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 刘易斯大鼠重症肌无力（EA重症肌无力）涉及神经肌肉 由T细胞依赖性抗体应答引起的针对 连接后乙酰胆碱受体（AChR）。 结果是软弱， 在大鼠中观察到的AChR症状非常相似， 患有重症肌无力（myasthenia gravis）的人类患者。 然而，在这方面， 虽然抗AChR抗体似乎是神经肌肉疾病的直接原因， 在人类患者的功能障碍中，已经观察到， 令人不安的缺乏相关性之间的滴度循环抗体和 症状的严重程度。 为了识别更多 抗AChR抗体和疾病之间的有用关系， 本研究的目的是确定在EA重症肌无力模型中， 系统，这些参数决定了自身免疫何时转化为 病理 我们将利用两种老鼠品系， 一个个体中的高抗体滴度转化为 而另一个人的抗体滴度很高， 转化为轻微或没有疾病。 换句话说，校长 研究人员打算问为什么，即使刘易斯和Wistar Furth大鼠 菌株在产生这种抗体方面同样有效， 一方面（在刘易斯大鼠中）观察到易感性， 另一方面观察到抗病性（在Wistar Furth大鼠中）。 的 这项研究建议的基本前提是，一些，但不是全部，抗AChR， 抗体可以引起疾病（可能与确切的抗体的差异有关）。 产生的抗体的结合特异性）。 因此，主要 拟议研究的目标是开发过去观测的方法， 主要研究者的实验室所做的说明可以澄清， 刘易斯大鼠重症肌无力疾病严重程度直接 由总人口的一小部分的反应性决定 AChR反应性B细胞的数量。 到目前为止，大鼠B的致病亚群 细胞已被发现，至少部分，与独特型 最近发现了一种由单克隆抗Id抗体（11E10）识别的决定簇 在这个实验室里准备的。 识别和表征1）特定 抗AChR抗体的克隆型/独特型子集，其最直接 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表明， 到更直接的诊断和监测人类疾病的策略， 也可能为未来的研究提供新的、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.