A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NTal region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CTal region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.

中文翻译：

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FH 预防新生血管性 AMD 的机制。


补体因子 H (FH) 基因的一个常见等位基因 (402H) 是年龄相关性黄斑变性 (AMD) 的主要危险因素，而 AMD 是导致老年人失明的主要原因。 AMD 的发生和进展部分涉及血管和炎症成分，原因是补体系统 (AP) 替代途径的失调。中央视力的丧失是由于脉络膜萎缩和/或异常新血管形成造成的。 FH（AP 的主要抑制剂）与 AMD 中脉络膜新生血管（CNV）之间的功能联系仍不清楚。在用作新生血管 AMD (nAMD) 模型的 CNV 小鼠模型中，眼内人重组 FH (recFH) 与目前使用的抗 VEGF（血管内皮生长因子）抗体一样有效地减少 CNV，减少 C3 裂解片段、膜的沉积攻击复合体 (MAC) 和 CNV 病变部位的小胶质细胞/巨噬细胞招募标记。与此形成鲜明对比的是，携带H402风险变异的recFH对CNV没有影响，表明与疾病病因学存在因果关系。只有含有 CCPs1-4 C3 转化酶抑制结构域和 CCP7 结合结构域的 recFH NTal 区域 (recFH1-7) 发挥了所有不同的生物学效应。含有 CCP7 和 CCPs19-20 结合域的 CTal 区域 (recFH7-20) 具有抗血管生成作用，但不会减少小胶质细胞/巨噬细胞的募集。 recFH1-20和recFH-CCP7-20的抗血管生成作用均由血小板反应蛋白-1 (TSP-1)上调引起，与C3裂解片段的产生无关。这项研究提供了对 FH 在 nAMD 中的机制作用的见解，并促使人们重新考虑其治疗潜力。