ROLE OF MHC CLASS I IN THE GENERATION OF AUTOIMMUNE DISEASES

MHC I类基因，其提供免疫监视， 细胞内病原体，通过激素控制动态调节。 在甲状腺中，促甲状腺激素（TSH）抑制I类 转录，同时触发甲状腺球蛋白的产生， 甲状腺激素的分泌反过来又刺激I类基因 转录。这两种激素共同产生了一个动态的循环， I类法规。这些发现使我们认为， 调节维持细胞表面呈现的恒定水平 自身抗原;未能适当调节MHC I类基因将 导致自身抗原的过度呈递，并有助于 自身免疫性疾病的产生。根据这一假设，我们 在自身免疫系统性狼疮的实验模型中， 红斑和睑缘炎，不能表达I类的动物是 抵抗疾病。这种阻力不是由于未能 在不存在I类的情况下产生CD 8 + T细胞，因为CD 8-/-动物 对疾病非常敏感。相反，阻力似乎是 由于未能在外围表达I类。因此，在收养 转移实验，对SLE样疾病的易感性是 由接受者的I类状态决定，而不是I类 供体脾细胞的状态。研究正在进行中， 定义外周I类表达在诱导中的作用， 自身免疫性疾病的传播。 我们还研究了诱导疾病的影响， 我们已经证明，药物MMI可以降低I类 在体外和体内表达。MMI处理的小鼠 实验性SLE或睑缘炎可降低 疾病我们还发现，在NZBxNZW小鼠中， 自发性系统性自身免疫病，I类表达水平 随着年龄的增长而显著增加。MMI治疗还降低了 和这种自发性自身免疫性疾病的发病率。

MHC class I genes, which provide immune surveillance against intracellular pathogens, are dynamically regulated by hormonal control. In the thyroid, thyroid stimulating hormone (TSH) represses class I transcription while triggering the production of thyroglobulin and secretion of thyroid hormone which, in turn, stimulates class I gene transcription. Together, these two hormones generate a dynamic cycle of class I regulation. These findings led us to suggest that this dynamic regulation maintains a constant level of cell surface presentation of self antigens; failure to appropriately regulate MHC class I genes would lead to excessive presentation of self antigens, and contribute to the generation of autoimmune disease. Consistent with this hypothesis, we have shown that in experimental models of autoimmune systemic lupus erythematosus and blepharitis, animals that fail to express class I are resistant to disease. This resistance is not due to the failure to generate CD8+ T cells in the absence of class I, since CD8-/- animals are highly susceptible to disease. Rather, the resistance appears to be due the failure to express class I in the periphery. Thus, in adoptive transfer experiments, susceptibility to the SLE-like disease is determined by the class I status of the recipient, not the class I status of the donor spleen cells. Studies are in progress to further define the role of peripheral class I expression in the induction and propagation of autoimmune disease. We also have studied the effect on induction of disease of a pharmacological agent, MMI, that we have shown reduces class I expression both in vitro and in vivo. MMI-treatment of mice with experimental SLE or blepharitis reduces the incidence and severity of disease. We have also found that in NZBxNZW mice, that develop a spontaneous systemic autoimmune disease, levels of class I expression increase significantly with age. MMI-treatment also reduces the severity and incidence of this spontaneous autoimmune disease.