Role of MHC Class I in the Generation of Autoimmune Dise

MHC I类基因，提供针对细胞内病原体的免疫监视，受激素控制的动态调节。在甲状腺中，促甲状腺激素（TSH）抑制I类基因转录，同时触发甲状腺球蛋白的产生和甲状腺激素的分泌，这反过来又刺激I类基因转录。这两种激素共同产生一种 I类调节的动态循环。这些发现使我们认为，这种动态调节维持了细胞表面呈递自身抗原的恒定水平;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。与这一假设相一致，我们已经表明，在自身免疫性系统性红斑狼疮和睑缘炎的实验模型中，未能表达I类的动物对疾病具有抵抗力。这种抗性不是由于在缺乏I类的情况下不能产生CD 8 + T细胞，因为CD 8-/-动物对疾病高度易感。相反，这种阻力似乎是由于未能在外围表达第一类。因此，在过继转移实验中，SLE样疾病的易感性是由受体的I类状态决定的，而不是供体脾细胞的I类状态。为了研究I类在自发性自身免疫性疾病病因学中的作用，我们检查了SLE的NZBxNZW小鼠模型。我们已经发现，在NZBxNZW小鼠中，I类表达水平随着年龄的增长而显著增加。MMI治疗可预防实验性SLE，也可降低这种自发性自身免疫性疾病的严重程度和发病率。为了直接确定I类在这种自发性疾病中的作用，将b2-微球蛋白敲除基因引入每个亲本菌株中。在完全I类缺陷NZB X NZW F1小鼠与杂合子I类+/-和I类+/+ NZB X NZW F1小鼠中比较疾病的发展。有趣的是，尽管所有b2-微球蛋白敲除基因杂合的品系对自身免疫性疾病的发作具有抗性，但相对于I类+/+ F1小鼠，完全缺乏I类表达的F1小鼠更易感。这些发现与以下解释一致，即减少的I类降低了具有保护性的自身抗原的呈递水平。然而，在没有任何I类的情况下，CD 8 + T细胞不能发育，这消除了保护性抑制细胞群。需要进行实验来检验这一假设。

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. To study the role of class I in the etiology of spontaneous autoimmune disease, we have examined the NZBxNZW murine model of SLE. We have found that in NZBxNZW mice, levels of class I expression increase significantly with age. MMI-treatment, which prevents experimental SLE, also reduces the severity and incidence of this spontaneous autoimmune disease. To directly determine the role of class I in this spontaneous disease, the b2-microglobulin knock-out gene was introduced into each of the parental strains. Development of disease was compared in the completely class I-deficient NZB X NZW F1 mice with heterozygous Class I+/- and Class I+/+ NZB X NZW F1 mice. Interestingly, whereas all strains heterozygous for the b2-microglobulin knock-out gene were resistant to the onset of autoimmune disease, relative to the class I +/+ F1 mice, the F1 mice completely deficient in class I expression were more susceptible. These findings are consistent with the interpretation that reduced class I reduces the level of presentation of self-antigens which is protective. However, in the absence of any class I, CD8+ T cells fails to develop which eliminates a protective suppressor cell population. Experiments to test this hypothesis will need to be performed.