Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of various diseases of the neuromuscular system and design effective therapies. Current studies involve patients with polymyositis, dermatomyositis, inclusion body myositis, motor neuron diseases including post-polio syndrome, demyelinating polyneuropathies, neuromuscular diseases associated with HIV infection, metabolic myopathies, hypokalemic periodic paralysis, certain dystrophies, and stiff-person syndrome. Persistent or mutant poliovirus is sought in patients with post-polio syndrome and ALS. The mechanism of post-polio fatigue, a common and disabling symptom in many patients, is examined by analysis of the neuroendocrine axis, magnetic resonance spectroscopy and sleep studies. In inflammatory myopathies, the role of cytokines TGF-beta and IL-1 and metalloproteinases MMP-2 and MMP-9 in promoting amyloid formation and persistent endomysial inflammation were studied. The antigenic specificity and in situ clonal expansion of the endomysial T cells of patients with inflammatory myopathies and neuropathies was studied by examining the T cell receptor profile and sequencing the CDR3 region. The capacity of the muscle fiber or the Schwann cell to behave as antigen-presenting cells and bind to their ligands, CTLA-4 and CD28, on T cells was examined. The lack of apoptosis in muscle and T cells was explored by studying IAP-like proteins and mRNA expression. The mechanism by which anti-retroviral nucleoside analogs cause mitochondrial dysfunction and mDNA deletion in muscle and nerve was investigated. The cytotoxic basis of anti-GAD antibodies in patients with stiff-man syndrome was investigated and changes in the antibody titers were studied in vivo and in vitro as well as during therapy. The role of amphiphysin and GAD in this disease, as well as other autoimmune disorders affecting synaptic transmission, are being explored. The cause of distal myopathies associated with cardiomyopathies was examined and mutations in the desmin gene were discovered in the same patients. The functional role of these mutations was studied in transfected cell lines. The type of glucolipids recognized as antigens by certain IgM-associated paraproteinemic neuropathies was also examined.Randomized-controlled clinical trials were conducted with high-dose intravenous immunoglobulin in patients with polymyositis, dermatomyositis, inclusion body myositis, certain autoimmune demyelinating polyneuropathies and in the stiff-person syndrome. Experimentally, the suppression of the endomysial inflammatory response in TGF-beta double knock-out mice was studied using fibronectin peptide motifs as experimental therapies.
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