Pathogenesis of autoimmune myositis: Role of MHC Class 1

自身免疫性肌炎的发病机制：MHC 1 类的作用

• 批准号: 7037612
• 负责人: KANNEBOYINA NAGARAJU
• 金额: $ 35.66万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037612
• 关键词: I kappa B beta; MHC class I antigen; autoimmune disorder; cysteine endopeptidases; disease /disorder model; endoplasmic reticulum; enzyme activity; gene expression profiling; genetically modified animals; laboratory mouse; laser capture microdissection; molecular pathology; muscle contraction; muscle proteins; myofibrils; myositis; northern blottings; nuclear factor kappa beta; pathologic process; posttranslational modifications; proteomics; sarcoplasmic reticulum; serine threonine protein kinase; striated muscles; thapsigargin; western blottings

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.

描述（由申请人提供）： 目前尚无针对系统性自身免疫性风湿病的具体疗法。开发特异性和有效的疗法需要定义疾病发病过程中重要的途径。 MHC 1 类肌炎小鼠模型是识别此类途径的有力工具。该提案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 类转基因小鼠具有人类自身免疫性多发性肌炎的多种特征，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只能部分改善肌纤维损伤和功能障碍，这表明肌纤维中 MHC I 类的过度表达也会启动细胞自主（肌纤维）途径的特定序列，从而导致肌肉损伤。因此，在该模型中，免疫细胞和骨骼肌细胞似乎在全面的自身免疫性肌炎的表现中发挥作用。因此，我们提出，表达 MHC I 类的肌纤维中的骨骼肌细胞损伤部分是由细胞毒性 T 淋巴细胞诱导的，部分是由细胞内稳态的扰动（ER 应激反应）引起的。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均高度上调。确定 ER 应激反应机制和 NF-kB 通路在 MHC I 类表达纤维中的作用及其在肌纤维损伤和功能障碍中的作用是该提案的主要优先事项。这一假设的追求是：a) 阻断体内 ER 应激反应途径和 NF-kB 途径的关键成员，b) 通过基因和蛋白质表达谱鉴定介导肌肉纤维损伤和功能障碍的新免疫和非免疫途径。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，而且还将有可能确定人类肌炎治疗干预的新靶点。