PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS

Lambert-Eaton肌无力综合征(LES)是一种免疫球蛋白介导的 外周胆碱能突触的副肿瘤性自身免疫性疾病 导致肌肉无力和自主神经功能障碍的传播， 与小细胞肺癌(SCLC)高度相关。自身免疫性疾病 LES似乎是多克隆免疫球蛋白抗肿瘤反应的副产品 针对神经元型电压门控钙通道的表达 在SCLC中。在LES患者中产生的抗VGCC抗体 各式各样的细节。有些与(omega-CgTx)结合是反应性的 分子(推测为VGCC)在人脑神经元和小细胞肺癌中表达。 这种特异性的免疫球蛋白在一些小细胞肺癌患者中也被发现。 没有莱斯。这项研究的长期目标是改善 LES和小细胞肺癌的诊断和治疗。 拟议研究的工具包括：200份冰冻的特征血清 LES患者：冷冻保存的淋巴细胞来自48例LES患者 对照组患者；新鲜人脑标本；omega-CgTx-GVIA(高 一些神经性VGCC抗原的亲和配体 可由LES抗体免疫共沉淀)；定义的SCLC系结合以下成分 小细胞肺癌和神经细胞膜；CDNA探针和寡核苷酸引物及 编码大鼠神经元omega-CgTx结合(N型)VGCC原型的探针； 由omega-CgTx结合的小细胞肺癌的RNA构建的cDNA文库(Lambda Gt11) 从人脑神经元中分离出来的。 其具体目的是：1)对VGCC样抗原进行鉴定和测序 与LES-Ig G结合的小细胞肺癌的抗原，以及 致病免疫球蛋白的靶点；ii)使用纯化、重组和合成 多肽VGCC抗原和单抗(MAb)，以确定 免疫学上与VGCC相关的分子(和表位) LES的发病机制；iii)建立新的动物模型以研究 神经肌肉和自主神经突触缺陷的病理生理学基础 莱斯。

The Lambert-Eaton myasthenic syndrome (LES) is an IgG-mediated paraneoplastic autoimmune disorder of peripheral cholinergic synaptic transmission that causes muscle weakness and autonomic dysfunction, and is highly associated with small cell lung carcinoma (SCLC). Autoimmunity in LES appears to be the byproduct of a polyclonal IgG anti-tumor response directed against neuronal-type voltage-gated Ca2+ channels (VGCC) expressed in SCLC. The anti-VGCC antibodies produced in patients with LES have diverse specificities. Some are reactive with (omega-CgTx)-binding molecules (presumptive VGCC) expressed in human brain neurons and SCLC. IgGs of this specificity are also found in some patients who have SCLC without LES. The long-term objectives of this research are to improve the diagnosis and treatment of both LES and SCLC. Tools for the proposed studies include: frozen characterized sera from 200 LES patients: cryopreserved lymphocytes from 48 LES patients and numerous control patients; fresh specimens of human brain; omega-CgTx-GVIA (a high affinity ligand for some of the neuronal VGCC antigens that are immunoprecipitable by LES IgG); defined SCLC lines binding components of SCLC and neuronal membranes; CDNA probes and oligonucleotide primers and probes encoding a prototypic rat neuronal omega-CgTx-binding (N-type) VGCC; CDNA libraries (lambda gt11) made from RNAs of an omega-CgTx-binding SCLC lineand from human brain neurons. The Specific Aims are 1) to characterize and sequence the VGCC-like antigen of SCLC to which LES IgG binds, and the neuronal VGCC antigens that are targets for pathogenic IgG; ii) to use purified, recombinant and synthetic peptide VGCC antigens, and monoclonal antibodies (Mabs), to define immunologically the VGCC molecules (and epitopes) relevant to the pathogenesis of LES; iii) to develop new animal models to investigate the pathophysiological basis of neuromuscular and autonomic synaptic defects of LES.