B细胞活化因子促进B细胞表达白介素35在系统性红斑狼疮中的作用及机制研究

B cell activating factor (BAFF) can induce B cell abnormal survival, break self-immunotolerance and play an important role in the development of systemic lupus erythematosus (SLE). Belimumab, the inhibitor of BAFF, was the only biological targeted drug for SLE approved by the US Food and Drug Administration. However, the clinical trials and after-market application indicated side effects and poor efficacy in some SLE patients; the mechanism is unclear. Based on the international research advances and our previous results, we found that BAFF can induce the B cells derived from spleen of MRL-lpr mice to produce IL-35, which is a newly indentified cytokine to suppressive auto-immunity through Breg or i35-Bregs. Therefore we plan to research the role and mechanisms of B cells- deprived IL-35 induced by BAFF in the development of SLE, in order to complete parts of pathogenesis of SLE and help the indication chosen of BAFF inhibitor for the treatment of SLE patients, as well as provide the basic research data for the new possible IL-35 targeted therapy.

研究表明B细胞活化因子BAFF能够诱导B细胞异常存活，打破自身免疫耐受，在SLE的发生和发展中发挥重要作用，其抑制剂Belimumab是唯一经FDA批准用于SLE的治疗的生物靶向药物，对大多数患者获得较好的效果，但该药物上市后发现其对某些SLE患者反应不佳以及副作用较为明显，其原因不清楚。基于国内外研究进展及我们前期工作基础发现，BAFF除了促进B细胞异常活化外，还能够促进MRL-lpr狼疮小鼠脾脏B细胞产生IL-35，IL-35为较新的抑制性细胞因子，可能通过Breg或i35-Bregs发挥抑制自身免疫的效应。因此我们拟研究BAFF促进B细胞产生IL-35在系统性红斑狼疮中的作用及机制，对SLE发病机制的进行补充阐明，并为SLE患者使用BAFF拮抗剂治疗适应症的选择提供参考，以及将来rIL-35靶点治疗提供理论基础。

B细胞活化因子BAFF能够诱导B细胞异常存活，打破自身免疫耐受，在SLE的发生和发展中发挥重要作用。我们发现在SLE患者皮损中BAFF及IL-35升高，并且呈正相关。同时，我们使用MRL-Faslpr/狼疮鼠模型，检测血清BAFF水平明显升高，并在体内外实验中均发现BAFF可与TACI结合诱导脾脏MZ B细胞产生IL-35。进一步研究发现该产生IL-35的B细胞亚群具有CD5+ CD1dhiFcgRIIbhi独特的细胞表型，并来源于脾脏MZ B细胞。我们使用了抗BAFF抗体体内外作用于狼疮鼠脾脏B细胞，发现封闭BAFF受体BAFFR后，小鼠脾脏中p35+EBI3+B细胞的百分比下降，血清中BAFF以及IL35的表达下降，细胞凋亡增加，证明了抗BAFFR抗体的有效性，该研究不仅揭示了BAFF在自免疾病中的免疫调节作用，丰富了其参与免疫反应的机制，也为抗BAFF治疗长期疗效欠佳提供重要新依据。