Immune-mediated diseases appear to be increasing in prevalence in the population. These disorders are thought to be the result of chronic immune activation by selected environmental exposures in genetically susceptible individuals. The reasons for these reported increases in immune-mediated diseases are unclear, although our increasing exposure to novel immune-altering biologics, foods, drugs, and devices may play a role in this phenomenon. We are investigating the pathogenesis, and environmental/genetic risk factors, that lead to these diseases that result in high morbidity and mortality. Specific investigations underway include: A. Immunogenetic risk factors for, and pathogenesis of, selected connective tissue and autoimmune diseases that develop following exposure to biologics (including vaccines), drugs, foods, and medical devices. Sera and cell banks and large databases of clinical and genetic data, are being developed from idiopathic myositis patients around the world, both adult and pediatric, to compare the environmentally-related cases to this population and to gain an understanding of these disorders in different populations. Recent studies have shown that the phenotypic expression and genetic risks for myositis differ in different ethnic groups in different geographic environments. Preliminary data also suggest that the myositis that develops after silicone implants and certain vaccines may differ from idiopathic myositis in clinical features and autoantibodies. Studies of the capsules surrounding explanted silicone mammary prostheses imply that ongoing immune responses to silicone involve activation of macrophages, B cells and T lymphocytes via selected TCR utilization, and that the same T cell clones are found in both capsules and affected tissues. Genetic risk factors for development of L-tryptophan-associated eosinophilia myalgia syndrome (EMS) are being studied. Preliminary data from case control exposure studies suggest that certain HLA DQA1 alleles may be risk factors for development of EMS and many of its sequelae. Better definition of risk factors for such adverse events, and understanding their mechanisms, could lead to appropriate changes in products to enhance safety and screening of populations that could prevent or minimize these adverse events. B. Mechanisms for development of autoimmunity. Recent data suggest that microchimerism may play a role in the pathogenesis of several autoimmune diseases. Both PBMC (CD4+ and CD8+ cells)and target tissues(muscle and skin)from juvenile myositis patients have been shown to contain maternal cells by FISH and HLA-C PCR suggesting GVH-like pathogenetic mechanisms, and possible new approaches to the treatment of myositis. C. Assessment of myositis disease activity and damage. Given the inadequacies of current methods, new disease assessment tools are being developed and validated to apply to all forms of myositis in both adults and children, via an international multispeciality collaboration, with the intent of ultimately defining improvement and deterioration. This should enhance the consistency by which clinical trials are performed, the capacity to compare different treatments, and the efficiency of testing promising novel therapeutic agents.

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