Role of Nitirc Oxide in Experimental Myasthenia Gravis

描述（由申请人提供）：实验性自身免疫性重症肌无力（EAMG）是一种神经肌肉疾病，可通过纯化乙酰胆碱受体（AChR）免疫诱导大鼠和小鼠等啮齿动物。神经肌肉功能障碍与突触后肌膜上针对AChR的自身抗体的产生有关。由此导致的AChR功能异常导致人体MG的收缩功能低下、肌肉无力和快速疲劳特征。从人类和动物研究中可以清楚地看出，对AChR具有反应性的抗体虽然是最重要的疾病决定因素，但并不是唯一的疾病决定因素。此外，与TH1和TH2活性平衡相关的细胞因子可能在EAMG疾病症状的严重程度中发挥重要作用。根据下面提出的初步研究，一氧化氮（NO）可能是一种有效的免疫调节剂，能够产生有益和有害的影响，可能是一种肌肉来源的因素，可能影响疾病的严重程度和进展。因此，在EAMG大鼠模型中，评估肌源性NO影响疾病进展的潜力是本项目的主要目标。在这项研究中使用的一般策略是通过监测骨骼肌在体内暴露于EAMG免疫介质（即与乙酰胆碱受体（AChR）和特定细胞因子产生细胞亚群反应的抗体）后，寻找iNOS/NO产生与EAMG之间的联系。本项目的具体目标如下：评估Lewis和WF大鼠个体克隆型achr反应性抗体种类与INOS/ no诱导活性的关系。具体目标2。评价achr反应性T细胞对大鼠骨骼肌INOS/NO表达的影响。具体目标3。确定一氧化氮产生对EAMG相关免疫活性的影响。具体目标测定NO产生对achr免疫Lewis大鼠疾病易感性和achr免疫Wistar Furth大鼠抗病能力的影响。

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.