Intrathymic expression of neuromuscular acetylcholine receptors and the immunpathogenesis of myasthenia gravis

There is a large body of circumstantial evidence highlighting a primary role of the thymus in the pathogenesis of MG. Nevertheless, the etiologic link remains to be forged. We are reexamining the hypothesis that AChR expressed in the thymus drives the pathogenic autoimmune response. To this end, we have established a model of intrathymic inflammation that is localized to the thymic medulla and demonstrated that this inflammatory process promotes the nonspecific entry of peripheral CD4+ T cells into the thymus. Using this model, we are in the process of determining whether (a) AChR-reactive CD4+ T cell homing to the thymus is augmented by a concurrent intrathymic inflammatory response to an unrelated antigen, and (b) AChR-reactive T cell immigrants undergo activation following their engagement of autoantigen in this inflammatory milieu, provide help for the production of anti-AChR antibodies by immigrant autoreactive B cells, and thereby promote the development of a myasthenic syndrome.