上海交通大学医学院附属仁济医院风湿病学科科研人员新近在系统性红斑狼疮研究中取得新突破，找到了红斑狼疮治疗的新靶点。研究论文日前刊登在国际免疫学领域著名学术刊物《免疫学》（The Journal of Immunlogy）杂志上。
系统性红斑狼疮是一种自身免疫系统疾病，女性患病率接近1％。，尤其多发于育龄女性。医学科学家普遍认为人体内承担防御功能的T淋巴细胞发生紊乱是导致该病的主要原因。那么，是什么原因造成了T淋巴细胞的功能紊乱呢？近年来，国际上将研究目标定位于微小RNA（核糖核酸）。
据介绍，微小RNA被科学家称为人体的“精细调节器”。在人类基因组计划结束后，人们发现编码蛋白质的基因只占总基因组的约2%，而占人类基因组95%的非编码序列是产生非编码RNA的源泉。这些非编码RNA充当着细胞调控者的角色，在细胞分化凋亡、生物发育、疾病发生等方面均起到重要作用。而微小RNA就是其中的一种非编码RNA，它们通过调控T淋巴细胞等重要的免疫细胞功能，维护着人体内积极、健康的免疫反应。
此次，上海仁济医院风湿病学科科研人员在研究中发现了两种微小RNA，即miR-21和miR-148a。在红斑狼疮病人体内，这两种微小RNA的数量多于健康人，而这种增多使得T淋巴细胞失控。在正常情况下，免疫系统在遭受攻击时，微小RNA能够调控T淋巴细胞参与的免疫反应。一旦微小RNA失控，就会造成T淋巴细胞功能的紊乱，最终导致自身免疫性疾病的发生。
上海交通大学医学院附属仁济医院、上海风湿病学研究所所长沈南教授在接受记者采访时说：“这证明miR-21和miR-148a是红斑狼疮治疗的靶点之一。今后一旦研发出调节微小RNA的相关药物以及有效的给药途径，就会对红斑狼疮治疗产生积极的作用。”（黄欢、胡德荣）（生物谷Bioon.com）
生物谷推荐原文出处：
The Journal of Immunology doi:10.4049/jimmunol.0904060
MicroRNA-21 and MicroRNA-148a Contribute to DNA Hypomethylation in Lupus CD4+ T Cells by Directly and Indirectly Targeting DNA Methyltransferase 1
Wen Pan,*,1 Shu Zhu,,1 Min Yuan,* Huijuan Cui,*, Lijia Wang,* Xiaobing Luo,*, Jia Li,* Haibo Zhou,*, Yuanjia Tang,*, and Nan Shen*,
*Joint Molecular Rheumatology Laboratory, Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, Laboratory of Immunity and Diseases, Institute of Health Sciences, and Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Systemic lupus erythematosus is a complex autoimmune disease caused by genetic and epigenetic alterations. DNA methylation abnormalities play an important role in systemic lupus erythematosus disease processes. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states, including human lupus. Whereas previous studies have shown miRNAs can regulate DNA methylation by targeting the DNA methylation machinery, the role of miRNAs in aberrant CD4+ T cell DNA hypomethylation of lupus is unclear. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. This in turn leads to the overexpression of autoimmune-associated methylation-sensitive genes, such as CD70 and LFA-1, via promoter demethylation. Further experiments revealed that miR-21 indirectly downregulated DNMT1 expression by targeting an important autoimmune gene, RASGRP1, which mediated the Ras–MAPK pathway upstream of DNMT1; miR-148a directly downregulated DNMT1 expression by targeting the protein coding region of its transcript. Additionally, inhibition of miR-21 and miR-148a expression in CD4+ T cells from patients with lupus could increase DNMT1 expression and attenuate DNA hypomethylation. Together, our data demonstrated a critical functional link between miRNAs and the aberrant DNA hypomethylation in lupus CD4+ T cells and could help to develop new therapeutic approaches.
