Role of Nitirc Oxide in Experimental Myasthenia Gravis

描述(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，可通过纯化的乙酰胆碱受体(AChR)在啮齿动物(如大鼠和小鼠)中诱导。神经肌肉功能障碍与产生针对突触后肌膜上AChR的自身抗体有关。由此导致的AChR功能异常导致人MG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都清楚地看到，对AChR具有反应性的抗体虽然是最显著的疾病决定因素，但并不是唯一的疾病决定因素。此外，与TH1/TH2活性平衡相关的细胞因子可能在EAMG的疾病症状严重程度中发挥重要作用。根据下面介绍的初步研究，一氧化氮(NO)很可能是一种既有好处也有坏处的强大免疫调节剂，可能是一种肌肉衍生因子，可能会影响疾病的严重程度和进展。因此，本项目的主要目标是评估肌源性NO在EAMG大鼠模型中影响疾病进展的可能性。在这项研究中使用的一般策略是通过监测体内暴露于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)后的骨骼肌，寻找iNOS/NO产生与EAMG之间的联系。本项目的具体目标如下：具体目标1.评估Lewis和WF大鼠个体克隆型AchR反应性抗体的iNOS/NO诱导活性。具体目的2.评价AchR反应性T细胞对大鼠骨骼肌iNOS/NO表达的影响。具体目的3.确定NO产生对EAMG相关免疫活动的影响。具体目的4.检测NO的产生对AChR免疫的Lewis大鼠的疾病易感性和AChR免疫的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.