Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration.
Heparan sulfate, including that in Bruch's membrane, inhibits the complement alternative pathway: implications for age-related macular degeneration.
复制标题
DOI：
10.4049/jimmunol.0903596
复制
发表时间：
2010-11-01
期刊：
影响因子：
--
通讯作者：
Rickman CB
中科院分区：
文献类型：
--
作者：
Kelly U;Yu L;Kumar P;Ding JD;Jiang H;Hageman GS;Arshavsky VY;Frank MM;Hauser MA;Rickman CB
补体系统的激活和抑制之间的不平衡已经涉及许多常见疾病的病因。关键补体液相调节蛋白补体因子H（CFH）的同种异型变体与年龄相关性黄斑变性（AMD）密切相关，AMD是世界范围内视觉功能障碍的主要原因，尽管其在AMD发病机制中的具体作用仍不清楚。CFH分离自携带与AMD风险最强相关的两种非同义编码变体V62/H402（风险单倍型变体）、I62/Y 402（非风险单倍型变体）和V62/Y 402的组合的个体。这些蛋白质用于两个功能测定（基于细胞表面和液相），测量CFH在因子I介导的C3 b裂解中的辅因子活性。虽然没有检测到辅因子活性的变体特异性差异，但当将硫酸乙酰肝素（HS）加入这些测定中时，它加速了C3 b裂解的速率，并且这种效应可以通过HS硫酸化程度进行调节。布鲁赫膜/脉络膜，AMD中的组织损伤部位，含有高浓度的糖胺聚糖，包括HS。将人Bruch膜/脉络膜加入到液相测定中加速了C3 b裂解，并且在用肝素酶III处理组织后失去了这种作用。CFH变体与从老年非AMD供体眼睛分离的布鲁赫膜/脉络膜的结合是相似的，结合的CFH的功能活性也是相似的。这些发现完善了我们对HS和补体相互作用的理解，并支持了这些相互作用在布鲁赫膜/脉络膜中正常衰老和AMD之间的过渡中发挥作用的假设。
An imbalance between activation and inhibition of the complement system has been implicated in the etiologies of numerous common diseases. Allotypic variants of a key complement fluid phase regulatory protein, complement factor H (CFH), are strongly associated with age-related macular degeneration (AMD), a leading cause of worldwide visual dysfunction, although its specific role in AMD pathogenesis is still not clear. CFH was isolated from individuals carrying combinations of two of the non-synonymous coding variants most strongly associated with AMD risk, V62/H402 (risk haplotype variants), I62/Y402 (non-risk haplotype variants), and V62/Y402. These proteins were used in two functional assays (cell surface- and fluid phase-based) measuring cofactor activity of CFH in the factor I-mediated cleavage of C3b. Though no variant-specific differences in the cofactor activity were detected, when heparan sulfate (HS) was added to these assays it accelerated the rate of C3b cleavage and this effect could be modulated by degree of HS sulfation. Bruch’s membrane/choroid, a site of tissue damage in AMD, contains high concentrations of glycosaminoglycans, including HS. Addition of human Bruch’s membrane/choroid to the fluid phase assay accelerated the C3b cleavage and this effect was lost after treatment of the tissue with heparinase III. Binding of CFH variants to Bruch’s membrane/choroid isolated from elderly, non-AMD donor eyes, was similar, as was the functional activity of bound CFH. These findings refine our understanding of interactions of HS and complement and support the hypothesis that these interactions play a role in the transition between normal aging and AMD in Bruch’s membrane/choroid.
登录
查看更多内容
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：
5.4
作者：
Giannakis, E;Jokiranta, TS;Gordon, DL
通讯作者：
Gordon, DL
影响因子：
4.4
作者：
Ferreira, Viviana P.;Herbert, Andrew P.;Pangburn, Michael K.
通讯作者：
Pangburn, Michael K.
影响因子：
56.9
作者：
Edwards, AO;Ritter, R;Farrer, LA
通讯作者：
Farrer, LA
影响因子：
4.8
作者：
Herbert, Andrew P.;Deakin, Jon A.;Barlow, Paul N.
通讯作者：
Barlow, Paul N.