Activation of the endoplasmic reticulum stress response in autoimmune myositis: Potential role in muscle fiber damage and dysfunction

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-κB 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.