Pathogenesis of autoimmune myositis: Role of MHC Class 1

描述（由申请人提供）： 全身性自身免疫性风湿病目前尚无特异性治疗方法。开发特异性和有效的治疗方法需要确定疾病发病的重要途径。MHC 1类肌炎小鼠模型是鉴定此类途径的有力工具。这项建议的长期目标是确定负责自身免疫性肌炎中骨骼肌损伤和功能障碍的分子途径。MHC I类转基因小鼠产生了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，淋巴细胞和巨噬细胞的缺乏仅部分改善肌纤维损伤和功能障碍，这表明肌纤维中MHC I类的过表达也引发导致肌肉损伤的细胞自主（肌纤维）途径的特定序列。因此，在该模型中，免疫细胞和骨骼肌细胞似乎在完全爆发的自身免疫性肌炎的表现中起作用。因此，我们提出，骨骼肌细胞损伤的MHC I类表达肌纤维可以部分诱导细胞毒性T淋巴细胞和部分细胞内稳态的扰动（ER应激反应）。我们的初步实验清楚地表明，ER应激反应途径在人类肌炎和小鼠模型中都高度上调。明确ER应激反应和NF-kB通路在MHC I类表达纤维中的作用机制及其在肌纤维损伤和功能障碍中的作用是本提案的主要优先事项。该假设通过以下方式进行：a）在体内阻断ER应激反应途径和NF-κ B途径的关键成员，和B）通过基因和蛋白质表达谱鉴定介导肌纤维损伤和功能障碍的新的免疫和非免疫途径。所提出的目标不仅将定义转基因小鼠体内肌纤维损伤和功能障碍的主要机制，而且还可能确定人类肌炎治疗干预的新靶点。

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.