PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

这项研究的总体目标是描述 抗乙酰胆碱受体(抗AChR) 抗体诱导抗体介导的免疫功能异常 自身免疫性疾病重症肌无力(MG)。它涉及到一个 实验性自身免疫的三种形式分析 重症肌无力(EAMG)，在我们的实验室描述，是 通过注射抗AChR的单抗(MAb)诱导。这个 急性肺炎在单次注射单抗后出现，并与 伴有肌肉终板的细胞炎症和坏死 薄膜。慢性期，在反复发作后发生 注射，其特征是简化的终板膜 在没有炎症的情况下AChR含量降低，因为 这是MG的典型症状。然而，这些动物未能证明 明显的虚弱或电生理证据阻塞 神经肌肉传递。超急性的形式，这是 仅由阻断AChR功能的抗AChR单抗诱导，可能 被视为慢性形式的镜像，即有标记的 用形态学方法阻断神经肌肉传递 普通端板。这项提案的具体目标包括 分析了这两种产品的生产机制 大鼠EAMG的超急性和慢性型。A更多 然后将使用各种类型制作完整的MG模型 通过不同的机制发挥作用的mAbs，可能在 在疾病过程中的不同时间。最后是 从这些动物研究中得出的假说将通过 慢性支气管炎患者血清抗体特征分析 MG与疾病特征的关系。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 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 其他鲜为人知的自身免疫性疾病。

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.