Intrathymic Pathogenesis of Myasthenia Gravis

重症肌无力的胸腺内发病机制

• 批准号: 6362038
• 负责人: ARNOLD I LEVINSON
• 金额: $ 30.12万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362038
• 关键词: Retroviridae; T lymphocyte; acetylcholine; autoantigens; beta galactosidase; cell migration; disease /disorder model; inflammation; laboratory mouse; myasthenia gravis; neurotransmitter receptor; pathologic process; thymus; transfection

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.

描述（由申请人提供）：胸腺被认为是一种 在重症肌无力（MG）的发病机制中起重要作用， 以骨骼肌无力为特征的自身免疫疾病。然而，其作用 仍然是个谜自身抗原乙酰胆碱 受体（AChR），在胸腺提出了假设，免疫力，这一点， 自身蛋白质可能在这个器官中被启动或永久存在。整体 本建议的目的是通过以下方式增进我们对机制的理解： 对这种自身抗原的免疫反应可能会在 胸腺有待检验的假设是， 胸腺髓质中的不相关抗原导致进入胸腺髓质的增加。 胸腺外周T细胞。在这些胸腺移民中包括T 对乙酰胆碱受体亲和力低的细胞。这样的T细胞在体内被激活 在炎症胸腺的局部环境中， 胸腺基质AChR、MHC抗原和共刺激分子的表达 细胞该项目的具体目标是：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 相对于正常胸腺，向发炎胸腺的迁移增强，3） 确定胸腺T细胞移民是否被新自身抗原激活 在发炎的胸腺中表达，以及4）确定AChR特异性T细胞是否 迁移到发炎的胸腺，被局部表达的 自身抗原引发肌无力综合征基于逆转录病毒的载体 系统将用于通过靶向表达 一种不相关的抗原，β-半乳糖苷酶， 对该蛋白免疫的小鼠的上皮。这些研究提供了一个新的 探讨胸腺在MG发病机制中的作用。