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 cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, prompting an ongoing study that 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, it was found that the Schwann cells express markers for Antigen Presenting Cells while the autoinvasive CD4+ T cells express the co-stimulatory molecules CTLA and CD28 at the protein and mRNA level. The mechanism of action of IVIg in affecting these molecules and other autoantibodies has been addressed. In an effort to identify peripheral nerve antigens responsible for the demyelinating neuropathy and find effective therapies, a new controlled therapeutic study has been designed using a humanized monoclonal antibody against B cell clones. This study correlates clinical responses with the binding affinity of IgM to anti-glycoconjugate antibodies. In patients with Stiff Person Syndrome (SPS), intrathecal synthesis of anti-GAD-specific IgG antibodies was documented. 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. A randomized-controlled clinical trial with high-dose intravenous immunoglobulin was conducted in SPS patients and demonstrated efficacy of the drug, confirming the autoimmune nature of the disease. After treatment, the anti-GAD65 antibody titers diminished. This is the first immunotherapy proven effective in the disease. In an effort to find the responsible autoantigen, T cell clones were established from the CSF of several patients with SPS; the role of GAD as well as other peptides serving as antigens is currently explored. During the investigation of patients with IBM, a group of distinct hereditary distal myopathies associated with cardiomyopathy was identified on the basis of clinicopathological criteria. Additional studies have shown that this disease is 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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