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首页> 外文期刊>Progress in retinal and eye research >The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.
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The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

机译：补体系统在衰老和与年龄有关的黄斑变性中的关键作用：再次提出了假设。

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During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE-choroid complex - thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that appears to be compromised in genetically susceptible individuals.
机译：在过去的十年中，在阐明与年龄有关的黄斑变性（AMD）的生物学基础方面取得了巨大的进步，黄斑变性是西方人群不可逆转失明的最常见原因。在这段时间内，出现了两条截然不同的证据，暗示慢性局部炎症和AMD发病机制中补体级联的激活。首先，许多补体系统蛋白，补体激活剂和补体调节蛋白被确定为玻璃疣的分子成分，玻璃疣是与早期AMD相关的标志性细胞外沉积物。随后，遗传研究发现AMD与几种与补体途径相关的基因的变体之间具有高度显着的统计关联，这些基因包括：补体因子H（CFH），补体因子H相关1和3（CFHR1和CFHR3），补体因子B（CFB），补码成分2（C2）和补码成分3（C3）。在本文中，我们重新审视了最初的假设，即布鲁赫膜水平的慢性局部炎症和免疫介导的事件在玻璃疣生物发生中以及在AMD的病理生物学中起着至关重要的作用。其次，我们报告了对一系列63种补体相关基因中的其他AMD相关多态性进行新筛选的结果。第三，我们确定并表征了RPE-脉络膜复合物中的局部补体系统-从而为补体系统在眼衰老和AMD中的作用增加了生物复杂性的新维度。最后，我们评估最明显的最新证据，这些证据直接影响补体在AMD发病机理和进展中的作用。总的来说，这些最新发现强烈重申了补体系统在AMD中的重要性。他们为进一步的研究奠定了基础，这些研究可能导致AMD的转录疾病特征的识别，并加快了新治疗方法的开发，这些方法将恢复似乎在遗传易感人群中受损的补体调节活性。

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