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CONTRIBUTION OF MYOSITIS AUTOANTIBODIES TO COMPROMISED SKELETAL MUSCLE MEMBRANE REPAIR

Myositis is an idiopathic autoimmune disorder characterized by severe skeletal muscle inflammation and degeneration. Treatment of myositis is limited to systemic immunological suppression and development of future therapeutic strategies is contingent upon the elucidation of pathogenic mechanisms. The development of this disease is thought to result, at least in part, from intracellular antigen exposure producing an autoimmune response. The identification of autoantibodies generated during disease progression has proven to have clinical value in disease diagnosis. Recent studies in the Weisleder group show that muscle antigen exposure due to compromised membrane resealing accompanies myositis progression. Membrane resealing is an important physiological process for maintaining cellular integrity. There are multiple mechanisms that contribute to membrane resealing in eukaryotic cells. Mechanisms include endo‐ and exocytosis, budding, wound shedding and wound constriction. Some models rely on the translocation of intracellular vesicles to form a patch at the injury site. This translocation occurs through the use of motor proteins in which vesicles fuse with the membrane in a Ca2+ dependent manner, similar to the neurotransmitter release process. TRIM72, a TRIM family E3 ubiquitin ligase, has been identified as an essential component of the cell membrane resealing machinery. Various studies have demonstrated TRIM72's role in mediating sensing and vesicle translocation crucial in membrane repair, through the aid of motor proteins. Our study identified TRIM72 as a novel myositis specific autoantigen (MSA) and showed altered TRIM72 expression in myositis patient skeletal muscle biopsies. Due to TRIM72's role in membrane resealing and association with the progression of myositis, we hypothesize that TRIM72 proteins act as auto‐antigens following membrane injury resulting in autoantibodies that inactivate TRIM72, thereby compromising membrane resealing and increasing inflammation. Myositis patient sera, both positive and negative for TRIM72 autoantibodies, will be tested using a glass bead damage assay to determine their effects in the membrane resealing impairment associated with myositis progression. Laser injury assays will be performed to confirm the findings. We observe decreased membrane resealing capacities for TRIM72 autoantibody positive patient sera represented by a significantly higher lactate dehydrogenase (LDH) release as measured in our glass bead assay. These findings help elucidate the mechanisms underlying myositis progression and may improve the diagnosis and prognosis of patients suffering from myositis. These findings may contribute to the overall understanding of autoimmune disorders and musculoskeletal diseases.