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，可通过用纯化的乙酰胆碱受体（AChR）免疫接种在啮齿动物（如大鼠和小鼠）中诱导。神经肌肉功能障碍与针对突触后肌肉膜上AChR的自身抗体的产生有关。由此产生的AChR功能异常导致人MG的低效收缩功能、肌无力和快速疲劳特征。从人和动物研究中清楚地看出，尽管最主要的疾病决定因素是具有抗AChR反应性的抗体，但它不是唯一的疾病决定因素。此外，与TH 1与TH 2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起重要作用。 根据以下初步研究，一氧化氮（NO）是一种既能产生有益作用又能产生有害作用的强效免疫调节剂，可能是一种肌肉源性因子，可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潜力。本研究中使用的一般策略是通过监测体内暴露于EAMG的免疫介质（即，与乙酰胆碱受体（AChR）反应的抗体和产生乙酰胆碱的细胞的特定亚群）。该项目的具体目标如下：具体目标1。评价与刘易斯和WF大鼠的个体克隆型ACHR反应性抗体种类相关的INOS/NO诱导活性。 具体目标2。评估ACHR反应性T细胞影响大鼠骨骼肌INOS/NO表达的能力。 具体目标3。确定NO产生对EAMG相关免疫活动的影响。 具体目标4。测定NO产生对AChR免疫刘易斯大鼠疾病易感性和AChR免疫Wistar Furth大鼠疾病抵抗力的影响。

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.