Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Invest Ophthalmol Vis Sci. 2012 Sep 25;53(10):6628-37. doi: 10.1167/iovs.12-9587.
To determine if the progression of age-related macular degeneration (AMD) is associated with complement activation in the eye.
Immunohistochemistry and ELISAs were used to determine the distribution, concentration, and activation of the alternative pathway complement proteases factor B (FB) and factor D (FD) and the central complement protein C3 in genotyped human postmortem donor eyes graded as having no or minimal drusen (category 1; controls), large drusen (category 3), and large drusen with advanced AMD (category 4).
C3, FB, and FD were present in vitreous and Bruch's membrane choroid (BM/C) interface of the macula of eyes in all tested AMD severity categories (n = 100). C3, FB, and FD were predominantly located to the choroidal vasculature and Bruch's membrane and, together with the serum proteins transferrin and albumin, elevated in BM/C extracts of category 4 eyes (n = 23) compared with category 1 eyes (n = 24). A significant increase in FB activation was found only in vitreous of category 4 eyes (n = 23) compared with category 1 eyes (n = 25). Genetic variants of complement factor H (CFH), C3, C2, and FB associated with increased risk of AMD were correlated with alternative pathway complement activation in vitreous, but not with complement proteins in BM/C protein extracts.
Increased activation of the alternative complement pathway in vitreous was controlled by disease stage and genetic variation in the complement pathway, supporting a role for complement activation in AMD disease pathogenesis.
确定年龄相关性黄斑变性（AMD）的进展是否与眼部补体激活有关。
采用免疫组织化学和 ELISA 法检测经基因分型的人死后供眼，确定替代途径补体蛋白酶因子 B（FB）和因子 D（FD）以及中央补体蛋白 C3 的分布、浓度和激活情况，这些供眼分为无或仅有最小玻璃膜疣（1 类；对照）、大玻璃膜疣（3 类）和大玻璃膜疣伴晚期 AMD（4 类）。
C3、FB 和 FD 存在于所有 AMD 严重程度类别（n=100）的玻璃体和黄斑部脉络膜（BM/C）界面的视网膜中。C3、FB 和 FD 主要定位于脉络膜血管和玻璃膜，与血清蛋白转铁蛋白和白蛋白一起，在 4 类眼（n=23）的 BM/C 提取物中升高，而在 1 类眼（n=24）中则降低。仅在 4 类眼（n=23）的玻璃体中发现 FB 激活显著增加，而在 1 类眼（n=25）中则没有。与 AMD 风险增加相关的补体因子 H（CFH）、C3、C2 和 FB 的遗传变异与玻璃体中替代途径补体激活相关，但与 BM/C 蛋白提取物中的补体蛋白无关。
玻璃体中替代补体途径的激活增加受疾病阶段和补体途径遗传变异的控制，支持补体激活在 AMD 发病机制中的作用。
