Identification of factor H-like protein 1 as the predominant complement regulator in Bruch's membrane: implications for age-related macular degeneration.
Identification of factor H-like protein 1 as the predominant complement regulator in Bruch's membrane: implications for age-related macular degeneration.
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DOI：
10.4049/jimmunol.1401613
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发表时间：
2014-11-15
期刊：
影响因子：
--
通讯作者：
Bishop PN
中科院分区：
文献类型：
--
作者：
Clark SJ;Schmidt CQ;White AM;Hakobyan S;Morgan BP;Bishop PN
对细胞外基质（ECM）的先天免疫的严格调节是整个人体免疫稳态的重要组成部分，而眼睛中这种调节的破坏被认为直接导致年龄相关性黄斑变性（AMD）的进展。血浆补体调节因子 H (FH) 被认为是保护 ECM 免受补体激活破坏的主要调节因子。然而，在这里我们证明了 FH 的截短形式，称为 H 因子样蛋白 1 (FHL-1)，是人类视网膜下 ECM 层（称为布鲁赫膜）中的主要调节蛋白。布鲁赫膜是 AMD 疾病发病机制的主要部位，也是 AMD 标志性病变玻璃疣的形成部位。我们发现 FHL-1 可以被动地通过 Bruch 膜扩散，而全尺寸的糖基化 FH 则不能。 FHL-1 主要通过与硫酸乙酰肝素的相互作用与布鲁赫膜结合，我们发现 CFH 基因中常见的 Y402H 多态性与 AMD 风险增加相关，会减少 FHL-1 与硫酸乙酰肝素的结合。我们还表明，FHL-1 保留在玻璃膜疣中，而 FH 覆盖在病变周围，可能会抑制其清除。我们的结果确定了人眼中补体调节的新机制，这凸显了治疗策略的潜在新途径。
The tight regulation of innate immunity on extracellular matrix (ECM) is a vital part of immune homeostasis throughout the human body and disruption to this regulation in the eye is thought to contribute directly to the progression of age-related macular degeneration (AMD). The plasma complement regulator factor H (FH) is believed to be the main regulator that protects ECM against damaging complement activation. However, here we demonstrate that a truncated form of FH, called factor-H like protein 1 (FHL-1), is the main regulatory protein in the layer of ECM under human retina, called Bruch’s membrane. Bruch’s membrane is a major site of AMD disease pathogenesis and where drusen, the hallmark lesions of AMD, form. We show that FHL-1 can passively diffuse through Bruch’s membrane, whereas the full sized, glycosylated, FH cannot. FHL-1 is largely bound to Bruch’s membrane through interactions with heparan sulfate and we show that the common Y402H polymorphism in the CFH gene, associated with an increased risk of AMD, reduces the binding of FHL-1 to this heparan sulfate. We also show that FHL-1 is retained in drusen while FH coats the periphery of the lesions, perhaps inhibiting their clearance. Our results identify a novel mechanism of complement regulation in the human eye, which highlights potential new avenues for therapeutic strategies.
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影响因子：
4.4
作者：
Keenan, Tiarnan D. L.;Pickford, Claire E.;Bishop, Paul N.
通讯作者：
Bishop, Paul N.
影响因子：
4.1
作者：
FONTAINE, M;DEMARES, MJ;RIPOCHE, J
通讯作者：
RIPOCHE, J
DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
3.5
作者：
Hecker, Laura A.;Edwards, Albert O.;Oppermann, Martin
通讯作者：
Oppermann, Martin
影响因子：
3.5
作者：
Cipriani, Valentina;Leung, Hin-Tak;Yates, John R. W.
通讯作者：
Yates, John R. W.