Mechanisms of Disease: signaling pathways and immunobiology of inflammatory myopathies

The signaling pathways involved in the irnmunobiology of polymyositis, dermatomyositis, and inclusion-body myositis are outlined in this Review, which is based oil research performed during the past 10 years. In dermatomyositis, the complement cascade is activated and the expression of cytokines and chemokines is upregulated. In polymyositis and inclusion-body myositis, autoinvasive CD8(+) T cells are clonally expanded. This T-cell subset possesses conserved amino-acid sequences in complementarity-determining region 3 of the T-cell receptor and, via the perforin pathway, exerts a myotoxic effect oil muscle fibers that express major histocompatibility complex (MHC) class I molecules. In all inflammatory myopathies, molecules associated with T-cell transmigration and cytokine signaling, as well as chemokines and their receptors, are strongly expressed by endothelial and inflammatory cells. Early in the pathogenesis of polymyositis and inclusion-body myositis, expression of MHC class I molecules oil muscle fibers is upregulated, even in the absence of autoinvasive CD8(+) T cells. Emerging data indicate that such continuous upregulation of the expression of MHC class I molecules oil muscle fibers leads to all endoplasmic reticulum stress response, intracellular accumulation of misfolded glycoproteins, and activation of nuclear factor kappa B pathways, which call further stimulate formation of MHC class I-CD8 complexes, resulting in a self-sustaining inflammatory response. Advances in our understanding of the signaling pathways involved in the pathogenesis of these inflammatory myopathies are expected to result in the identification of novel therapeutic targets for these diseases.