Complement Regulation at Necrotic Cell Lesions Is Impaired by the Age-Related Macular Degeneration-Associated Factor-H His402 Risk Variant
Complement Regulation at Necrotic Cell Lesions Is Impaired by the Age-Related Macular Degeneration-Associated Factor-H His402 Risk Variant
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DOI：
10.4049/jimmunol.1002488
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发表时间：
2011-10-15
影响因子：
4.4
通讯作者：
Zipfel, Peter F.
中科院分区：
文献类型：
--
作者：
Lauer, Nadine;Mihlan, Michael;Zipfel, Peter F.
年龄相关性黄斑变性是西方国家主要的致盲形式，与因子H基因中的一个常见单核苷酸多态性（rs1061170/Y402H）有关，该基因编码两种补体抑制剂因子H和FHL1。然而，第7结构域中这种酪氨酸（402）→组氨酸的替换所产生的功能影响尚未明确界定。在本研究中，我们发现酪氨酸（402）→组氨酸的序列变异影响因子H通过单体C - 反应蛋白（mCRP）在坏死的视网膜色素上皮细胞表面特定区域的募集。mCRP增强因子H和FHL1的保护性酪氨酸（402）变体的附着，从而更有效地控制补体，并进一步提供抗炎环境。此外，我们证明mCRP在坏死的视网膜色素上皮细胞表面产生，并且这种新形成的mCRP与细胞损伤标记物膜联蛋白V共定位。结合在细胞表面的因子H - mCRP复合物使补体失活，并减少促炎细胞因子TNF -α的释放。这种mCRP介导的在坏死膜损伤处的补体抑制和抗炎活性受因子H的第402位残基影响，并确定了mCRP、因子H以及mCRP - 因子H复合物的新作用。酪氨酸（402）因子H变体保护能力的增强能够更好、更有效地清除细胞碎片，减少炎症和病理变化。《免疫学杂志》，2011年，187卷：4374 - 4383页
Age-related macular degeneration is a leading form of blindness in Western countries and is associated with a common SNP (rs 1061170/Y402H) in the Factor H gene, which encodes the two complement inhibitors Factor H and FHL1. However, the functional consequences of this Tyr(402) His exchange in domain 7 are not precisely defined. In this study, we show that the Tyr(402) His sequence variation affects Factor H surface recruitment by monomeric C-reactive protein (mCRP) to specific patches on the surface of necrotic retinal pigment epithelial cells. Enhanced attachment of the protective Tyr(402) variants of both Factor H and FHL1 by mCRP results in more efficient complement control and further provides an anti-inflammatory environment. In addition, we demonstrate that mCRP is generated on the surface of necrotic retinal pigment epithelial cells and that this newly formed mCRP colocalizes with the cell damage marker annexin V. Bound to the cell surface, Factor H-mCRP complexes allow complement inactivation and reduce the release of the proinflammatory cytokine TNF-alpha. This mCRP-mediated complement inhibitory and anti-inflammatory activity at necrotic membrane lesions is affected by residue 402 of Factor H and defines a new role for mCRP, for Factor H, and also for the mCRP-Factor H complex. The increased protective capacity of the Tyr(402) Factor H variant allows better and more efficient clearance and removal of cellular debris and reduces inflammation and pathology. The Journal of Immunology, 2011, 187: 4374-4383.