Inflammatory, immune, and viral aspects of inclusion-body myositis.
Muscle biopsies from patients with sporadic inclusion-body myositis (sIBM) consistently demonstrate that the inflammatory T cells almost invariably invade intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded by T cells. This indicates two concurrently ongoing processes, an autoimmune mediated by cytotoxic T cells and a degenerative manifested by the vacuolated muscle fibers and deposits of amyloid-related proteins. The autoimmune features of IBM are highlighted by the strong association of the disease with: a) HLA I, II antigens, in frequency identical to classic autoimmune diseases; b) other autoimmune disorders in up to 32% of the patients, autoantibodies, paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with increasingly recognized frequency (up to 13 known cases); and d) antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells with rearranged T-cell receptor genes that persist over time, even in different muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory molecules. In contrast to IBM, in various dystrophies the inflammatory cells are clonally diverse and the muscle fibers do not express MHC-I or costimulatory molecules in the pattern seen in IBM. Like other chronic autoimmune conditions with coexisting inflammatory and degenerative features (i.e., primary progressive MS), IBM is resistant to conventional immunotherapies. Recent data suggest that strong anti-T cell therapies can be promising and they are the focus of ongoing research.
Dalakas
Marinos C
MC
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA. dalakasm@ninds.nih.gov
D000368:Aged; D000682:Amyloid / Q000378:metabolism; D001327:Autoimmune Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D018925:Chemokines / Q000502:physiology; D016207:Cytokines / Q000502:physiology; D018450:Disease Progression; D004351:Drug Resistance; D005260:Female; D015329:Gene Rearrangement, T-Lymphocyte; D020022:Genetic Predisposition to Disease; D015658:HIV Infections / Q000150:complications; D006680:HLA Antigens / Q000032:analysis; D015490:HTLV-I Infections / Q000150:complications; D006801:Humans; D008297:Male; D045726:Metalloproteases / Q000502:physiology; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000209:etiology / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D010265:Paraproteinemias / Q000150:complications; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D014617:Vacuoles / Q000648:ultrastructure
D000682:Amyloid; D018925:Chemokines; D016207:Cytokines; D006680:HLA Antigens; D045726:Metalloproteases