Individuals who develop diseases in association with antibodies or T lymphocytes which react with self structures are said to have autoimmunity. Autoimmune disorders, most of which are connective tissue diseases, probably result from environmental agents acting upon genetically-susceptible hosts with subsequent immune activation and pathology. We are studying the epidemiology and pathogenesis of human autoimmune diseases to define etiologic factors, devise more effective therapies, and ultimately possibly prevent some of these diseases. Specific projects include: A) Defining the human leukocyte antigen (HLA), T cell receptor (TCR), and immunoglobulin (Gm) genes associated with autoantibodies specific to a group of diseases, which are characterized by chronic inflammation of muscle or myositis. Within the last year, the laboratory has used molecular HLA DR, DP, and DQ gene typing of genomic DNA, collected from over 250 myositis patients representing all the major clinical and autoantibody groups, to show associations of DR-beta, DQ- alpha, and Gm allotype genes with each of the myositis-specific autoantibodies and with certain clinical subgroups. Similar molecular studies of TCR gene expression in the periphery and target organs of myositis patients are also underway. Our recent data show that TCR restrictions exist in target tissues, and that muscle-infiltrating T cells differ in their CDR3 antigen-binding sequences in different clinical and serologic groups. These findings have important implications to many vaccines and other protein-based therapeutics that are licensed or in clinical trials and may induce adverse reactions as a result of immunologic hyper-responsiveness. B) Worldwide studies of the epidemiology of myositis attempting to associate immunogenetics, clinical signs and symptoms, geographic location, season of disease- onset, and therapeutic responses in the different clinical and autoantibody subsets. Preliminary data suggests that strong associations of the above do exist, and that seasonal and geographic clustering of myositis onset occurs in groups of patients defined by myositis-specific autoantibodies. C) Foods, drugs, biologics, devices and other environmental agents, that have been implicated in the development of connective tissue diseases, are being investigated re specific host risk factors associated with these disorders, and the clinical, serologic and genetic differences from that seen in the same idiopathic diseases. Current findings suggest that silicone gel from breast implants induce plasmacytomas in genetically- susceptible mice and autoimmunity in women with certain HLA genes. These and related data have important implications for many biologics, drugs and devices, both licensed and in clinical trials, that may result in adverse events including life-threatening diseases.
