Role of MHC Class I in the Generation of Autoimmune Diseases

MHC I 类在自身免疫性疾病产生中的作用

• 批准号: 6433163
• 负责人: DINAH 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/6433163
• 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. 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 2-microglobulin knock-out gene was introduced into each of the parental strains. Development of disease was monitored in the class I deficient F2 mice.

MHC I类基因提供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类转录，同时触发甲状腺球蛋白的产生和甲状腺激素的分泌，进而刺激I类基因的转录。这两种荷尔蒙共同产生了I类调节的动态循环。这些发现使我们认为，这种动态调节维持着自身抗原在细胞表面的恒定提呈水平；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发生。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和睑缘炎的实验模型中，未能表达I类基因的动物对疾病具有抵抗力。这种抵抗并不是由于在没有I类的情况下无法产生CD8+T细胞，因为CD8-/-动物对疾病非常敏感。相反，这种阻力似乎是由于未能在外围国家表达I类。因此，在过继转移实验中，对类SLE疾病的易感性取决于受者的第I类状态，而不是供者脾细胞的第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，我们研究了NZBxNZW系统性红斑狼疮小鼠模型。我们发现，在NZBxNZW小鼠中，I类基因的表达水平随着年龄的增长而显著增加。MMI治疗可以预防实验性的SLE，也可以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类基因在这种自发性疾病中的作用，将2-微球蛋白敲除基因引入每个亲本菌株中。对I类缺陷F2小鼠的疾病发展进行了监测。