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-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.
Nagaraju
Kanneboyina
K
Johns Hopkins School of Medicine, Baltimore, Maryland 21224, USA. knagaraj@jhmi.edu
Casciola-Rosen
Livia
L
Lundberg
Ingrid
I
Rawat
Rashmi
R
Cutting
Shawna
S
Thapliyal
Rachana
R
Chang
Jason
J
Dwivedi
Sunita
S
Mitsak
Megan
M
Chen
Yi-Wen
YW
Plotz
Paul
P
Rosen
Antony
A
Hoffman
Eric
E
Raben
Nina
N
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*