IMMUNOBIOLOGY OF AUTOIMMUNITY

我们的目标是研究胸腺内的 自身免疫力。具体调查是基于一项新的 胸腺在至少一种形式的胸腺中的作用的概念 自身免疫，神经肌肉疾病重症肌无力 (毫克)。大多数胸腺上皮细胞结构性地表达Ia， 髓上皮细胞表达烟碱型乙酰胆碱 受体(AChR)，MG的抗原。人们对此已有很多了解 抗AChR自身抗体在慢性阻塞性肺疾病失败中的作用 MG的神经肌肉传递，但对此一无所知 为什么会产生这些抗体。重症肌无力患者的胸腺是一个主要部位 产生抗乙酰胆碱受体抗体。它经常被移除是 其次是疾病的缓解。胸腺经历了 15%的MG患者有肿瘤性转化。研究 在这项提案中概述了胸腺上皮细胞的作用 启动AChR自身免疫的细胞。 需要检验的假设是：i)AChR与 胸腺上皮细胞是主要的免疫原 自发获得性MG；ii)这种免疫原性被促进 通过激活垂直传播的前病毒基因；三) 抗AChR自身抗体的产生反映了一种 抗肿瘤/病毒免疫反应在原位进展 胸腺；iv)胸腺上表达的AChR的一些表位 上皮细胞是神经外胚层特有的，表达 选择性地作用于颅骨(眼球)肌肉。长期的 目标是找到新的和更有效的方法的基础 治疗重症肌无力。被检测的材料包括正常胸腺 来自小鼠、大鼠和人类的组织以及冷冻保存的胸腺 MG患者的组织和胸腺瘤。新城疫AKR/J株 小鼠，它有90%的胸腺肿瘤发生率和 实验性自身免疫性MG的矛盾易感性 (EAMG)，将作为一种新的模型进行研究 胸腺瘤与重症肌无力的关系。方法包括培养 胸腺上皮细胞和胸腺瘤，探查 免疫学和~(32)P-c DNA共表达AChR和 病毒或癌基因产物，T细胞克隆的产生， 检测胸腺上皮细胞呈递AChR的能力， 胸腺瘤AKR/J小鼠EAMG敏感性检测 被抗gp70抗体抑制的新生儿， 胸腺和胸腺AChR抗原性的血清学比较 头盖骨和四肢肌肉。

Our goal is to investigate the intrathymic genesis of autoimmunity. Specific investigations are based on a new concept of the role of the thymus in at least one form of autoimmunity, the neuromuscular disease myasthenia gravis (MG). Most thymic epithelial cells express Ia constitutively, and medullary epithelial cells express nicotinic acetylcholine receptors (AChR), the antigen of MG. Much is known about the role of anti-AChR autoantibodies in causing failure of neuromuscular transmission in MG, but nothing is known about why these antibodies arise. In MG the thymus is a major site of anti-AChR antibody production. Its removal frequently is followed by remission of the disease. The thymus undergoes neoplastic transformation in 15% of MG patients. Studies outlined in this proposal concern the role of thymic epithelial cells in initiating autoimmunity to AChR. Hypotheses to be tested are that: i) AChR associated with thymic epithelial cells is the primary immunogen of spontaneously acquired MG; ii) this immunogenicity is promoted by activation of vertically transmitted proviral genes; iii) production of anti-AChR autoantibodies reflects an anti-tumor/virus immune response that is progressing in situ in the thymus; iv) some epitopes of the AChR expressed on thymic epithelial cells are neuroectoderm-specific and are expressed selectively on cranial (oculobulbar) muscles. The long-term goal is to find a basis for new and more effective methods of treating MG. Materials to be tested include normal thymus tissues from mice, rats and humans, and cryopreserved thymus tissue and thymomas from MG patients. The AKR/J strain of mouse, which has a 90% incidence of thymic tumors and a paradoxical susceptibility to experimental autoimmune MG (EAMG), will be investigated as a novel model of the relationship between thymoma and MG. Methods include culture of thymic epithelial cells and thymomas, probing immunologically and with 32P-cDNA for coexpression of AChR and viral or onc gene products, generation of T cell clones, testing ability of thymic epithelial cells to present AChR, testing EAMG susceptibility in AKR/J mice with thymoma suppressed by neonatal treatment with anti-gp70 antibodies, serologic comparisons of the antigenicity of AChR in thymus and cranial and limb muscles.