AUTOIMMUNE PARANEOPLASTIC SYNDROMES

这项计划的目标是确定自体抗原在 胆碱能神经元是致病抗体的靶点 兰伯特-伊顿肌无力综合征(LES)。长距离的 目标是为LES设计抗原特异性治疗方法。引人注目 LES的特征包括超过55%的致命性死亡 肺癌、小细胞(燕麦细胞)癌(SCC)和高 甲状腺和胃成分的自身抗体的流行。 虚弱是由于乙酰胆碱排出不足所致。 (ACh)来自运动神经末梢对神经冲动的反应。 将患者血清中的免疫球蛋白注射到小鼠体内引起 与LES相似的神经传递缺陷。 有相当多的证据表明，胆碱能的异常 LES中神经传递受损的神经元是由 作为抗肿瘤反应而启动的自身免疫反应 针对鳞状细胞癌的神经元相关分化抗原。 电压敏感的钙通道被认为是 抗原。本项目旨在研究鳞状细胞癌的质膜。 对于与LES抗体反应的抗原和分子 与胆碱能神经元上与ACh相关的那些 放手。 LES患者的抗体将进行病理生理测试 胆碱能药物对克隆系和初级制剂的影响 神经元，使用微量分析来测量电压依赖的内流 ~(45)Ca~(2+)和~3H-ACh的释放。一种新的快速被动转移 小鼠LES模型的建立有助于分析其发病机制 对LES中的ACh量子释放受损负责。孤立 鱼雷电器官的胆碱能神经末梢 加州将被调查为潜在的丰富来源 LES抗原。蜗牛地理圆锥的omega毒素， 对压敏钙离子具有较高的亲和力和特异性 突触前神经末梢的通道，是一种很有前途的工具 鉴定LES抗原。由以下公司制造的单抗 SCC或胆碱能免疫大鼠的杂交瘤 神经元成分，以及来自LES患者的B细胞系，将 用于鉴定和纯化LES抗原。 这笔赠款的下一阶段的目标是1)确定和 纯化LES抗原，2)建立LES动物模型 基于主动免疫测试新的治疗模式 用于LES；3)开发诊断LES和/或LES的血清学试验 SCC；4)确定SCC、LES和 甲状旁腺自身免疫。

This project's objective is to identify the autoantigen in cholinergic neurons that is the target of pathogenic antibodies in the Lambert-Eaton myasthenic syndrome (LES). The long-range goal is to devise antigen-specific therapy for LES. Striking features of LES include a greater than 55% incidence of a lethal lung cancer, small cell (oat cell) carcinoma (SCC), and a high prevelence of autoantibodies to thyroid and stomach constituents. Weakness results from a deficient exocytosis of acethylcholine (ACh) from motor nerve terminals in response to a nerve impulse. Injection of IgG from serum of patients into mice causes a neurotransmission defect similar to that of LES. There is considerable evidence that the abnormality of cholinergic neurons that impairs neurotransmission in LES results from an autoimmune response that is initiated as an anti-tumor response directed against a neuron-related differentiation antigen of SCC. Voltage-sensitive Ca2+ channels have been implicated as the antigen. This project aims to examine plasma membranes of SCC for antigens reactive with LES antibodies and for molecules related to those on cholinergic neurones that are relevant to ACh release. LES patients' antibodies will be tested for pathophysiologic effects on clonal lines and primary preparations of cholinergic neurons, using microassays to measure voltage-dependent influx of 45Ca2+ and release of 3H-ACh. A new rapid passive transfer model of LES in mice will facilitate analysis of the mechanisms responsible for impaired release of ACh quanta in LES. Isolated cholinergic nerve terminals from the electric organ of Torpedo californica will be investigated as a potentially rich source of the LES antigen. The omega toxin of the snail Conus geographus, which has high affinity and specificty for voltage-sensitive Ca2+ channels of presynaptic nerve terminals, is a promising tool for identifying the LES antigen. Monoclonal antibodies made by hybridomas from rats immunized with SCC or cholinergic neuronal components, and by B cell lines from LES patients, will be used to identify and purify the LES antigen. The aims in the next period of this grant are 1) to identify and purify the LES antigen, 2) to develop an animal model of LES based on active immunization for testing new modes of therapy for LES; 3) to develop serologic tests for diagnosis of LES and/or SCC; and 4) to identify the Link between SCC, LES and thyrogastric autoimmunity.