PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

重症肌无力的致病机制

• 批准号: 3399863
• 负责人: DAVID P RICHMAN
• 金额: $ 10.82万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3399863
• 关键词: acetylcholine; acute disease /disorder; autoimmune disorder; chronic disease /disorder; electromyography; electron microscopy; electrophysiology; monoclonal antibody; myasthenia gravis; pathologic process; tissue /cell culture

This proposal is designed to use two recent observations made in our laboratory to determine the mechanisms by which antibodies to acetylcholine receptor (AChR) induce myasthenia gravis (MG). The observations, which run somewhat counter to current theories, are: l) monoclonal antibodies (mcabs) that block the function of intact AChR induce severe acute myasthenia in the absence of histological abnormalities; 2) chronic administration in rats of anti-AChR mcabs incapable of blocking AChR function results in the histological abnormalities of MG in the absence of clinical or electromyographic abnormality. We propose to determine the precise nature of the chronic syndrome to establish whether the histological abnormality has pathogenic significance or whether it represents the healed stage of a more severe endplate injury similar to the acute phase of experimental myasthenia (EAMG). We also propose to determine whether the addition of either mcabs that block AChR function, mcabs more efficient in inducing increased AChR turnover, or combinations of many mcabs are required to produce the complete MG picture of histological, clinical, and electrophysiological abnormalities. We will make use of purified anti-AChR mcabs and Ig fragments and will study clinical weakness, electromyographic function, miniature endplate potential amplitudes, muscle content of AChR and AChR-mcab complexes, light and electron microscopic changes, and a number of serological and immune parameters. The combination of immunological, biochemical, electrophysiological, and pathological techniques should provide information on the sequence of events that leads to MG. This information may well suggest new means of treating or preventing this disease. In addition, since our present knowledge of MG makes it a "model" autoimmune disease, the information gained in this study will likely be applicable to other less well-understood autoimmune diseases.

这项建议旨在利用我们最近的两个观察结果， 实验室来确定乙酰胆碱抗体 受体（AChR）诱导重症肌无力（MG）。 观察结果显示， 与目前的理论有些相反的是：l）单克隆抗体 阻断完整AChR功能的单克隆抗体诱导严重的急性 无组织学异常的肌无力; 2）慢性 在大鼠中施用不能阻断AChR的抗AChR单克隆抗体 功能导致MG的组织学异常， 临床或肌电图异常。 我们建议确定 慢性综合征的确切性质，以确定是否 组织学异常是否具有致病意义， 代表更严重终板损伤的愈合阶段， 实验性肌无力急性期（EAMG）。 我们亦建议 确定是否添加阻断AChR功能的单克隆抗体， 更有效地诱导AChR周转增加的单克隆抗体，或组合 的许多单克隆抗体需要产生完整的MG图片， 组织学、临床和电生理异常。 我们将 利用纯化的抗AChR单克隆抗体和IG片段， 临床虚弱，肌电功能，微型终板电位 振幅、AChR和AChR-Mcab复合物的肌肉含量、光和 电镜变化，以及一些血清学和免疫学变化， 参数 免疫学，生物化学， 电生理和病理技术应该提供 关于导致MG的事件序列的信息。 这些信息 很可能为治疗或预防这种疾病提供了新的方法。 在 此外，由于我们目前对MG的了解使其成为自身免疫性“模型”， 疾病，本研究中获得的信息可能适用于 其他不太了解的自身免疫性疾病。