IL-4/Ikaros/Nr4a1调控自身反应性无能B细胞激活后凋亡在系统性红斑狼疮发病机制中的研究

自身抗体的产生是系统性红斑狼疮（SLE）免疫损伤的根本，B细胞无能是实现外周免疫耐受的最重要机制。我们在前期研究中发现SLE中IL-4能够激活无能B细胞（BND）持续产生自身抗体，但具体机制尚不明确。IKZF1是SLE的易感基因，其编码蛋白Ikaros在免疫耐受维持中发挥重要作用，Ikaros靶向调控的蛋白Nr4a1能够诱导细胞凋亡，但Ikaros/Nr4a1在SLE中BND的调控机制尚不明确。我们前期的研究发现IL-4诱导SLE的BND表达Ikaros水平低下，提示IL-4/Ikaros/Nr4a1通路异常可能导致SLE的BND过度激活。本项目拟利用免疫无能的小鼠模型，在细胞和分子的水平探讨IL-4/Ikaros/Nr4a1调控BND活化和凋亡的作用和机制；在临床样本和狼疮小鼠中研究BND激活后Ikaros/Nr4a1表达水平低下与疾病的关系；为SLE的发病机理提供新的思路。

The production of autoantibodies is the basis of tissue and organ damage in systemic lupus erythematosus (SLE). B cell anergy is an important mechanism to achieve immune tolerance. In our previous research project, we found that IL-4 in SLE can persistently activate anergic B cells(BND) to produce autoantibodies, but the specific mechanism is not clear. IKZF1 is a susceptible gene of SLE, and its coding protein Ikaros plays an important role in the maintenance of immune tolerance of anergy B cells. NR4A1, which is the target gene of IKZF1, can induce cells apoptosis. Our previous study found that the expression of Ikaros induced by IL-4 in BND was low in SLE, suggesting that the abnormal IL-4/Ikaros pathway may be involved in the over activation of BND in SLE. In this project, we intend to explore the effect and mechanism of IL-4/Ikaros/NR4A1 on the activation and apoptosis of BND at the cellular and molecular level by using the classical mouse model of anergy, to verify the relationship between the low level of Ikaros and the disease activity in clinical samples and mouse models. Our study may open up a novel insight to understand the defect of immune tolerance, which may provide new strategy or target for the therapy of SLE.