Shaw Peter X, Stiles Travis, Douglas Christopher, Ho Daisy, Fan Wei, Du Hongjun, Xiao Xu
Department of Ophthalmology and Shiley Eye Institute, University of California San Diego, San Diego, CA, USA.
Huaxi Hospital, Sichuan University, China.
AIMS Mol Sci. 2016;3(2):196-221. doi: 10.3934/molsci.2016.2.196. Epub 2016 May 11.
Age-related macular degeneration (AMD) is a leading cause of vision loss affecting tens of millions of elderly worldwide. Early AMD is characterized by the appearance of soft drusen, as well as pigmentary changes in the retinal pigment epithelium (RPE). These soft, confluent drusen can progress into two forms of advanced AMD: geographic atrophy (GA, or dry AMD) or choroidal neovascularization (CNV, or wet AMD). Both forms of AMD result in a similar clinical progression in terms of loss of central vision. The exact mechanism for developing early AMD, as well as triggers responsible for progressing to advanced stage of disease, is still largely unknown. However, significant evidence exists demonstrating a complex interplay of genetic and environmental factors as causes of AMD progression. Multiple genes and/or single nucleotide polymorphisms (SNPs) have been found associated with AMD, including various genes involved in the complement pathway, lipid metabolism and extracellular matrix (ECM) remodeling. Of the known genetic contributors to disease risk, the CFH Y402H and HTRA1/ARMS polymorphisms contribute to more than 50% of the genetic risk for AMD. Environmentally, oxidative stress plays a critical role in many aging diseases including cardiovascular disease, cancer, Alzheimer's disease and AMD. Due to the exposure to sunlight and high oxygen concentration, the oxidative stress burden is higher in the eye than other tissues, which can be further complicated by additional oxidative stressors such as smoking. Increasingly, evidence is accumulating suggesting that functional abnormalities of the innate immune system incurred via high risk genotypes may be contributing to the pathogenesis of AMD by altering the inflammatory homeostasis in the eye, specifically in the handling of oxidation products. As the eye in non-pathological instances maintains a low level of inflammation despite the presence of a relative abundance of potentially inflammatory molecules, we have previously hypothesized that the tight homeostatic control of inflammation via the innate immune system is likely critical for avoidance of disease progression. However, the presence of a multitude of potential triggers of inflammation results in a sensitive balance in which perturbations thereof would subsequently alter the inflammatory state of the retina, leading to a state of chronic inflammation and pathologic progression. In this review, we will highlight the background literature surrounding the known genetic and environmental contributors to AMD risk, as well as a discussion of the potential mechanistic interplay of these factors that lead to disease pathogenesis with particular emphasis on the delicate control of inflammatory homeostasis and the centrality of the innate immune system in this process.
年龄相关性黄斑变性（AMD）是全球数千万老年人视力丧失的主要原因。早期AMD的特征是出现软性玻璃膜疣以及视网膜色素上皮（RPE）的色素变化。这些软性、融合性玻璃膜疣可进展为两种晚期AMD形式：地图样萎缩（GA，或干性AMD）或脉络膜新生血管形成（CNV，或湿性AMD）。两种形式的AMD在中心视力丧失方面导致相似的临床进展。早期AMD发生的确切机制以及疾病进展至晚期的触发因素在很大程度上仍不清楚。然而，有大量证据表明遗传和环境因素之间存在复杂的相互作用，是AMD进展的原因。已经发现多个基因和/或单核苷酸多态性（SNP）与AMD相关，包括参与补体途径、脂质代谢和细胞外基质（ECM）重塑的各种基因。在已知的疾病风险遗传因素中，CFH Y402H和HTRA1/ARMS多态性占AMD遗传风险的50%以上。在环境方面，氧化应激在许多衰老相关疾病中起关键作用，包括心血管疾病、癌症、阿尔茨海默病和AMD。由于暴露于阳光和高氧浓度，眼睛中的氧化应激负担比其他组织更高，吸烟等额外的氧化应激源可能会使情况更加复杂。越来越多的证据表明，通过高风险基因型引发的先天性免疫系统功能异常可能通过改变眼睛中的炎症稳态，特别是在氧化产物的处理方面，导致AMD的发病机制。由于在非病理情况下，尽管存在相对丰富的潜在炎症分子，眼睛仍维持低水平的炎症，我们之前推测通过先天性免疫系统对炎症进行严格的稳态控制可能对避免疾病进展至关重要。然而，多种潜在炎症触发因素的存在导致了一种敏感的平衡，其中对其的干扰随后会改变视网膜的炎症状态，导致慢性炎症状态和病理进展。在这篇综述中，我们将重点介绍围绕已知的AMD风险遗传和环境因素的背景文献，并讨论这些因素导致疾病发病机制的潜在机制相互作用，特别强调对炎症稳态的精细控制以及先天性免疫系统在这一过程中的核心地位。
