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: 2463796
• 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/2463796
• 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，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一个动态循环 一级监管。这些发现使我们认为， 动态调节维持细胞表面的恒定水平 自身抗原呈递;未能适当调节MHC I类基因将导致自身抗原的过度呈递， 并导致自身免疫性疾病的产生。符合 这个假设，我们已经表明，在实验模型中， 自身免疫性系统性红斑狼疮和睑缘炎，动物， 未能表达I类抗病性。该电阻 不是由于在缺乏类的情况下不能产生CD 8 + T细胞， I，因为CD 8-/-动物对疾病高度易感。而是 耐药性似乎是由于未能表达I类， 外围因此，在过继转移实验中， SLE样疾病由患者的I类状态决定， 受体，而不是供体脾细胞的I类状态。研究 正在进一步定义外围设备I类的作用 在自身免疫性疾病的诱导和传播中的表达。 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治疗还减少了 这种自发性自身免疫性疾病的严重程度和发病率。