Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy.
Alternative Pathway Dysregulation and the Conundrum of Complement Activation by IgG4 Immune Complexes in Membranous Nephropathy.
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DOI：
10.3389/fimmu.2016.00157
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发表时间：
2016
影响因子：
7.3
通讯作者：
Borza DB
中科院分区：
文献类型：
--
作者：
Borza DB
膜性肾病（MN）是肾病综合征的主要病因之一，是由IgG抗体介导的一种非炎症性免疫性肾脏疾病，可形成肾小球上皮下免疫复合物。在原发性MN中，自身抗体靶向足细胞表面表达的蛋白质，通常是磷脂酶A2受体（PLA2R1）。病理学由补体激活驱动，导致足细胞损伤和蛋白尿。本文概述了补体激活和调节MN的机制，解决的矛盾，抗PLA2R1和其他抗体引起的主要MN主要是（但不完全）IgG 4，IgG亚类，不固定补体。除了免疫复合物，肾小球基底膜（GBM）在MN中的改变可能导致旁路途径（AP）的调节受损。AP放大补体调节蛋白保护不足的表面上的补体激活。尽管足细胞受到细胞结合调节剂的保护，但GBM必须募集血浆因子H，其抑制携带某些聚阴离子（如硫酸乙酰肝素（HS）链）的宿主表面上的AP。由于正常GBM中存在的HS链在MN中丢失，我们认为H因子的局部补体调节可能因此受损。因此，MN中GBM HS的丧失产生了促进补体激活的局部扩增的微环境，补体激活进而可以通过免疫复合物中IgG的亚群经由经典途径或凝集素途径启动。详细了解MN中补体激活和失调的机制对于设计更有效的治疗方法非常重要。
Membranous nephropathy (MN), a major cause of nephrotic syndrome, is a non-inflammatory immune kidney disease mediated by IgG antibodies that form glomerular subepithelial immune complexes. In primary MN, autoantibodies target proteins expressed on the podocyte surface, often phospholipase A2 receptor (PLA2R1). Pathology is driven by complement activation, leading to podocyte injury and proteinuria. This article overviews the mechanisms of complement activation and regulation in MN, addressing the paradox that anti-PLA2R1 and other antibodies causing primary MN are predominantly (but not exclusively) IgG4, an IgG subclass that does not fix complement. Besides immune complexes, alterations of the glomerular basement membrane (GBM) in MN may lead to impaired regulation of the alternative pathway (AP). The AP amplifies complement activation on surfaces insufficiently protected by complement regulatory proteins. Whereas podocytes are protected by cell-bound regulators, the GBM must recruit plasma factor H, which inhibits the AP on host surfaces carrying certain polyanions, such as heparan sulfate (HS) chains. Because HS chains present in the normal GBM are lost in MN, we posit that the local complement regulation by factor H may be impaired as a result. Thus, the loss of GBM HS in MN creates a micro-environment that promotes local amplification of complement activation, which in turn may be initiated via the classical or lectin pathways by subsets of IgG in immune complexes. A detailed understanding of the mechanisms of complement activation and dysregulation in MN is important for designing more effective therapies.