Ardeljan Christopher P, Ardeljan Daniel, Abu-Asab Mones, Chan Chi-Chao
Histology Core, Laboratory of Immunology, National Eye Institute/National Institutes of Health, Bethesda, Maryland 20892-1857, MD, USA.
Human Genetics Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, MD, USA.
J Clin Med. 2014;3(4):1542-60. doi: 10.3390/jcm3041542.
The etiology of Age-related Macular Degeneration (AMD) remains elusive despite the characterization of many factors contributing to the disease in its late-stage phenotypes. AMD features an immune system in flux, as shown by changes in macrophage polarization with age, expression of cytokines and complement, microglial accumulation with age, etc. These point to an allostatic overload, possibly due to a breakdown in self vs. non-self when endogenous compounds and structures acquire the appearance of non-self over time. The result is inflammation and inflammation-mediated cell death. While it is clear that these processes ultimately result in degeneration of retinal pigment epithelium and photoreceptor, the prevalent type of cell death contributing to the various phenotypes is unknown. Both molecular studies as well as ultrastructural pathology suggest pyroptosis, and perhaps necroptosis, are the predominant mechanisms of cell death at play, with only minimal evidence for apoptosis. Herein, we attempt to reconcile those factors identified by experimental AMD models and integrate these data with pathology observed under the electron microscope-particularly observations of mitochondrial dysfunction, DNA leakage, autophagy, and cell death.
尽管在年龄相关性黄斑变性（AMD）晚期表型中已明确了许多致病因素，但其病因仍不明确。AMD的特征是免疫系统处于动态变化中，这表现为巨噬细胞极化随年龄的变化、细胞因子和补体的表达、小胶质细胞随年龄的积累等。这些都表明存在适应性负荷过载，这可能是由于随着时间的推移，内源性化合物和结构呈现出非自身的外观，导致自身与非自身的区分出现障碍。结果是炎症以及炎症介导的细胞死亡。虽然很明显这些过程最终会导致视网膜色素上皮和光感受器的退化，但导致各种表型的主要细胞死亡类型尚不清楚。分子研究和超微结构病理学均表明，焦亡，或许还有坏死性凋亡，是起作用的主要细胞死亡机制，而凋亡的证据极少。在此，我们试图梳理实验性AMD模型所确定的那些因素，并将这些数据与电子显微镜下观察到的病理学结果——特别是线粒体功能障碍、DNA泄漏、自噬和细胞死亡的观察结果——相结合。
