IMMUNE MECHANISMS IN THE INDUCTION OF MURINE MYASTHENIA

重症肌无力(MG)及其实验模型已成为 自身免疫研究的重要疾病，因为 自身抗原，烟碱型乙酰胆碱受体(AChR)，是一种 纯化的和性质良好的蛋白质。这项提案涉及 自体免疫的诱导和繁殖问题 重症肌无力；目前对MG或 任何其他自身免疫性疾病。有两个主要的推力， 每个都涉及一个概念--独特型网络和 免疫调节--理解自身免疫的核心。 第一个涉及抗AChR自身免疫的启动和 一种独特的类似肌无力的疾病，在小鼠和兔子中通过 独特型网络中的“内部图像”。我们使用 针对AChR配体的单抗以及 蛇毒AChR结合部分的合成肽 和狂犬病病毒，将极大地促进我们的 前期工作。第二个主旨是阐明 绕过免疫调节机制的机制 和临床上的弱点在小鼠模型中传播 肌无力。 我们的初步工作表明，我们诱发的疾病 利用抗神经毒素抗体，网络诱导肌无力 综合征(NIMS)，在许多方面类似于实验性肌无力 方法：正常动物在免疫后会变得容易疲劳 Tensilon逆转了疲软，出现了抗AChR抗体，并且 使用重复神经刺激的肌电图术显示 肌无力的特征。我们这一代的单抗 针对AChR配体及其合成肽将 允许使用高度净化的“内部图像”作为免疫原。 就像我们之前的研究一样，免疫动物的“内在形象” 将进行临床、血清学、肌电分析， 还有药理上的。这些信息将预测自然界 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“内在意象”的意义。最后，SERA 来自重症肌无力和Lambert-Eaton的患者 综合症将接受测试，以确定它们与 AChR的各种“内部图像”。 我们已经在NIMS和小鼠实验中发现 肌无力(EAMG)只有一小部分免疫小鼠出现 临床虚弱，尽管有证据表明所有人都存在亚临床疾病 老鼠。尽管目前的教条是这样做的原因是 老鼠的神经肌肉有很高的“安全系数” 传播，我们觉得临床上缺乏虚弱可能是 由于这些动物的高效免疫调节 可能会削弱自身免疫的强度，即致病性 回应。我们计划通过干预来调查这个问题 使用辐射、环磷酰胺、 抗抑制单抗，抗抑制细胞 和他们的因素，小鼠品系具有假定的抑制细胞 缺陷和雌激素。我们也会通过调剂的方式进行评估 抑制细胞耗尽或扩增的实验 辅助性T细胞数量的增加将增加频率和 疾病的严重程度。

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.