IMMUNE MECHANISMS IN THE INDUCTION OF MURINE MYASTHENIA

重症肌无力（MG）及其实验模型已成为 研究自身免疫的重要疾病，因为 自身抗原，烟碱乙酰胆碱受体（AChR），是一种 纯化和充分表征的蛋白质。 该提案涉及 自身免疫的诱导和传播问题， 肌无力;现在对MG或 任何其他自身免疫性疾病 有两个主要的推力， 每一个都涉及一个概念--独特型网络， 免疫调节是理解自身免疫的核心。 第一个涉及抗AChR自身免疫的启动， 一种独特的，类似肌无力症的疾病， 独特型网络中的“内部图像”。 我们使用 针对AChR配体的单克隆抗体，以及 蛇毒乙酰胆碱受体结合部分的合成肽 和狂犬病病毒，将大大促进我们的 前期工作 第二个重点是阐明 绕过免疫调节机制的机制 和临床虚弱在小鼠模型中传播， 肌无力 我们的初步研究表明我们诱发的疾病 使用抗神经毒素抗体， 综合征（NIMS），类似于实验性肌无力在一些 方法：正常动物免疫后产生疲劳 Tenglutamine逆转的虚弱，出现抗AChR抗体， 使用重复神经刺激的肌电图显示， 肌无力特征。 我们的单克隆抗体 针对AChR配体的合成肽， 允许使用高度纯化的“内部图像”作为免疫原。 在我们以前的研究“内部图像”免疫动物 将进行临床、血清学、肌电图分析， 和。 这些信息将预测 最有可能产生临床症状的“内部图像” 疾病，以及提供有关功能的信息 各种形式的“内在形象”的意义。 最后，sera 从重症肌无力和Lambert-Eaton 综合征将测试他们的能力，以相互作用的 AChR的各种“内部图像”。 我们发现，在NIMS和小鼠实验中， 肌无力（EAMG）只有少数免疫小鼠表现出 临床虚弱，尽管所有患者均存在亚临床疾病的证据 小鼠 虽然目前的教条是，这是因为 老鼠的神经肌肉有很高的“安全系数”， 传播，我们认为，缺乏临床弱点可能是 由于这些动物的高效免疫调节， 可减弱自身免疫性疾病的强度，即致病性， 反应 我们计划通过干扰 使用辐射、环磷酰胺 对比抑制，抗抑制细胞的单克隆抗体 和它们的因子，具有推定的抑制细胞的小鼠品系 缺陷和雌激素 我们也将通过转让进行评估 实验是否耗尽抑制细胞或扩增 辅助性T细胞群体的增加会增加频率， 疾病的严重性。

Myasthenia gravis(MG) and its experimental models have become important diseases for the study of autoimmunity because the autoantigen, the nicotinic acetylcholine receptor(AChR), is a purified and well-characterized protein. This proposal addresses the problems of induction and propagation of autoimmunity in myasthenia; very little is known now about these topics in MG or any other autoimmune disease. There are two major thrusts, each dealing with a concept--the idiotype network and immunoregulation--central to the understanding of autoimmunity. The first deals with the initiation of anti-AChR autoimmunity and a unique, myasthenia-like disease in mice and rabbits via "internal images" within the idiotype network. Our use of monoclonal antibodies directed against AChR ligands, as well as synthetic peptides of the AChR-binding portion of snake toxins and rabies virus, will considerably facilitate extension of our preliminary work. The second thrust is the elucidation of the mechanisms by which immunoregulatory mechanisms are bypassed and clinical weakness propagated in the mouse model of myasthenia. Our preliminary work has shown that the disease we have induced using the anti-neurotoxin antiboides, network-induced myasthenic syndrome (NIMS), resembles experimental myasthenia in a number of ways: normal animals after immunization develop fatigable weakness reversed by Tensilon, anti-AChR antibodies appear, and electromyography using repetitive nerve stimulation reveals myasthenic features. Our generation of monoclonal antibodies directed against AChR ligands and their synthetic peptides will allow the use of a highly purified "internal image" as immunogens. As in our previous studies "internal image" -immunized animals will be analyzed clinically, serologically, electromyographically, and pharmacologically. This information will predict the nature of the "internal image" that is most likely to generate clinical disease, as well as providing information about the functional significance of various forms of "internal image". Finally, sera from patients with myasthenia gravis and Lambert-Eaton syndrome will be tested for their ability to interact with the various "internal images" of AChR. We have found that in both NIMS and murine experimental myasthenia (EAMG) only a minority of immunized mice manifest clinical weakness despite evidence for subclinical disease in all mice. Although the current dogma is that the reason for this is that mice have a high "safety factor" of neuromuscular transmission, we feel that the lack of clinical weakness may be due to highly efficient immunoregulation in these animals that may diminish the strength, i.e. pathogenicity, of the autoimmune response. We plan to investigate this question by interfering with immune suppression using irradiation, cyclophosphamide, contrasuppression, monoclonal antibodies against suppressor cells and their factors, mouse strains having putative suppressor cell defects, and estrogen. We will also assess by transfer experiments whether depletion of suppresor cells or amplification of the helper T cell population will increase the frequency and severity of disease.