Clinical, laboratory and therapeutic studies were conducted to determine etiology (autoimmunity, neurotoxicity, genetics) of various neuromuscular diseases and design, or apply, effective therapies. Studies in FY07 involved patients with: a) inflammatory myopathies with emphasis on inclusion body myositis (IBM); b) inherited vacuolar myopathies with emphasis on hereditary IBM due to GNE mutations and desmin-related myopathies; 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 are examined longitudinally. 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, ICOS-L and PDI are upregulated and the muscle fiber may function as Antigen Presenting cell. Because cytokines share common antigenic determinants with the Alzheimer-like beta-APP amyloid deposits, an interrelationship between these molecules was explored. A linear relationship was found between cytokines, chemokines and amyloid-related degenerating molecules not only in vivo in the patient's muscles but also in vitro in human myotubes. At the clinical level, a longitudinal study examining the natural history of IBM has been completed. To suppress the myocytotoxic effect of T cells, a therapeutic and investigational clinical trial has begun using CAMPATH, a humanized monoclonal antibody that induces a sustained depletion of mature T cells allowing for toleragenic T cell responses. The study has been completed and is being analysed.? ? In demyelinating neuropathies associated with IgM autoantibodies to MAG and glycolipids,a new controlled therapeutic study was performed using Rituximab, a humanized monoclonal antibody against B cell clones. The study is now completed and the data are being analysed. Preliminary analysis demonstrates that Rituximab is effective in the disease in some subgroups and exerts its action by enhancing immunoregulatory T cells.? ? In an effort to find responsible autoantigens in patients with Stiff Person Syndrome (SPS), T cell clones were established from the CSF and being tested against combinatorial peptide libraries. Using proteomics in the patients' serum, the antigenic peptide GABARAP (GABA-Receptor Associated Protein), was found to be reduced. Further, anti-GABARAP antibodies were detected in up to 65% of SPS patients. These antibodies may destabilize the GABAA receptors and play a role in inducing the dysfunction of GABAergic pathways and the reduced level of GABA in the patients' brains as demonstrated with MRS spectroscopy. A new double-blind clinical trial using the B cell-depleting monoclonal antibody Rituximab has been completed and all 23 patients have been enrolled. The data is undergoing analysis. The origin of phobias, a common feature in SPS patients, was being explored using a series of neurocognitive measurements. It was found that the phobias are secondary to disability and not due to the primary disease.? ? In patients with hereditary IBM due to mutations in the GNE gene we observed a defect in glycosylation of muscle proteins and reduction of alpha-dystroglycan. A pilot clinical trial using intravenous immunoglobulin in an effort to increase muscle glycosylation was completed in 4 patients. The results are promising and are currently analyzed. A phenotype/genotype correlation has been completed in patients with hereditary myopathies due to pathogenic mutations in the desmin gene. It has been concluded that desmin myopathy is a distinct disease affecting intermediate filaments and the type of mutations may dictate clinical severity or presence of cardiomyopathy.
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