AUTOIMMUNITY TO CALCIUM CHANNELS IN LAMBERT EATON SYNDRO

Lambert-Eaton肌无力综合征（LES）中的自身免疫反应被认为是由肿瘤，特别是小细胞肺癌（SCLC）的存在引发的。 神经肌肉接头处（NMJ）的突触前钙通道是I型糖尿病中抗体的靶点。S患者，因此可以合理地假设SCLC细胞中假定的自身抗原具有与在人NMJ中发现的P/O型Ca 2+通道相同的分子特征。目前的提议旨在验证一个中心假设：SCLc细胞表达ω-蛇毒素WA敏感的P/Q型电压依赖性Ca 2+通道（VDCC），其在这种疾病中充当主要免疫原;这些通道启动并维持LBS患者的自身免疫应答，并且如此产生的自身抗体然后在NMJ处与靶抗原发生破坏性交叉反应。该建议的长期目标是双重的：1）鉴定启动和维持L.S;（2）确定它们在以该病为特征的外周运动和自主神经系统功能障碍的临床表现中的致病作用。本研究将追求四个具体目标：[1]确定L[2]使用稳定转染的人胚肾（HBK 293）细胞系和非洲爪蟾卵母细胞中表达的克隆α 1 Ca 2+通道亚单位电流确定LBS IgG的交叉反应性; [3]开发和表征Lambert-Baton综合征（EALES）的实验性自身免疫动物模型;和[4]确定被动转移LES小鼠NMJ的P/Q型Ca 2+通道与突触结合蛋白功能障碍。

The autoimmune response in the Lambert-Eaton myasthenic syndrome (LES), is thought to be triggered by the presence of a tumor, particularly small-cell lung cancer (SCLC). Presynaptic calcium channels at the neuromuscular junction (NMJ) are the target of the antibodies in IS patients, thus it is reasonable to assume that the putative autoantigens in SCLC cells possess the same molecular characteristics as the P/O-type Ca2+ channels found at the human NMJ. The current proposal is aimed at verifying a central hypothesis: SCLc cells express omega-agatoxin WA-sensitive P/Q-type voltage-dependent Ca2+ channels (VDCCs), which act as the primary immunogen in this disease; these channels initiate and maintain LBS patient's autoimmune response and the autoantibodies so produced then destructively cross-react with the target antigens at the NMJ. The long term objective of this proposal is two-fold: 1) to identify the primary and secondary autoantigens that initiate and maintain the production of pathogenic antibodies in LS; and 2) to determine their pathogenic role in clinical manifestation of the peripheral motor and autonomic nervous system dysfunctions characterizing this disease. This study will pursue four Specific Aims: [1] To determine the specificity of LS autoantibodies for subtypes of VDCCs; [2] To determine the cross-reactivity of LBS IgG using cloned alpha1 Ca2+ channel subunit currents expressed in stably transfected human embryonic kidney (HBK293) cell lines and Xenopus oocytes; [3] To develop and characterize an experimental autoimmune animal model of the Lambert-Baton syndrome (EALES); and [4] To determine P/Q-type Ca2+ channel vs. synaptotagmin dysfunction at the NMJs of mice with passively transferred LES.