Pathogenesis of autoimmune myositis: Role of MHC Class 1

描述(由申请人提供)： 目前还没有针对系统性自身免疫性风湿病的特殊治疗方法。开发特效的治疗方法需要定义在疾病发病中重要的途径。MHC-1类肌炎小鼠模型是识别这种途径的有力工具。这项建议的长期目标是确定导致自身免疫性肌炎骨骼肌损伤和功能障碍的分子途径。MHC I类转基因小鼠表现出人类自身免疫性多发性肌炎的几个特征，包括肌炎特异性自身抗体。初步实验表明，缺乏淋巴细胞和巨噬细胞只能部分改善肌肉纤维的损伤和功能障碍，这表明MHC-I类分子在肌肉纤维中的过度表达还启动了一系列特定的细胞自主(肌纤维)通路，导致肌肉损伤。因此，在这个模型中，免疫细胞和骨骼肌细胞似乎都在全面的自身免疫性肌炎的表现中发挥了作用。因此，我们认为表达肌纤维的MHC-I类分子对骨骼肌细胞的损伤部分是由细胞毒性T淋巴细胞引起的，部分是由细胞内稳态的扰动(内质网应激反应)引起的。我们的初步实验清楚地表明，内质网应激反应通路在人类肌炎和小鼠模型中都高度上调。明确内质网应激反应机制和核因子-kB通路在MHC I类表达纤维中的作用及其在肌肉纤维损伤和功能障碍中的作用是这项提议的主要优先事项。这一假说是通过a)在体内阻断内质网应激反应通路和核因子-kB通路的关键成员，以及b)通过基因和蛋白质表达谱来识别介导肌肉纤维损伤和功能障碍的新的免疫和非免疫通路。拟议的目标不仅将确定转基因小鼠体内肌肉纤维损伤和功能障碍的主要机制，还可能确定治疗人类肌炎的新靶点。

DESCRIPTION (provided by applicant): Specific therapies are not currently available for systemic autoimmune rheumatic diseases. Development of specific and effective therapies requires the definition of pathways important in the disease pathogcncsis. The MHC class 1 mouse model of myositis is a powerful tool to identify such pathways. The long term goals of this proposal are to define the molecular pathways responsible for the skeletal muscle damage and dysfunction in autoimmune myositis. The MHC class I transgenic mice develop several features of human autoimmune polymyositis including myositis-specific autoantibodies. Preliminary experiments showed that the absence of lymphocytes and macrophages only partially ameliorates muscle fiber damage and dysfunction suggesting that over-expression of MHC class I in myofibers also initiates a specific sequence of ceil autonomous (myofiber) pathways leading to muscle damage. Thus, in this model both immune cells and skeletal muscle cells appear to play a role in the manifestation of full blown autoimmune myositis. Therefore, we propose that skeletal muscle cell damage in MHC class I expressing muscle fibers can partly be induced by cytotoxic T lymphocytes and partly by perturbation of intracellular homeostasis (ER stress response). Our preliminary experiments clearly show that the ER stress response pathway is highly up-regulated in both human myositis and in the mouse model. Defining the contribution of mechanisms of ER stress response and NF-kB pathways in MHC class I-expressing fibers and their role in muscle fiber damage and dysfunction is a major priority of this proposal. This hypothesis is pursued by a) blocking critical members of ER stress response pathway and NF-kB pathways in vivo, and b) identifying novel immune and non-immune pathways mediating muscle fiber damage and dysfunction by gene and protein expression profiling. The proposed aims will not only define predominant mechanisms of muscle fiber damage and dysfunction in vivo in transgenic mice but will also potentially identify new targets for therapeutic intervention in human myositis.