AUTOIMMUNE PARANEOPLASTIC SYNDROMES

本项目的目的是鉴定 胆碱能神经元是致病抗体的靶点， Lambert-Eaton myasthenic syndrome（LES） 远程 目的是设计LES的抗原特异性治疗。 引人注目 LES的特征包括大于55%的致死性 肺癌，小细胞（燕麦细胞）癌（SCC），以及高 甲状腺和胃成分自身抗体的流行。 虚弱是由于乙酰胆碱胞吐不足所致 (ACh)运动神经末梢对神经冲动的反应。 将患者血清中的IgG注射到小鼠体内， 与LES相似的神经传递缺陷。 有相当多的证据表明，胆碱能异常 LES中损害神经传递的神经元是由 作为抗肿瘤应答而启动的自身免疫应答 针对SCC的神经元相关分化抗原。 电压敏感性Ca 2+通道被认为是 抗原的 本项目旨在研究SCC的质膜 对于与LES抗体反应的抗原和对于分子 与ACh相关的胆碱能神经元上的那些相关 release. LES患者的抗体将进行病理生理学检测， 对克隆系和胆碱能原代制剂的影响 神经元，使用微量测定来测量电压依赖性内流 ~（45）Ca ~（2+）释放和~ 3 H-ACh释放。 一种新的快速被动传输 小鼠LES模型将有助于分析其机制 导致LES中ACh量子释放受损。 分离 电鳐电器官的胆碱能神经末梢 加利福尼亚州将被调查作为一个潜在的丰富的来源， LES抗原。 地质芋螺的欧米茄毒素， 其对电压敏感性Ca 2+具有高亲和力和特异性， 突触前神经末梢的通道，是一个有前途的工具， 识别LES抗原。 单克隆抗体由 来自SCC或胆碱能免疫的大鼠的杂交瘤 神经元成分，以及来自LES患者的B细胞系， 用于LES抗原的鉴定和纯化。 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 以主动免疫为基础， 用于LES; 3）开发用于诊断LES的血清学试验和/或 SCC;以及4）识别SCC、LES和 甲状腺胃自身免疫

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.