单核细胞IFI44L表达异常的分子机制及其在系统性红斑狼疮发病中的作用

Abnormal expression of interferon and interferon induced genes play an important role in pathogenesis of autoimmune diseases, especially in systemic lupus erythematosus (SLE). However, abnormal expression mechanism and specific role of most interferon induced genes are still unknown. As a novel kind of type I interferon induced genes, there have not been many research on IFI44L’s role in SLE. Our further experiments revealed that IFI44L expression significantly increased was peripheral blood mononuclear cells (PBMCs) of SLE patients and CD14+ monocyte was the most obvious subset. Besides, our studies found increase of IFI44L in SLE PBMCs was associated with hypomethylation of two sites in promoter of IFI44L. However, certain mechanism of such hypomethylation and specific role of IFI44L are still unclear. Based on our previous findings, this project is to investigate the upstream molecular mechanism of IFI44L increase in SLE monocyte, especially epigenetic mechanism. At the same time, through induced differentiation, we prepare to investigate the immune activity alteration of dendritic cell induced from monocyte after IFI44L expression changed and further verify this hypothesis by animal experiment. This project would help further elucidate the molecular mechanisms of immunological tolerance breakdown in SLE, and create potential new targets for diagnosis and treatment of SLE.

干扰素和干扰素诱导基因表达异常在自身免疫疾病尤其是系统性红斑狼疮(SLE)的发病中发挥重要作用，然而大部分干扰素诱导基因表达异常的机制和具体作用仍不清楚。IFI44L作为一种新发现的I型干扰素诱导基因，其在系统性红斑狼疮发病中的作用还没有很多研究。我们前期研究发现，SLE患者外周血单个核细胞中IFI44L的表达明显升高而且以CD14+单核细胞亚群升高最明显；SLE患者外周血IFI44L启动子区甲基化明显降低，但甲基化降低的机制和IFI44L在SLE发病中的具体作用还不清楚。我们拟在前期研究的基础上，探究SLE患者单核细胞中IFI44L表达升高的上游分子机制，以及IFI44L表达改变后对单核细胞诱导的树突状细胞免疫活性的影响，并进一步在动物实验中进行验证。本研究有望进一步阐明SLE免疫耐受破坏的分子机制，为SLE诊断和治疗创造新的靶点。

系统性红斑狼疮（SLE）是一种累及多器官、多系统的自身免疫性疾病，由于SLE受累的器官多，病情迁延不愈，给患者、家庭和社会带来了沉重的负担。近年来研究发现，干扰素和干扰素诱导基因表达异常在自身免疫疾病尤其是SLE的发病中发挥重要作用。我们前期研究发现，SLE患者外周血单个核细胞中IFI44L的表达明显升高而且以CD14+单核细胞亚群升高最明显；SLE患者外周血IFI44L启动子区甲基化明显降低，但甲基化降低的机制和IFI44L在SLE发病中的具体作用还不清楚。本项目通过体外实验，证实了STAT3是调控IFI44L表达的上游信号通路，STAT3可以通过募集TET2降低IFI44L启动子甲基化水平，从而促进IFI44L在SLE患者单核细胞中的表达升高。本项目还发现IFI44L表达升高后能明显提升树突状细胞的免疫活性和抗原提呈能力，并且增强naive T细胞向Th1和Th17细胞的分化，从而参与SLE疾病的发生和发展。本项目研究结果提示IFI44L可通过诱发单核细胞和树突状细胞免疫活性的改变，参与SLE发病和疾病发展，IFI44L有望成为SLE治疗新的基因靶点。本项目后续还将通过更大样本、更多不同类型SLE动物模型对上述机制进行验证，并进一步探讨通过干预IFI44L表达实现SLE治疗的新方法。