上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院風(fēng)濕病學(xué)科科研人員新近在系統(tǒng)性紅斑狼瘡研究中取得新突破,，找到了紅斑狼瘡治療的新靶點(diǎn)。研究論文日前刊登在國(guó)際免疫學(xué)領(lǐng)域著名學(xué)術(shù)刊物《免疫學(xué)》（The Journal of Immunlogy）雜志上,。
系統(tǒng)性紅斑狼瘡是一種自身免疫系統(tǒng)疾病,，女性患病率接近1％。,，尤其多發(fā)于育齡女性,。醫(yī)學(xué)科學(xué)家普遍認(rèn)為人體內(nèi)承擔(dān)防御功能的T淋巴細(xì)胞發(fā)生紊亂是導(dǎo)致該病的主要原因。那么,，是什么原因造成了T淋巴細(xì)胞的功能紊亂呢,？近年來(lái)，國(guó)際上將研究目標(biāo)定位于微小RNA（核糖核酸）,。
據(jù)介紹,，微小RNA被科學(xué)家稱為人體的“精細(xì)調(diào)節(jié)器”。在人類基因組計(jì)劃結(jié)束后,，人們發(fā)現(xiàn)編碼蛋白質(zhì)的基因只占總基因組的約2%,，而占人類基因組95%的非編碼序列是產(chǎn)生非編碼RNA的源泉。這些非編碼RNA充當(dāng)著細(xì)胞調(diào)控者的角色,，在細(xì)胞分化凋亡,、生物發(fā)育、疾病發(fā)生等方面均起到重要作用,。而微小RNA就是其中的一種非編碼RNA,，它們通過(guò)調(diào)控T淋巴細(xì)胞等重要的免疫細(xì)胞功能，維護(hù)著人體內(nèi)積極,、健康的免疫反應(yīng),。
此次,，上海仁濟(jì)醫(yī)院風(fēng)濕病學(xué)科科研人員在研究中發(fā)現(xiàn)了兩種微小RNA，即miR-21和miR-148a,。在紅斑狼瘡病人體內(nèi),，這兩種微小RNA的數(shù)量多于健康人，而這種增多使得T淋巴細(xì)胞失控,。在正常情況下,，免疫系統(tǒng)在遭受攻擊時(shí)，微小RNA能夠調(diào)控T淋巴細(xì)胞參與的免疫反應(yīng),。一旦微小RNA失控,，就會(huì)造成T淋巴細(xì)胞功能的紊亂，最終導(dǎo)致自身免疫性疾病的發(fā)生,。
上海交通大學(xué)醫(yī)學(xué)院附屬仁濟(jì)醫(yī)院,、上海風(fēng)濕病學(xué)研究所所長(zhǎng)沈南教授在接受記者采訪時(shí)說(shuō)：“這證明miR-21和miR-148a是紅斑狼瘡治療的靶點(diǎn)之一。今后一旦研發(fā)出調(diào)節(jié)微小RNA的相關(guān)藥物以及有效的給藥途徑,，就會(huì)對(duì)紅斑狼瘡治療產(chǎn)生積極的作用,。”（黃歡、胡德榮）（生物谷Bioon.com）
生物谷推薦原文出處：
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.
