PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

本研究的总体目标是表征序列 抗乙酰胆碱受体（抗 AChR）通过的事件 抗体会导致抗体介导的异常 自身免疫性疾病，重症肌无力（MG）。 它涉及一个 实验性自身免疫三种形式的分析 我们实验室描述的重症肌无力 (EAMG) 是 通过注射 AChR 单克隆抗体 (mAb) 诱导。 的 急性形式在单次注射 mAb 后发生，并与 伴有细胞炎症和肌肉终板坏死 膜。 慢性期，发生在反复 注射，其特点是简化的终板膜 在没有炎症的情况下，AChR 含量降低，如 是典型的 MG。 然而，这些动物未能证明 明显的无力或阻塞的电生理证据 神经肌肉传递。 超急性形式是 仅由阻断 AChR 功能的抗 AChR mAb 诱导，可能 被视为慢性形式的镜像，即标记 形态学上阻断神经肌肉传递 正常终板。 该提案的具体目标包括 分析两种物质的产生机制 大鼠中 EAMG 的超急性和慢性形式。 一个更多 MG的完整模型将使用各种类型来生产 单克隆抗体通过不同的机制发挥作用，也许在 病程的不同时期。 最后 从这些动物研究中得出的假设将由 分析患者的抗体特征 MG 与疾病特征的关系。 该研究将 广泛利用免疫学、生物化学、 电生理学和形态学技术。 知识点 从这种“模型”自身免疫性疾病的研究中获得的结果应该 为特异性免疫治疗的发展提供线索 MG 以及提供可能适用的信息 其他不太了解的自身免疫性疾病。

The overall goal of this study is to characterize the sequence of events through which anti-acetylcholine receptor (anti-AChR) antibodies induce the abnormalities in the antibody-mediated autoimmune disease, myasthenia gravis (MG). It involves an analysis of the three forms of experimental autoimmune myasthenia gravis (EAMG), described in our laboratory, that are induced by injection of monoclonal antibody (mAb) to AChR. The acute form follows a single injection of mAb and is associated with cellular inflammation and necrosis of the muscle endplate membrane. The chronic phase, which occurs after repeated injections, is characterized by simplified endplate membranes with decreased AChR content in the absence of inflammation, as is typical for MG. However, these animals failed to demonstrate significant weakness or electrophysiologic evidence of blocked neuromuscular transmission. The hyperacute form, which is induced only by anti-AChR mAbs that block AChR function, may be viewed as the mirror image of the chronic form i.e. marked blockade of neuromuscular transmission with morphologically normal endplates. The specific aims of this proposal consist of an analysis of the mechanisms involved in the production of both the hyperacute and the chronic forms of EAMG in rats. A more complete model of MG will then be produced using various types of mAbs acting via different mechanisms, and perhaps at different times in the course of the illness. Finally the hypotheses derived from these animal studies will be tested by analyzing the characteristics of the antibodies from patients with MG in relation to the disease characteristics. The study will make use of a wide range of immunologic, biochemical, electrophysiologic and morphologic techniques. The knowledge gained from the study of this "model" autoimmune disease should provide clues to the development of specific immunotherapy of MG as well as providing information that is likely to be applicable to other less well understood autoimmune diseases.