补体H因子相关蛋白3和1在肾脏伴有IgA沉积的狼疮性肾炎发病中的作用与机制研究

Complement alternative pathway activation plays an important role in the pathogenesis of lupus nephritis and IgA nephropathy. Complement factor H (CFH) is a key inhibitor of the alternative pathway, but CFH-related proteins, CFHR3 and CFHR1 (CFHR3-1), could reduce the regulatory activity of CFH at the surface. The deletion of CFHR3-1 (CFHR3-1Δ) is associated with genetic susceptibility for both SLE and IgA nephropathy，and is considered to be protective to IgA nephropathy. This study will focus on the population of lupus nephritis patients with renal IgA deposition. Our preliminary data demonstrated that this portion of patients presented with the less severe features of clinical manifestations, renal injury and renal outcome, compared with patients without renal IgA deposition. Therefore, we proposed that, in lupus nephritis patients with renal IgA deposition, CFHR3-1Δ might indirectly enhance CFH activity to inhibit complement activation, and thereby reduce manifestations of lupus nephritis. This study will further determine the incidence of CFHR3-1Δ in lupus nephritis patients and analyzed the association between CFHR3-1Δ and complement activation and renal outcome. Meanwhile, we will investigate the functions of CFHR3-1 on CFH activity, alternative pathway activation, and complement-induced renal injury, in turn, support our hypothesis that CFHR3-1Δ confers a protective effect against lupus nephritis development, which may contribute to a better understanding of the role of complement system in the pathogenesis of lupus nephritis.

补体旁路途径的活化与狼疮性肾炎及IgA肾病的发病均密切相关。H因子（CFH）是旁路途径活化的主要抑制因子，而CFH相关蛋白3和1（CFHR3-1）被认为可能在靶细胞局部抑制CFH活性。CFHR3-1基因缺失（CFHR3-1Δ）与SLE和IgA肾病的发病均有关，在IgA肾病中是保护性因素。本课题以肾脏伴有IgA沉积的狼疮性肾炎患者为研究对象，初步发现：该组患者临床及肾脏病理表现轻，肾脏预后好，其旁路途径未被充分激活。因此，推测其中可能存在CFHR3-1Δ，间接导致CFH活性增强，从而抑制旁路途径的过度活化而减轻病情。本课题拟进一步检测其中CFHR3-1Δ的发生率，分析其与补体活化及肾脏预后的相关性；并在体外实验中研究CFHR3-1对CFH生物学功能、补体活化及肾脏细胞免疫性损伤的影响，验证CFHR3-1Δ在狼疮性肾炎中起保护性作用的假设，为补体系统在狼疮性肾炎发病机制中的地位给予合理补充。

补体旁路途径的活化与狼疮性肾炎（LN）及IgA肾病（IgAN）的发病均密切相关。H因子（CFH）是旁路途径活化的主要抑制因子，而CFH相关蛋白3和1（CFHR3-1）被认为可能在靶细胞局部抑制CFH活性。CFHR3-1基因缺失（CFHR3-1Δ）与SLE和IgAN的发病均有关，在IgAN中是保护性因素。本研究以肾脏伴有IgA沉积的LN患者为新的视角，探讨补体CFHR3-1在LN发病机制中的作用。一方面，CFH rs6677604-AA/GA基因型与CFHR3-1Δ存在极强的连锁关系。我们在LN患者、非肾脏受累的SLE患者及健康人群中进行了rs6677604 SNP位点的检测以及基因-临床表型、补体活化水平关联性研究，发现在上述三组人群中，rs6677604-A/G基因位点及AA/GA/GG基因型的发生率均无显著性差异，并且不同基因型的LN患者的临床表型亦无显著性差异，但是不同基因型LN患者循环中补体活化水平检测提示rs6677604-AA/GA组患者血浆中可能存在对补体旁路途径活化的抑制因素。另一方面，我们从基因型、临床病理表型、补体活化水平等方面深入研究了肾脏伴有IgA沉积的LN患者的疾病特点，结果提示该组人群临床表现和肾脏病理损伤较轻，肾脏预后较好；尤其是肾脏伴有IgA沉积表型与LN肾脏病理多个慢性化损伤指标负相关，是肾脏预后的相对保护性因素。但是，肾脏伴有IgA沉积的LN患者与无此表型的患者相比，rs6677604-AA/GA基因型发生率无显著性差异。因此，我们推测与rs6677604-AA/GA基因型相关联的CFHR3-1Δ遗传背景在肾脏伴有IgA沉积的LN患者中是非特异性的。