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: 5201052
• 负责人: D SINGER
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 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/5201052
• 关键词: MHC class I antigen; autoimmune disorder; disease /disorder model; eyelid disorder; histocompatibility gene; hormone regulation /control mechanism; immunopharmacology; laboratory mouse; model design /development; systemic lupus erythematosus; thyroid hormones; thyrotropin

MHC Class I genes are subject to both homeostatic, tissue-specific regulation and dynamic regulation. Among the mechanisms of dynamic regulation are those mediated by hormones that either increase or decrease transcription of the genes. The observation that thyroid stimulating hormone (TSH) leads to decreased class I transcription, whereas thyroid hormone increases it, led to the hypothesis that failure to appropriately regulate MHC class I molecules may play a pivotal role in 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. In contrast, class I- animals are susceptible to EAE. To further characterize the role of class I expression in autoimmune disease, we have studied the effect on induction of disease of a pharmacological agent, MMI, that reduces class I expression. Treatment of mice with experimental SLE or blepharitis reduces the incidence and severity of disease. In addition, MMI-treatment of NZBXNZW mice, which develop a spontaneous systemic autoimmune disease, also significantly reduces the severity and incidence of immune complex deposits in their kidneys. Studies are in progress to determine the molecular mechanisms by which reduction of class I expression abrogates the development of certain classes of autoimmune disease.

MHC I类基因受体内平衡，组织特异性 监管和动态监管。在动态的机制中， 调节是由激素介导的， 减少基因的转录。 观察到甲状腺 刺激激素（TSH）导致I类转录减少， 而甲状腺激素则会使其增加，这导致了一种假设， 未能适当调节MHC I类分子可能会导致 在自身免疫性疾病的产生中起着关键作用。 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。 相比之下，类 I-动物对EAE易感。 为了进一步表征I类表达在自身免疫性疾病中的作用， 疾病，我们已经研究了诱导疾病的影响， 药物制剂MMI，其降低I类表达。 治疗患有实验性SLE或睑缘炎的小鼠降低了 疾病的发生率和严重程度。 此外，MMI治疗 NZBXNZW小鼠，其发展自发性全身性自身免疫疾病， 还可显著降低免疫缺陷的严重程度和发生率， 肾脏中的复杂沉积物 研究正在进行中，以确定分子机制， I类表达的减少废除了某些 自身免疫性疾病的分类。