补体活化异常与IgA肾病

Abnormal complement activation and IgA nephropathy

IgA肾病(IgAN)是由半乳糖缺陷的IgA1结合抗体后形成病原免疫复合物所介导的自身免疫性疾病,以IgA在肾小球系膜区沉积为特点。系膜区沉积的IgA主要为多聚体IgA1,通过活化系膜细胞产生大量炎症因子,进一步激活补体系统。补体通过替代途径和凝集素途径活化,在IgAN发病机制中发挥重要作用。替代途径产物备解素、H因子(FH)及凝集素途径产物甘露糖结合凝集素(MBL)、MBL相关丝氨酸蛋白酶(MASP)1和2及C4d等参与形成系膜区免疫沉积物。补体H因子相关基因(CFHR)蛋白产物通过与FH竞争性调节替代途径,减弱FH对补体活化的抑制作用。全基因组关联分析显示CFHR 1和CFHR 3缺失对IgAN有保护作用。IgA参与形成的免疫复合物导致补体活化后补体因子及其片段可作为IgAN的血清、尿液及肾组织生物标志物。新近文献报道进展型IgAN患者受益于抗补体治疗,但其长期疗效有待于临床研究进一步验证。本文将补体活化异常对IgAN产生的影响加以综述。

Immunoglobulin A nephropathy（IgAN）,an autoimmune disease mediated by pathogenic immune complexes consisting of galactose-deficient IgA1 bound by antibodies,is characterized by the deposition of IgA in the mesangium of glomeruli. The mesangial IgA has been found to consist mainly of polymeric IgA1 which drives the activation of the mesangial cells and results in excessive production of several inflammatory mediators. The activation of mesangial cells is amplified by the ability of IgA to activate the complement system,mainly via the alternative pathway and lectin pathway. Properdin and factor H（FH） in the alternative pathway and mannan-binding lectin,mannan-binding lectinassociated serine proteases 1 and 2,and C4d in the lectin pathway are present in the mesangial immunodeposition. Protein products of complement factor H-related genes（CFHR） 1 and 3 impact inhibition of complement by FH,in the way of competing with FH in the regulation of the alternative pathway. Genome-wide association studies identified deletion of CFHR1 and CFHR3 play a protective role in IgAN. Complement factors and fragments could serve as biomarkers of IgAN in serum,urine,and renal tissue,for IgA-immune complexes contribute to active complement system. Recently,several literatures reported patients with IgAN benefited from anti-complement therapy. However,the long-time effect still needs to be confirmed by clinical studies. In this review,we summarize the contribution of abnormal complement activation to IgAN.