title: Molecular immunology and genetics of inflammatory muscle diseases.
abstract: Polymyositis, dermatomyositis, and inclusion body myositis, although immunopathologically distinct, share 3 dominant histological features: inflammation, fibrosis, and loss of muscle fibers. Progress in molecular immunology and immunogenetics has enhanced our understanding of these cellular processes. Based on the T-cell receptor gene rearrangement, the autoinvasive CD8+ T cells in polymyositis and inclusion body myositis, but not dermatomyositis, are specifically selected and clonally expanded in situ by heretofore unknown muscle-specific autoantigens. The messenger RNA of cytokines is variably expressed, except for a persistent up-regulation of interleukin 1beta in inclusion body myositis and transforming growth factor beta in dermatomyositis. In inclusion body myositis, the interleukin 1, secreted by the chronically activated endomysial inflammatory cells, may participate in the formation of amyloid because it up-regulates beta-amyloid precursor protein (beta-APP) gene expression and beta-APP promoter and colocalizes with beta-APP within the vacuolated muscle fibers. In dermatomyositis, transforming growth factor beta is overexpressed in the perimysial connective tissue but is down-regulated after successful immunotherapy and reduction of inflammation and fibrosis. The degenerating muscle fibers express several antiapoptotic molecules, such as Bcl-2, and resist apoptosis-mediated cell death. In myositis, several of the identified molecules and adhesion receptors play a role in the process of inflammation, fibrosis, and muscle fiber loss, and could be targets for the design of semispecific therapeutic interventions.
authors.affiliation: Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1382, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Dalakas
mesh_terms: D017209:Apoptosis; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D003882:Dermatomyositis / Q000235:genetics* / Q000276:immunology*; D015536:Down-Regulation; D005355:Fibrosis / Q000276:immunology / Q000503:physiopathology; D005786:Gene Expression Regulation; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D002479:Inclusion Bodies; D007249:Inflammation / Q000276:immunology; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000473:pathology; D017285:Polymyositis / Q000235:genetics* / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D001324:Autoantigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D012333:RNA, Messenger