Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy.
Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy.
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DOI：
10.3389/fimmu.2018.01433
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发表时间：
2018
影响因子：
7.3
通讯作者：
Borza DB
中科院分区：
文献类型：
--
作者：
Luo W;Olaru F;Miner JH;Beck LH Jr;van der Vlag J;Thurman JM;Borza DB
膜性肾病是由 IgG 抗体形成肾小球上皮下免疫复合物引起的免疫性肾脏疾病。蛋白尿是由补体激活介导的，是 C5b-9 足细胞损伤的结果，但特定补体途径的作用尚不清楚。介导原发性膜性肾病的自身抗体主要是IgG4亚类，其不能激活经典途径。肾活检的组织学证据表明，凝集素和替代途径可能在膜性肾病中被激活，但这些途径的致病相关性仍不清楚。在这项研究中，我们评估了替代途径在小鼠膜性肾病模型中的作用。在诱导上皮下免疫复合物形成后，我们在野生型小鼠和 B 因子缺失小鼠中发现了类似的肾小球 IgG 沉积，而这些小鼠缺乏功能性替代途径。与野生型小鼠不同，缺乏 B 因子的小鼠不会出现蛋白尿，也不会出现 C3c 和 C5b-9 的肾小球沉积。 C5 缺陷小鼠的蛋白尿也有所减少，但并未完全消除。我们的结果提供了第一个直接证据，表明替代途径对于肾小球上皮下免疫复合物激活致病性补体是必需的，因此是实验性膜性肾病蛋白尿的关键介质。这些知识对于合理设计膜性肾病新疗法非常重要。
Membranous nephropathy is an immune kidney disease caused by IgG antibodies that form glomerular subepithelial immune complexes. Proteinuria is mediated by complement activation, as a result of podocyte injury by C5b-9, but the role of specific complement pathways is not known. Autoantibodies-mediating primary membranous nephropathy are predominantly of IgG4 subclass, which cannot activate the classical pathway. Histologic evidence from kidney biopsies suggests that the lectin and the alternative pathways may be activated in membranous nephropathy, but the pathogenic relevance of these pathways remains unclear. In this study, we evaluated the role of the alternative pathway in a mouse model of membranous nephropathy. After inducing the formation of subepithelial immune complexes, we found similar glomerular IgG deposition in wild-type mice and in factor B-null mice, which lack a functional alternative pathway. Unlike wild-type mice, mice lacking factor B did not develop albuminuria nor exhibit glomerular deposition of C3c and C5b-9. Albuminuria was also reduced but not completely abolished in C5-deficient mice. Our results provide the first direct evidence that the alternative pathway is necessary for pathogenic complement activation by glomerular subepithelial immune complexes and is, therefore, a key mediator of proteinuria in experimental membranous nephropathy. This knowledge is important for the rational design of new therapies for membranous nephropathy.
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影响因子：
7.3
作者：
Borza DB
通讯作者：
Borza DB
影响因子：
20.3
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