Laine Matti, Jarva Hanna, Seitsonen Sanna, Haapasalo Karita, Lehtinen Markus J, Lindeman Nina, Anderson Don H, Johnson Patrick T, Järvelä Irma, Jokiranta T Sakari, Hageman Gregory S, Immonen Ilkka, Meri Seppo
Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Haartmaninkatu 3, FI-00014 Helsinki, Finland.
J Immunol. 2007 Mar 15;178(6):3831-6. doi: 10.4049/jimmunol.178.6.3831.
Complement factor H (FH) is an important regulator of the alternative complement pathway. The Y402H polymorphism within the seventh short consensus repeat of FH was recently shown to be associated with age-related macular degeneration, the most common cause of irreversible blindness in the Western world. We examined the effects of this polymorphism on various FH functions. FH purified from sera of age-related macular degeneration patients homozygous for the FH(402H) variant showed a significantly reduced binding to C-reactive protein (CRP), an acute phase protein, as compared with FH derived from unaffected controls homozygous for the FH(402Y) variant. Strongly reduced binding to CRP was also observed with a recombinant fragment of FH (short consensus repeat 5-7) containing the same amino acid change. Because the interaction of CRP and FH promotes complement-mediated clearance of cellular debris in a noninflammatory fashion, we propose that the reduced binding of FH(402H) to CRP could lead to an impaired targeting of FH to cellular debris and a reduction in debris clearance and enhanced inflammation along the macular retinal pigmented epithelium-choroid interface in individuals with age-related macular degeneration.
补体因子H（FH）是替代补体途径的重要调节因子。最近发现，FH第七个短共识重复序列中的Y402H多态性与年龄相关性黄斑变性有关，年龄相关性黄斑变性是西方世界不可逆失明的最常见原因。我们研究了这种多态性对FH各种功能的影响。与来自FH(402Y)变体纯合未受影响对照的FH相比，从FH(402H)变体纯合的年龄相关性黄斑变性患者血清中纯化的FH与急性期蛋白C反应蛋白（CRP）的结合显著减少。在含有相同氨基酸变化的FH重组片段（短共识重复序列5-7）中也观察到与CRP的结合大幅减少。由于CRP与FH的相互作用以非炎症方式促进补体介导的细胞碎片清除，我们认为FH(402H)与CRP结合减少可能导致FH靶向细胞碎片的能力受损，碎片清除减少，并增强年龄相关性黄斑变性患者黄斑视网膜色素上皮-脉络膜界面的炎症。
