Idiopathic inflammatory myopathies comprise a group of connective tissue diseases that include dermatomyositis, polymyositis, and inclusion body myositis. Each of these conditions is characterized by chronic skeletal muscle inflammation and muscle fiber damage. Demonstration of persistent excessive expression of MHC class I molecules and an associated unfolded protein response (UPR) in affected muscle fibers in each of these conditions suggests a common mechanism for chronic muscle fiber injury. A central pathogenic role for MHC class I is indicated by a mouse model, in which chronic myositis is induced by conditional expression of a transgenic MHC class I molecule, H-2Kb, specifically in skeletal muscle fibers, which typically express very little endogenous MHC class I. Transgenic H-2Kb expression overwhelms the protein folding system of muscle fibers and activates an UPR, which appears to mimic what occurs in human myositis. Remarkably, several weeks of transgenic H-2Kb expression is all that is needed to induce self-sustaining myositis that is driven by increased expression of endogenous MHC class I molecules in muscle fibers, which persists long after transgenic H-2Kb expression is suppressed. The mechanism for induction and maintenance of endogenous MHC class I expression is unclear, though we theorize that type I interferons are involved, since they are potent inducers of MHC class I expression, and there is evidence for type I interferon action in affected muscle tissue in both mouse and human myositis. Additionally, we have recently discovered that the UPR can strongly enhance expression of type I interferons, particularly in the context of concurrent innate immune activation. This finding suggests a novel connection between the MHC class I-induced UPR and MHC class I-inducing type I interferons that leads us to hypothesize that UPR-induced type I interferons are produced by affected skeletal muscle fibers and are critical mediators of sustained endogenous MHC class I expression in the murine model of myositis. We will test this hypothesis by characterizing type I interferon production in muscle cells and tissue in response to excessive MHC class I expression and UPR activation, and by determining the role of type I interferon action in the mouse model of myositis by assessing the impact of type I interferon receptor deficiency. Ultimately, elucidating the mechanism of chronic myositis in the mouse model should make important contributions to understanding the mechanism of chronic human myositis, and provide strong rationale for development of novel treatments for human myositis that disrupt the proposed self-sustaining cycle of chronic disease. ? ? ?
