The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.
The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.
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DOI：
10.1016/j.preteyeres.2009.11.003
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发表时间：
2010-03
影响因子：
17.8
通讯作者：
Johnson, Lincoln V.
中科院分区：
文献类型：
--
作者：
Anderson, Don H.;Radeke, Monte J.;Gallo, Natasha B.;Chapin, Ethan A.;Johnson, Patrick T.;Curletti, Christy R.;Hancox, Lisa S.;Hu, Jane;Ebright, Jessica N.;Malek, Goldis;Hauser, Michael A.;Rickman, Catherine Bowes;Bok, Dean;Hageman, Gregory S.;Johnson, Lincoln V.
关键词：
在过去的十年中，在揭示年龄相关性黄斑变性（AMD）的生物学基础方面取得了巨大进展，AMD是西方人群中不可逆失明的最常见原因。在该时间范围内，出现了两种不同的证据，其涉及AMD发病机制中的慢性局部炎症和补体级联的激活。首先，许多补体系统蛋白、补体激活剂和补体调节蛋白被鉴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，遗传研究揭示了AMD与几种补体途径相关基因的变体之间的高度显著的统计学关联，包括：补体因子H（CFH）、补体因子H相关1和3（CFHR 1和CFHR 3）、补体因子B（CF B）、补体成分2（C2）和补体成分3（C3）。在这篇文章中，我们重新审视了我们最初的假设，即在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的生物发生中起着关键作用，并在AMD的病理生物学中起着重要作用。其次，我们报告了一个新的筛选结果，额外的AMD相关的多态性电池的63个补体相关基因。第三，我们确定并表征了RPE-脉络膜复合体中的局部补体系统-从而为补体系统在眼老化和AMD中的作用增加了一个新的生物复杂性维度。最后，我们评估了最突出的，最近的证据，直接承担的作用，补体在AMD的发病机制和进展。总的来说，这些最新的发现有力地重申了补体系统在AMD中的重要性。它们为进一步的研究奠定了基础，这些研究可能导致AMD的转录疾病特征的鉴定，并加速新治疗方法的开发，这些方法将恢复在遗传易感个体中似乎受到损害的补体调节活性。
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.
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DOI：
10.1016/s0140-6736(08)61348-3
发表时间：
2008-11-22
期刊：
Lancet (London, England)
影响因子：
--
作者：
Ennis S;Jomary C;Mullins R;Cree A;Chen X;Macleod A;Jones S;Collins A;Stone E;Lotery A
通讯作者：
Lotery A
影响因子：
5.2
作者：
Fagerness, Jesen A.;Maller, Julian B.;Seddon, Johanna M.
通讯作者：
Seddon, Johanna M.
DOI：
10.1073/pnas.222551899
发表时间：
2002-11-12
影响因子：
11.1
作者：
Crabb, JW;Miyagi, M;Hollyfield, JG
通讯作者：
Hollyfield, JG
影响因子：
56.9
作者：
Edwards, AO;Ritter, R;Farrer, LA
通讯作者：
Farrer, LA
影响因子：
20.3
作者：
Bossi, Fleur;Rizzi, Lucia;Tedesco, Francesco
通讯作者：
Tedesco, Francesco