title: Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction.
abstract: 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-kappaB 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 C(2)C(12) skeletal muscle cells.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, Maryland 21224, USA. knagaraj@jhmi.edu
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Livia
authors.initials: L
authors.lastname: Casciola-Rosen
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lundberg
authors.forename: Rashmi
authors.initials: R
authors.lastname: Rawat
authors.forename: Shawna
authors.initials: S
authors.lastname: Cutting
authors.forename: Rachana
authors.initials: R
authors.lastname: Thapliyal
authors.forename: Jason
authors.initials: J
authors.lastname: Chang
authors.forename: Sunita
authors.initials: S
authors.lastname: Dwivedi
authors.forename: Megan
authors.initials: M
authors.lastname: Mitsak
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Plotz
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.forename: Eric
authors.initials: E
authors.lastname: Hoffman
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology*; D020869:Gene Expression Profiling; D005805:Genes, MHC Class I / Q000276:immunology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000473:pathology; D009220:Myositis / Q000235:genetics / Q000276:immunology*; D020721:Nervous System Autoimmune Disease, Experimental; D013312:Stress, Physiological / Q000235:genetics / Q000276:immunology*