PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

本研究的总体目标是表征 抗乙酰胆碱受体（抗AChR） 抗体诱导抗体介导的 自身免疫性疾病，重症肌无力（MG）。 它涉及到一个 实验性自身免疫三种形式的分析 重症肌无力（EAMG），在我们的实验室中描述， 通过注射抗AChR的单克隆抗体（mAb）诱导。 的 单次注射mAb后出现急性形式， 伴有细胞炎症和肌肉终板坏死 膜的 慢性期，发生在反复 注射，其特征在于简化终板膜 在没有炎症的情况下，AChR含量降低， 这是典型的MG。 然而，这些动物未能证明 明显的虚弱或电生理证据表明 神经肌肉传递 超急性型， 仅由阻断AChR功能的抗AChR单克隆抗体诱导， 被视为慢性形式的镜像，即标记 阻断神经肌肉传递， 正常终板。 该提案的具体目标包括： 分析了生产过程中所涉及的机制， 超急性和慢性形式的EAMG大鼠。 一个更 MG的完整模型，然后将使用各种类型的 单克隆抗体通过不同的机制发挥作用， 在疾病的不同时期。 最后 这些动物研究的假设将通过以下方法进行检验： 分析结核病患者的抗体特征， MG与疾病特征有关。 这项研究将 利用广泛的免疫学，生物化学， 电生理学和形态学技术。 知识 从这种“模型”自身免疫性疾病的研究中获得的结果应该 为开发特异性免疫疗法提供线索。 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.