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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk
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Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk

机译：C3，B因子和H因子的常见多态性共同确定全身补体活性和疾病风险

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摘要

Common polymorphisms in complement alternative pathway (AP) proteins C3 (C3_(r10)2g), factor B (fB_(R32)Q), and factor H (fH_(V621)) are associated with age-related macular degeneration (AMD) and other pathologies. Our published work showed that fB_(R32Q) influences C3 convertase formation, whereas fH_(621) affects factor I co-factor activity. Here we show how C3_(r102)g (C3S/F) influences AP activity. In hemolysis assays, C3_(102)g activated AP more efficiently (EC_(50) C3_(102G): 157 nM; C3_(1O2R): 191 nM; P < 0.0001). fB binding kinetics and convertase stability were identical, but native and recombinant fH bound more strongly to C3b_(102R) (K_D C3b_(102R): 1.0 μM; C3b_(102G): 1.4 μM; P < 0.0001). Accelerated decay was unaltered, but fH cofactor activity was reduced for C3b_(102G). favoring AP amplification. Combining disease "risk" variants (C3_(102G). fB_(32R). and fH_(62V)) in add-back assays yielded sixfold higher hemolytic activity compared with "protective" variants (C3_(102R), fB_(32Q), and fH_(62l); P < 0.0001). These data introduce the concept of a functional complotype (combination of polymorphisms) defining complement activity in an individual, thereby influencing susceptibility to AP-driven disease.
机译：补体替代途径（AP）蛋白C3（C3_（r10）2g），因子B（fB_（R32）Q）和因子H（fH_（V621））的常见多态性与年龄相关性黄斑变性（AMD）和其他病理。我们发表的工作表明，fB_（R32Q）影响C3转化酶的形成，而fH_（621）影响因子I辅助因子的活性。在这里，我们显示C3_（r102）g（C3S / F）如何影响AP活动。在溶血试验中，C3_（102）g更有效地激活了AP（EC_（50）C3_（102G）：157 nM； C3_（1O2R）：191 nM； P <0.0001）。 fB结合动力学和转化酶稳定性相同，但天然和重组fH与C3b​​_（102R）的结合更牢固（K_D C3b_（102R）：1.0μM; C3b_（102G）：1.4μM; P <0.0001）。加速衰减没有改变，但C3b_（102G）的fH辅因子活性降低。有利于AP放大。与“保护性”变体（C3_（102R），fB_（32Q），“保护性”变体（C3_（102R），fB_（32Q），“保护性”变体（C3_（102R），fB_（32Q），和fH_（62l）; P <0.0001）。这些数据引入了定义个体补体活性的功能性组合（多态性的组合）的概念，从而影响了对AP驱动疾病的易感性。

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    Meike Heurich; Ruben Martinez-Barricarte; Nigel J. Francis; Dawn L. Roberts; Santiago Rodriguez de Córdoba; B. Paul Morgan; Claire L. Harrisa;

  • 作者单位

    Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain;

    Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, 28040 Madrid, Spain;

    Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;

    Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    inflammation; infection;

    机译：炎症;感染;

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