Zhao Yan-Feng, Zhu Li, Liu Li-Jun, Shi Su-Fang, Lv Ji-Cheng, Zhang Hong
Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China.
Peking University Institute of Nephrology, Beijing, China.
BMC Nephrol. 2017 Sep 29;18(1):301. doi: 10.1186/s12882-017-0722-3.
Accumulating evidences proved the important roles of circulating IgA1-containing immune complexes (cIgA1) in IgA nephropathy (IgAN). Galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG antibody have been identified as major components in cIgA1. Before, Gd-IgA1 was reported as a vital factor in IgAN, partly via of its pathogenic role to induce mesangial cells activation. However, we still lack direct evidences to clarify the biological effect of glycan-specific IgG antibody in IgAN.
In the present study, we enrolled 35 IgAN patients and 17 age- and sex-matched healthy controls. Using uniform aberrant glycosylated IgA1 molecules, and IgG from different individuals, we in vitro prepared IgG-ddIgA1 complexes, and compared the biological differences among these immune complexes regarding their proliferative and inflammatory effects on mesangial cells.
IgG-ddIgA1 complexes from both patients with IgA nephropathy (IgAN-IgG-dd-IgA1) and healthy controls (HC-IgG-dd-IgA1) could induce the proliferation of mesangial cells and up-regulate expression of MCP-1, IL-6 and CXCL1. The levels of mesangial cells proliferation induced by IgAN-IgG-dd-IgA1 were significantly higher than those induced by HC-IgG-dd-IgA1 (1.10 ± 0.05 vs. 1.03 ± 0.03; p < 0.001). However, the levels of secreted MCP-1, IL-6 and CXCL1 from mesangial cells challenged by IgAN-IgG-dd-IgA1 and HC-IgG-dd-IgA1 were comparable.
We found that glycan-specific IgG antibodies derived from patients with IgAN had the biological effect to induce mesangial cells proliferation. Moreover, in the present study we also established a method for in vitro preparation of pathogenic IgG-ddIgA1 complexes, which could be applied in future studies exploring IgAN pathogenesis.
越来越多的证据证明循环含IgA1免疫复合物（cIgA1）在IgA肾病（IgAN）中起重要作用。半乳糖缺陷型IgA1（Gd-IgA1）和聚糖特异性IgG抗体已被确定为cIgA1的主要成分。此前，Gd-IgA1被报道为IgAN中的一个关键因素，部分原因是其在诱导系膜细胞活化方面的致病作用。然而，我们仍然缺乏直接证据来阐明聚糖特异性IgG抗体在IgAN中的生物学效应。
在本研究中，我们纳入了35例IgAN患者和17例年龄及性别匹配的健康对照。使用统一的异常糖基化IgA1分子和来自不同个体的IgG，我们在体外制备了IgG-ddIgA1复合物，并比较了这些免疫复合物对系膜细胞的增殖和炎症作用的生物学差异。
IgA肾病患者（IgAN-IgG-dd-IgA1）和健康对照（HC-IgG-dd-IgA1）的IgG-ddIgA1复合物均可诱导系膜细胞增殖并上调MCP-1、IL-6和CXCL1的表达。IgAN-IgG-dd-IgA1诱导的系膜细胞增殖水平显著高于HC-IgG-dd-IgA1诱导的水平（1.10±0.05对1.03±0.03；p<0.001）。然而，IgAN-IgG-dd-IgA1和HC-IgG-dd-IgA1刺激的系膜细胞分泌的MCP-1、IL-6和CXCL1水平相当。
我们发现IgAN患者来源的聚糖特异性IgG抗体具有诱导系膜细胞增殖的生物学效应。此外，在本研究中我们还建立了一种体外制备致病性IgG-ddIgA1复合物的方法，该方法可应用于未来探索IgAN发病机制的研究。
