ROLE OF MHC CLASS I IN THE GENERATION OF AUTOIMMUNE DISEASES

I 类 MHC 在自身免疫性疾病产生中的作用

• 批准号: 6161086
• 负责人: D SINGER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6161086
• 关键词: MHC class I antigen; autoimmune disorder; disease /disorder model; disease /disorder proneness /risk; eyelid disorder; histocompatibility gene; hormone regulation /control mechanism; immunogenetics; immunopharmacology; laboratory mouse; molecular pathology; systemic lupus erythematosus; thyroid hormones; thyrotropin

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.

MHC I类基因，它提供对 细胞内的病原体，由激素控制动态调节。 在甲状腺中，促甲状腺激素(TSH)抑制第I类 转录同时触发甲状腺球蛋白和甲状腺球蛋白的产生 甲状腺激素的分泌，进而刺激第I类基因 抄写。这两种荷尔蒙共同产生了一个动态循环 第I类法规。这些发现使我们认为，这种动态 调节维持细胞表面呈现的恒定水平 自身抗原；如果不能适当地调节MHC I类基因将 导致自身抗原的过度提呈，并导致 自身免疫性疾病的产生。与这一假设一致，我们 已经证明在自身免疫性系统性红斑狼疮的实验模型中 红斑性红斑病和睑缘炎，不能表达I类的动物是 抗病的抗病的这种阻力并不是由于未能 在没有I类的情况下产生CD8+T细胞，因为CD8-/-动物 极易感染疾病。相反，阻力似乎是 由于未能在外围表示I类邮件。因此，在领养中 转移实验表明，对SLE样病的易感性为 由收件人的I类状态决定，而不是I类 供者脾细胞的状况。研究正在进行中，以进一步 确定外周血类I类表达在诱导和 自身免疫性疾病的传播。 我们还研究了阿司匹林的致病作用。 我们已经证明的药理试剂MMI可以降低I类 在体外和体内均有表达。MMI对小鼠的治疗作用 实验性系统性红斑狼疮或眼缘炎降低了发病率和严重性 疾病。我们还发现，在NZBxNZW小鼠中，发生了一种 自发性全身性自身免疫性疾病，I类基因表达水平 随着年龄的增长显著增加。MMI治疗也减轻了严重程度 以及这种自发性自身免疫性疾病的发病率。