系统性红斑狼疮B细胞PI3K/Bach2信号通路调控异常机制研究

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by disturbed B cell homeostasis, which leads to autoantibody formation, immune complex deposition and tissue inflammation. Bach2 is a B-cell-specific transcription factor playing central role during B cell differentiation. Whether Bach2 is involved in the regulation of human SLE has not been reported. In our study, we found that the expression of Bach2 in SLE B cells was decreased in all peripheral B cell subsets, except for memory B cells. Moreover, the level of Bach2 expression was inversely correlated with the proportion of immature B cells. IL-21 could not increase the expression of Bach2 accompanied with significantly increased mRNA level of Blimp1 in SLE B cells. Defective PTEN/PI3K regulation contributes to B cell hyperresponsiveness in SLE. In this study, we will clarify whether the Bach2 expression by B cells was down-regulated in SLE patients. In the meantime, explore its function and mechanism. Then we will investigate how IL-21-mediated PTEN/PI3K pathway affects Bach2/Blimp1 expression in SLE, and participates in the abnormal regulation of B cells differentiation into plasma cells. These could provide a theoretical basis for exploring PI3K/Bach2 as a new immunotherapeutic target for SLE.

系统性红斑狼疮（SLE）是一种以B细胞稳态失衡、自身抗体产生、免疫复合物堆积为主要特点的自身免疫性疾病。Bach2是B细胞发育为浆细胞过程中重要转录调控因子，它是否参与调节SLE患者B细胞异常分化过程未见报道。我们发现，Bach2在SLE患者多种B细胞亚群中表达下调，且immature B细胞Bach2表达水平与其细胞比例呈负相关；SLE患者B细胞存在IL-21上调Bach2缺陷、Blimp1异常表达增加现象；且SLE患者PTEN/PI3K通路参与IL-21调控B细胞异常。本项目将明确Bach2在SLE患者B细胞中的异常表达情况；阐明其异常调控的作用和机制；明确SLE患者PTEN/PI3K通路缺陷是否调控Bach2/Blimp1异常，导致B细胞分化异常。旨在初步探索PI3K/Bach2通路作为SLE新的免疫治疗靶点的可能性。

系统性红斑狼疮（SLE）是一种以B细胞稳态失衡、自身抗体产生、免疫复合物堆积为主要特点的自身免疫性疾病。该疾病会对多器官造成较严重损伤，危害性严重，但目前尚无根治SLE的药物，且现有药物副作用较大，因此临床急切需要探索新的诊断治疗靶点。Bach2是B细胞发育为浆细胞过程中重要的转录调控因子，它是否参与调节SLE患者B细胞异常分化过程未见报道。我们的研究表明，SLE患者存在B细胞过度分化且Bach2的表达下调；Bach2的表达减少与SLE疾病活动度具有相关性；受Bach2抑制调控的浆细胞分化关键调节转录因子Blimp1的出现过度表达，可以解释B细胞过度分化；通过机制研究我们发现，SLE患者B细胞Bach2表达下降的原因是出核增多降解增加造成的；最后我们证明SLE患者B细胞存在IL-21诱导PTEN/PI3K信号通路缺陷，是Bach2/Blimp1信号通路异常的原因。本研究揭示了SLE患者发病过程中，B细胞存在PI3K/Bach2/Blimp1通路紊乱，造成B细胞稳态失衡且过度分化，为探索新的免疫治疗靶点提供重要理论依据。

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