Intrathymic Pathogenesis of Myasthenia Gravis

描述(申请人提供)：胸腺被认为是一种 重症肌无力在发病机制中的重要作用 以骨骼肌无力为特征的自身免疫性疾病。然而，它的作用是 这仍然是一个谜。自身抗原乙酰胆碱的表达 胸腺中的受体(AChR)，提出了对此免疫的假说 自身蛋白质可能在这个器官中被启动或永久存在。整体而言 这项建议的目的是通过以下方式加强我们对机制的理解 对这种自身抗原的免疫反应可能是在 胸腺。需要检验的假设是，对一种 胸腺髓质中的无关抗原导致进入胸腺 外周T细胞的胸腺。在这些胸腺移居者中包括T 具有低亲和力AChR受体的细胞。这样的T细胞在体内被激活 它们接触的发炎胸腺的局部环境上调 AChR、MHC抗原和共刺激分子在胸腺基质中的表达 细胞。这个项目的具体目标是1)进一步描述我们的 小鼠胸腺炎症模型，2)确定外周T细胞 与正常胸腺相比，炎症胸腺的迁移能力更强。 确定胸腺T细胞移行者是否被新的自身抗原激活 在炎症的胸腺中表达，以及4)确定AChR特异性T细胞 迁移到发炎的胸腺，通过局部表达而激活 自身抗原并引发肌无力综合症。一种基于逆转录病毒的载体 系统将被用于通过靶向表达来诱导胸腺炎症 胸腺髓质中一种无关的抗原--β-半乳糖苷酶 对该蛋白免疫的小鼠上皮细胞。这些研究提供了一种新颖的 探讨胸腺在MG发病机制中的作用。

DESCRIPTION (provided by applicant): 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.