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 unkown muscle-specific autoantigens. The messenger RNA of cytokines is variably expressed, except for a persistent up-regulation of interleukin 1β in inclusion body myositis and transforming growth factor β 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 β-amyloid precursor protein (β-APP) gene expression and β-APP promoter and colocalizes with β-APP within the vacuolated muscle fibers. In dermatomyositis, transforming growth factor β 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.