Clinical and laboratory studies are conducted to determine etiology (infection, immunity and/or genetics) of various neuromuscular diseases and design effective therapies. Current studies involve patients with inflammatory myopathies (polymyositis, dermatomyositis, inclusion body myositis), motor neuron disorders with emphasis on post-polio syndrome, demyelinating polyneuropathies, hypokalemic periodic paralysis, dystrophies with emphasis on desmin and desmin related myopathies, and the stiff-person syndrome (SPS). In inflammatory myopathies, the mechanism of T cell invasion and the antigen-driven T cell responses are examined. Specifically, the role of cytokines, TGF-beta, 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 was studied by examining the T cell receptor profile and sequencing of the CDR3 region. The capacity of the muscle fibers to behave as antigen-presenting cells and bind to their ligands CTLA-4 and CD28 on T cells, was studied. The lack of apoptosis in the muscle and endomysial T cells was explored by studying IAP- like proteins and their mRNA's. Experimentally, the suppression of endomysial inflammatory response was studied in TGF-beta double knock-out mice, using fibronectin peptide motifs as novel therapies. In demyelinating neuropathies it was found that the Schwann cells behave as Antigen Presenting Cells. They express BB1, while the autoinvasive CD4+ T cells express the co-stimulatory molecules CTLA and CD28 at the protein and mRNA level. In the neuropathies caused by nucleoside analogues, there was mitochondiral dysfunction in the axon and Schwann cell and depletion of the nerve's mtDNA due to inhibition of the gamma-DNA polymerase. In patients with SPS, intrathecal synthesis of anti-GAD specific IgG antibodies was documented. The role of anti-GAD antibodies in suppressing the synthesis of GABA in vivo was explored by examining the GABA level in the CSF and the brain using MRS spectroscopy. The cause of distal myopathies associated with cardiomyopathies was examined and mutations in the desmin gene were identified. The functional role of these mutations was studied in transfected cell lines and the solubility of mutant desmin filaments was explored. A phenotype/genotype correlation is now performed in patients with this mutation. Randomized-controlled clinical trials with high-dose intravenous immunoglobulin have been completed in patients with dermatomyositis, inclusion body myositis and SPS. Changes in the cytokines profile and the anti-GAD65 antibody titers were determined after therapy and correlated with clinical response.
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