抗磷脂抗体诱导中性粒细胞释放NETs致抗磷脂综合征肾病的机制研究

Antiphospholipid Syndrome nephropathy (APSN) is characterized by acute thrombotic microangiopathy and chronic microangiopathy. APSN is related with the poor prognosis of patient with antiphospholipid syndrome. The mechanism of antiphodpholipid antibody (aPL) inducing APSN is unclear. Our previous studies indicated that aPL can induce thrombotic microangiopathy in vivo, and aPL can stimulating release of neutrophil extracellular traps (NETs) by Neutrophils in vitro study. Based on the pathologic finding of antiphospholipid antibodies up-regulate the mammalian target of rapamycin complex (mTORC) pathway in renal vascular endothelial cells. We postulated that aPL can induce acute thrombotic microangiopathy and chronic microangiopathy in kidney by stimulating release of NETs by neutrophils. In this study, we plan to investigate the regulation of mTOR signaling in aPL stimulating release of NETs by neutrophils, and the mechanism of aPL up-regulating mTOR pathway in renal vascular endothelial cells proliferation which is the feature of chronic microangiopathy in kidney. We also investigate the role of mTOR inhibitor in the treatment of APSN in animal model, and provide the evidence of new therapy strategy for APSN.

抗磷脂综合征肾病（APSN）表现为急性肾小球微血栓形成和慢性肾微小血管病变，严重影响患者的近期和远期预后。抗磷脂抗体（aPL）致APSN的发病机制仍不清楚。我们前期研究证实aPL抗体在体内外可引起肾小球微血栓形成，且aPL可通过诱导中性粒细胞释放NETs参与血栓形成。APSN的肾脏病理显示mTOR通路的活化与APSN慢性血管病变相关，但具体机制不清。所以我们推测aPL不但可通过激活中性粒细胞释放NETs而促进肾脏微血栓的形成，并通过NETs激活血管内皮细胞mTOR信号途径致血管的慢性病变。本研究利用APS患者外周血、肾脏病理和人单克隆抗磷脂抗体CL15免疫狼疮小鼠，研究aPL促中性粒细胞NETs产生的通路，并证实aPL通过活化肾脏血管内皮细胞mTOR信号通路引起慢性微小肾血管病变的机制。通过体内外实验探索mTOR特异性抑制剂在治疗APSN的潜在临床价值，为APSN治疗新策略提供实验基础。

抗磷脂综合征(APS)目前被认为是获得性易栓症最常见的原因，临床上主要表现为血栓形成或病理妊娠。抗磷脂综合征肾病表现为急性肾小球微血栓形成和慢性肾微小血管病变，严重影响患者的近期和远期预后。本课题研究了抗磷脂抗体致APSN的发病机制。我们发现，mTOR通路介导了抗磷脂抗体激活中性粒细胞释放NETs，mTOR抑制剂雷帕霉素可一定程度抑制抗磷脂抗体对于中性粒细胞的活化作用。该研究结果有望为临床上提供可能的治疗靶点。另外，我们基于APS-上海数据库，在大样本的中国APS患者中检测了5种诊断标准外的抗磷脂抗体，结合患者的临床资料分析，我们发现诊断标准外的抗磷脂抗体对于APS及血清阴性APS患者的诊断及对于APS患者相关临床症状的风险评估均具有重要的价值。