Pathogenesis of myasthenia gravis.
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 auto-antigen 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.
Marx
A
A
Department of Pathology, University of Würzburg, Germany.
Wilisch
A
A
Schultz
A
A
Gattenlöhner
S
S
Nenninger
R
R
Müller-Hermelink
H K
HK
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001323:Autoantibodies / Q000032:analysis / Q000378:metabolism; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D011950:Receptors, Cholinergic / Q000032:analysis / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013945:Thymoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D013953:Thymus Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology
D001323:Autoantibodies; D011950:Receptors, Cholinergic