PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS

Lambert-Eaton肌无力综合征（LES）是IgG介导的 周围胆碱能突触的副肿瘤性自身免疫性疾病 传输，导致肌肉无力和自主神经功能障碍， 与小细胞肺癌（SCLC）高度相关。 自身免疫 LES似乎是多克隆IgG抗肿瘤反应的副产物 针对神经元型电压门控钙通道（VGCC）表达 在SCLC。 LES患者产生的抗VGCC抗体 多样的特性。 一些与（ω-CgTx）结合反应 分子（假定VGCC）在人脑神经元和SCLC中表达。 这种特异性的IgG也在一些患有SCLC的患者中发现 没有LES。 这项研究的长期目标是改善 LES和SCLC的诊断和治疗。 拟议研究的工具包括：来自200名 LES患者：来自48例LES患者和许多 对照患者;新鲜人脑标本; ω-CgTx-GVIA（高剂量） 一些神经元VGCC抗原的亲和配体， 可通过LES IgG免疫沉淀）;确定的SCLC细胞系结合 SCLC和神经元膜; cDNA探针和寡核苷酸引物， 编码原型大鼠神经元ω-CgTx结合（N型）VGCC的探针; 由ω-CgTx结合SCLC的RNA制备的cDNA文库（λ gt 11） 从人脑神经元中提取。 具体目的是：1）对VGCC样抗原进行表征和测序 与LES IgG结合的SCLC的神经元VGCC抗原，以及与LES IgG结合的神经元VGCC抗原。 致病性IgG的靶点; ii）使用纯化的、重组的和合成的 肽VGCC抗原和单克隆抗体（Mab），以确定 在免疫学上，与VGCC相关的VGCC分子（和表位）被认为是免疫原性的。 LES的发病机制; iii）开发新的动物模型来研究LES的发病机制。 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.