The thymus has been considered to play an important role in the pathogenesis of myasthenia gravis (MG), a prototypic autoimmune disease characterized by skeletal muscle weakness. However, its role still remains a mystery. The expression of the autoantigen, acetylcholine receptor (AChR), in the thymus has raised the hypothesis that immunity to this self-protein may be initiated or perhaps perpetuated in this organ. The overall objective of this proposal is to enhance our understanding of mechanisms by which an immune response to this self-antigen might be engendered in the thymus. The hypothesis to be tested is that an inflammatory reaction to an irrelevant antigen in the thymic medulla leads to augmented entry into the thymus of peripheral T cells. Included amongst these thymic immigrants are T cells with low affinity receptors for AChR. Such T cells become activated in the local milieu of the inflamed thymus where they engage upregulated expression of AChR, MHC antigens and co-stimulatory molecules on thymic stromal cells.
The Specific Aims of this project are to 1) further characterize our murine model of thymic inflammation, 2) determine if peripheral T cell immigration to an inflamed thymus is enhanced relative to a normal thymus, 3) determine if thymic T cell immigrants are activated by a neo-self-antigen expressed in an inflamed thymus, and 4) determine if AChR specific T cells migrate to an inflamed thymus, become activated by locally expressed autoantigen and initiate a myasthenic syndrome. A retroviral based vector system will be used to induce thymic inflammation by targeting the expression of an irrelevant antigen, beta-galactosidase, in the thymic medullary epithelium of mice immunized to this protein. These studies provide a novel approach to elucidate the role of the thymus in the pathogenesis of MG.
| Levinson, Arnold I (2013) Modeling the intrathymic pathogenesis of myasthenia gravis. J Neurol Sci 333:60-7 |
| Levinson, Arnold I; Song, Decheng; Gaulton, Glen et al. (2004) The intrathymic pathogenesis of myasthenia gravis. Clin Dev Immunol 11:215-20 |
| Levinson, Arnold I; Zheng, Yi; Gaulton, Glen et al. (2003) Intrathymic expression of neuromuscular acetylcholine receptors and the immunpathogenesis of myasthenia gravis. Immunol Res 27:399-408 |
| Levinson, Arnold I; Zheng, Yi; Gaulton, Glen et al. (2003) A new model linking intrathymic acetylcholine receptor expression and the pathogenesis of myasthenia gravis. Ann N Y Acad Sci 998:257-65 |
