IMMUNOBIOLOGY OF AUTOIMMUNITY

我们的目标是研究胸腺内发生的 自身免疫 具体调查是根据一项新的 概念的作用胸腺在至少一种形式的 自身免疫，神经肌肉疾病重症肌无力 （MG）. 大多数胸腺上皮细胞组成型表达Ia， 和髓质上皮细胞表达烟碱乙酰胆碱 受体（AChR），MG的抗原。 很多人都知道 抗AChR自身抗体在导致 MG中的神经肌肉传递，但目前还不清楚 这些抗体产生的原因 在重症肌无力中，胸腺是主要部位， 抗乙酰胆碱受体抗体的产生。 它的去除经常是 随后疾病缓解。 胸腺经历了 15%的MG患者发生肿瘤转化。 研究 在这项提案中概述了胸腺上皮细胞的作用， 细胞启动自身免疫AChR。 有待检验的假设是：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 通过垂直传播的前病毒基因的激活; iii） 抗AChR自身抗体的产生反映了 抗肿瘤/病毒免疫反应，正在原位进展， 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异性的， 选择性地作用于颅（眼延髓）肌肉。 长期 目标是为新的和更有效的方法找到基础， 治疗MG。 待测材料包括正常胸腺 小鼠、大鼠和人类的组织以及冷冻保存的胸腺 组织和胸腺瘤。 AKR/J株 小鼠，其具有90%的胸腺肿瘤发病率， 实验性自身免疫性MG的反常易感性 （EAMG），将作为一种新的模型进行研究， 胸腺瘤与MG的关系 方法包括培养 胸腺上皮细胞和胸腺瘤， 免疫学上和与32 P-cDNA共表达AChR和 病毒或onc基因产物，T细胞克隆的产生， 测试胸腺上皮细胞呈递AChR的能力， 在患有胸腺瘤的AKR/J小鼠中测试EAMG敏感性 新生儿用抗gp 70抗体治疗可以抑制这种抑制作用， 胸腺和胸腺AChR抗原性的血清学比较 颅骨和四肢肌肉。

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.