Activation of the endoplasmic reticulum stress response in autoimmune myositis - Potential role in muscle fiber damage and dysfunction
Activation of the endoplasmic reticulum stress response in autoimmune myositis - Potential role in muscle fiber damage and dysfunction
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DOI：
10.1002/art.21103
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发表时间：
2005-06-01
影响因子：
--
通讯作者：
Raben, N
中科院分区：
文献类型：
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作者：
Nagaraju, K;Casciola-Rosen, L;Raben, N
客观的。人类炎症性肌病的病因和发病机制仍不清楚。多项研究结果表明，炎症程度与临床疾病或肌纤维结构变化的严重程度并不一致，表明非免疫途径可能导致肌炎的发病机制。本研究旨在调查肌炎患者和 I 类主要组织相容性复合体 (MHC) 转基因小鼠肌炎模型中的这些途径。方法。我们使用生化、免疫组织化学和基因表达谱分析检测了人类肌炎患者和 I 类 MHC 转基因小鼠的肌肉组织的非免疫途径。结果。骨骼肌纤维中 I 类 MHC 的上调是人类炎症性肌病的早期且一致的特征。肌炎患者肌纤维的 I 类 MHC 染色显示细胞表面和内部反应性的网状模式。在人类肌炎患者和小鼠模型的肌肉组织中，内质网（ER）应激反应、未折叠蛋白反应（葡萄糖调节蛋白78途径）和ER超负荷反应（NF-κB途径）途径显着激活。野生型小鼠 I 类 MHC (H-2K(b)) 的异位表达而非 H-2K(b) 的可降解糖基化突变体在 C2C12 骨骼肌细胞中诱导 ER 应激反应。结论。这些结果表明，内质网应激反应可能是导致自身免疫性肌炎骨骼肌损伤和功能障碍的主要非免疫机制。干扰该途径的策略可能对患有这种疾病的患者具有治疗价值。
Objective. The etiology and pathogenesis of human inflammatory myopathies remain unclear. Findings of several studies suggest that the degree of inflammation does not correlate consistently with the severity of clinical disease or of structural changes in the muscle fibers, indicating that nonimmune pathways may contribute to the pathogenesis of myositis. This study was undertaken to investigate these pathways in myositis patients and in a class I major histocompatibility complex (MHC)-transgenic mouse model of myositis.Methods. We examined muscle tissue from human myositis patients and from class I MHC-transgenic mice for nonimmune pathways, using biochemical, immunohistochemical, and gene expression profiling assays.Results. Up-regulation of class I MHC in skeletal muscle fibers was an early and consistent feature of human inflammatory myopathies. Class I MHC staining in muscle fibers of myositis patients showed both cell surface and a reticular pattern of internal reactivity. The pathways of endoplasmic reticulum (ER) stress response, the unfolded protein response (glucose-regulated protein 78 pathway), and the ER overload response (NF-kappa B pathway) were significantly activated in muscle tissue of human myositis patients and in the mouse model. Ectopic expression of wild-type mouse class I MHC (H-2K(b)) but not degradable glycosylation mutants of H-2K(b) induced ER stress response in C2C12 skeletal muscle cells.Conclusion. These results indicate that the ER stress response may be a major nonimmune mechanism responsible for skeletal muscle damage and dysfunction in autoimmune myositis. Strategies to interfere with this pathway may have therapeutic value in patients with this disease.