DETERMINANTS OF DISEASE IN EXPERIMENTAL MYASTHENIA GRAVI

描述：(申请人摘要)：实验性自身免疫性肌无力 Lewis大鼠的重症肌无力涉及一种神经肌肉 由T细胞依赖性抗体反应引起的对 连接后乙酰胆碱受体(AChR)。其结果是软弱和 大鼠快速发作的疲劳与AChR的症状非常相似 人类重症肌无力(MG)患者。然而， 尽管抗AChR抗体似乎是神经肌肉疾病的直接原因 在人类功能障碍患者中，已经观察到有一种 令人不安的是，循环抗体效价和 症状的严重程度显示。因此，为了确定更多 抗AChR抗体与疾病之间的有用关系 拟议研究的目标是在重症肌无力模型中定义 系统中，这些参数规定了自动免疫何时转换为 病理学。将利用两个似乎模仿的老鼠品系 一个人体内的高抗体滴度转化为 转化为严重疾病，而另一个人的抗体效价高 转化为轻微的疾病或没有疾病。换句话说，校长 调查人员打算问为什么，即使刘易斯和维斯塔尔·弗思都是老鼠 菌株在产生这种抗体方面同样有效，这是一种疾病 一方面(在Lewis大鼠身上)观察到易感性，另一方面 另一方面(在Wistar Furth大鼠中)观察到抗病能力。这个 这项研究提案的基本前提是一些，但不是全部，抗AChR 抗体可致病(可能与不同的 产生的抗体的结合特异性)。因此，主要的 拟议研究的目标是发展过去观察到的 可澄清首席调查员实验室所做的说明 Lewis大鼠重症肌无力的疾病严重程度直接 由总人口中一小部分人的反应能力决定的 对AChR有反应的B细胞。到目前为止，老鼠B的致病亚群 已经发现，细胞至少部分地与独特型 抗ID单抗(11E10)最近识别的决定簇 在这个实验室准备的。识别和表征1)特定的 最直接的抗AChR抗体的克隆型/独特型亚群 负责诱发重症肌无力的疾病症状和2) 调节辅助性T细胞免疫优势亚群的影响可能指向 到诊断和监测人类疾病的更直接的策略， 也可能为未来提供新的、更有选择性的目标 免疫疗法。

DESCRIPTION: (Applicant's abstract): Experimental autoimmune myasthenia gravis (EAmyasthenia gravis) in Lewis rats involves a neuromuscular impairment caused by a T cell dependent antibody response against the post-junctional acetylcholine receptor (AChR). The result is weakness and rapid onset fatigue in the rats very similar to AChR symptoms observed in human patients with myasthenia gravis (myasthenia gravis). However, although anti-AChR antibodies appear to be the direct cause of neuromuscular dysfunction in human patients, it has been observed that there is a disturbing lack of correlation between the titer of circulating antibody and the severity of symptoms demonstrated. Thus, in order to identify more useful relationships between anti-AChR antibody and disease, the overall goal of the proposed study is to define, in the EAmyasthenia gravis model system, those parameters that dictate when autoimmunity translates into pathology. Advantage will be taken of two rat strains that appear to mimic the human scenario in which high antibody titer in one individual translates into severe disease, while high antibody titer in another individual translates into mild or no disease. In other words, the principal investigator intends to ask why, even though both Lewis and Wistar Furth rat strains are equally efficient at producing such antibodies, is disease susceptibility observed on the one hand (in Lewis rats) and disease-resistance observed on the other hand (in Wistar Furth rats). The basic premise of this research proposal is that some, but not all, anti-AChR antibodies can cause disease (perhaps related to differences of the exact binding specificity of the antibodies produced). Therefore, the primary goal of the proposed study is to develop means by which past observations made by the principal investigator's laboratory can be clarified indicating that disease severity in EAmyasthenia gravis in Lewis rats is directly determined by the responsiveness of a small subset of the total population of AChR-responsive B cells. Thus far, the disease-causing subset of rat B cells has been found to be associated, at least in part, with an idiotypic determinant recognized by a monoclonal anti-Id antibody (11E10) recently prepared in this laboratory. Identifying and characterizing 1) specific clonotypic/idiotypic subsets of anti-AChR antibody that are most directly responsible for inducing disease symptoms in EAmyasthenia gravis and 2) the influence of immunodominant subsets of regulating helper T cells may point to more direct strategies for diagnosing and monitoring disease in humans, and may also provide new, more selective, targets for future immunotherapies.