Autoantibodies to membrane repair proteins in myositis

Project Summary Idiopathic inflammatory myopathies (IIM) are a group of inflammatory disorders characterized by muscle weakness and are associated with significant morbidity and mortality. Inflammation and muscle injury are the central histology features observed in IIM muscle. Both adaptive and innate immune responses are involved in the pathogenesis of IIM but the pathogenic mechanisms are not yet well defined. Current treatment options for myositis are limited and focus largely on the use of broad-spectrum immunosuppressive drugs that often lead to significant complications. Previous studies with synaptotagmin VII null (SytVII-/-) mice displayed impaired membrane repair capacity and developed mild myositis at two months of age, suggesting that antigen presentation of internal skeletal muscle proteins may play a role in initiating or exacerbating myositis. We generated a more robust model of inflammatory myositis by combining the SytVII-/- model with scurfy mice that have a regulatory T cell deficiency (FoxP3-/Y/SytVII-/-). Adoptive transfer of lymph node cells from FoxP3-/Y/SytVII- /- mice into Rag-1-/- mice lacking both T- and B-cells results in significant muscle inflammation. This finding also links the progression of myositis with defects in plasma membrane repair. The plasma membrane repair response is a conserved cellular response necessary to restore membrane integrity in myocytes and other cells as part of normal cellular physiology. Defects in membrane repair are linked to a variety of muscle diseases. Our previous work helped identify specific intracellular proteins as critical components of the membrane repair process. This application builds on our recently published work and new preliminary studies that identified novel autoantibodies in myositis patients against multiple proteins that are essential for the membrane repair. We also established that these autoantibodies can alter the membrane repair capacity of skeletal muscle. We hypothesize that compromised membrane repair leads to exposure of these membrane repair proteins to the extracellular space and that the autoantibodies produced against these proteins further compromise membrane repair and exacerbate the inflammatory response in myositis. Recent results support this hypothesis as increasing the levels of the antibodies in a myositis mouse model does elevate the pathologic hallmarks of myositis. We will test this hypothesis with three specific aims. Aim 1 will define the mechanistic role of autoantibodies against membrane repair proteins in myositis. Aim 2 will determine if patient autoantibodies directed against membrane repair proteins are sufficient to induce myositis. Aim 3 will test the efficacy of increasing membrane integrity of skeletal muscle as a novel therapeutic strategy to treat myositis. Our findings that compromised membrane repair contributes to the development and/or progression of myositis suggests a potential therapeutic approach for IIM.