Clinical, laboratory and therapeutic studies are conducted to determine etiology (autoimmunity, neurotoxicity, genetics) of various neuromuscular diseases and design, or apply, effective therapies. Current studies involve patients with: a) inflammatory myopathies with emphasis on inclusion body myositis (IBM); b) intermediate filament related disorders with emphasis on desmin-related neuromuscular disorders; c) demyelinating polyneuropathies; and d) the stiff-person syndrome(SPS). In inflammatory myopathies, the specificity of the T cell Receptors and the in situ clonal expansion of the endomysial T cells were examined. The studies have shown that in IBM the T cells are driven by specific antigens. To search for putative antigen(s), T cell clones have been established from the endomysial T cell infiltrates; candidate immunodominant peptides that drive the T cell responses and serve as autoantigens are currently explored using combinatorial peptide libraries. It has been found that in IBM chemokines and costimulatory molecules such as ICOS and ICOS-L are upregulated and the muscle fiber may function as Antigen Presenting cells. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an ongoing study explores the role of amyloid in triggering endomysial inflammation. The information will be useful in pursuing anti-amyloid strategies as potential therapy for IBM. To suppress the myocytotoxic effect of T cells and their putative role in enhancing the formation of beta-APP, a therapeutic and investigational clinical trial was designed using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. In demyelinating neuropathies associated with autoantibodies,a new controlled therapeutic study has started using a humanized monoclonal antibody against B cell clones. In an effort to identify peripheral nerve antigens responsible for the neuropathy, the study correlates clinical responses with the binding affinity of IgM to various glycoconjugates on the myelin sheath. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented and correlated with the clinical symptomatology. The anti-GAD antibodies appear to suppress the synthesis of GABA in vivo supporting the view that reduced GABA level is causatively related to the patients' symptoms. The manifestation of stiffness and heightened sensitivity as a result of dysfunction of the GABA-mediated inhibitory interneurons has been supported electrophysiologically by finding hyperexcitability of the brainstem interneuronal circuits. The GABA level in the brain was studied with MRS spectroscopy and the effect of therapies on GABA level is being examined. In an effort to find the responsible autoantigen in SPS patients, T cell clones were established from the CSF; the role of GAD as well as other peptides serving as antigens is explored. During the investigation of patients with IBM, two groups of distinct hereditary distal myopathies were identified. One group was related to mutations in the GNE gene resulting in abnormal glycosylation of muscle proteins. The other group, often associated with cardiomyopathy, was caused by pathogenic mutations in the desmin gene. The functional role of the mutations was studied in transfected cell lines and the solubility of mutant desmin filaments was explored. A phenotype/genotype correlation has now been completed in patients with mutant desmin. These studies have shown that desmin myopathy is a distinct disease affecting intermediate filaments (filamentopathy).
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