PCR (14)(15)(16), and for the adult-specific ⑀ subunit by less sensitive RNAase protection assays (MacLennan, C., D. Beeson, N. Willcox, A. Vincent, and J. Newsom-Davis, manuscript in preparation). Moreover, one group of mAbs against ␣ 371-380 of the cytoplasmic loop of the AChR ␣ subunit bind to the neoplastic epithelial cells (13), although they are apparently cross-reacting with a neurofilament protein (17,18). Since helper T cells might thus be sensitized by epitopes processed from individual subunits in these thymomas, their characterization should help to identify the original immunogen.…”

Recurrent Genetic Aberrations in Thymoma and Thymic Carcinoma

“…10,11 Whereas much has been learned about the pathogenesis of paraneoplastic autoimmunity in thymoma, 12,13 little is known about the molecular mechanisms of thymoma oncogenesis. In particular, in contrast to many other solid tumors, the genetic background of thymoma remains unknown so far.…”