Skerka Christine, Lauer Nadine, Weinberger Andreas A W A, Keilhauer Claudia N, Sühnel Jürgen, Smith Richard, Schlötzer-Schrehardt Ursula, Fritsche Lars, Heinen Stefan, Hartmann Andrea, Weber Bernhard H F, Zipfel Peter F
Department of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
Mol Immunol. 2007 Jul;44(13):3398-406. doi: 10.1016/j.molimm.2007.02.012. Epub 2007 Mar 30.
The common variant in the human complement Factor H gene (CFH), with Tyr402His, is linked to age-related macular degeneration (AMD), a prevalent disorder leading to visual impairment and irreversible blindness in elderly patients. Here we show that the risk variant CFH 402His displays reduced binding to C reactive protein (CRP), heparin and retinal pigment epithelial cells. This reduced binding can cause inefficient complement regulation at the cell surface, particularly when CRP is recruited to injured sites and tissue. In addition, we identify the Factor H-like protein 1 (FHL-1), an alternative splice product of the CFH gene as an additional protein that includes the risk residue 402, and thus confers risk for AMD. FHL-1 is expressed in the eye and the FHL-1 402His risk variant shows similar reduced cell binding and likely reduced complement regulatory functions on the cell surface. CFH and FHL-1 may act in concert in the eye and the reduced surface binding may result in inappropriate local complement control, which in turn can lead to inflammation, disturbance of local physiological homeostasis and progression to cell damage. As a consequence, these processes may lead to AMD pathogenesis.
人类补体因子H基因（CFH）中的常见变体Tyr402His与年龄相关性黄斑变性（AMD）相关，AMD是一种在老年患者中普遍存在的导致视力损害和不可逆失明的疾病。我们在此表明，风险变体CFH 402His与C反应蛋白（CRP）、肝素和视网膜色素上皮细胞的结合减少。这种结合减少会导致细胞表面补体调节效率低下，尤其是当CRP被募集到损伤部位和组织时。此外，我们鉴定出CFH基因的一种选择性剪接产物——类补体因子H蛋白1（FHL-1），它是另一种包含风险残基402的蛋白，因此会增加患AMD的风险。FHL-1在眼中表达，FHL-1 402His风险变体显示出类似的细胞结合减少情况，并且可能在细胞表面具有降低的补体调节功能。CFH和FHL-1可能在眼中协同作用，表面结合减少可能导致局部补体控制不当，进而引发炎症、局部生理稳态紊乱并发展为细胞损伤。因此，这些过程可能导致AMD的发病机制。
