Role of Nitirc Oxide in Experimental Myasthenia Gravis

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DESCRIPTION (provided by applicant): Experimental Autoimmune Myasthenia Gravis (EAMG) is a neuromuscular disease that can be induced in rodents such as rats and mice by immunization with purified acetylcholine receptor (AChR). Neuromuscular dysfunction is associated with the production of autoantibodies directed at the AChR on the post-synaptic muscle membrane. The resulting abnormal function of the AChR leads to inefficient contractile function, muscle weakness and rapid fatigue characteristic of human MG. it is clear from both human and animal studies that antibody with reactivity against the AChR, although the most prominent disease determining factor, is not the only disease-determining factor. In addition, cytokines associated with the balance of TH1 vs TH2 activities may play an important role in the severity of disease symptoms in EAMG. In light of pilot studies presented below, it is likely that nitric oxide (NO), a potent immunomodulator capable of both beneficial and deleterious effects, may be a muscle-derived factor that could influence disease severity and progression. Therefore, it is the primary goal of this project to evaluate the potential of muscle-derived NO to influence disease progression in the rat model of EAMG. The general strategy to be used in this investigation is to seek links between iNOS/NO production and EAMG by monitoring skeletal muscle following in vivo exposures to immune mediators of EAMG (i.e., antibodies reactive with the acetylcholine receptor (AChR) and particular subsets of cytokine-producing cells). The Specific Aims of this project are as follows: Specific Aim 1. Evaluate INOS/NO-inducing activity associated with individual clonotypic ACHR-reactive antibody species of Lewis and WF rats. Specific Aim 2. Evaluate the ability of ACHR-reactive T cells to influence the expression of INOS/NO by rat skeletal muscle. Specific Aim 3. Determine influences of NO production on immune activities associated with EAMG. Specific Aim 4. Determine influences of NO production on the disease-susceptibility of the AChR-immune Lewis rat and the disease-resistance of the AChR-immune Wistar Furth rat.