Inflammatory Mechanisms of Age-Related Macular Degeneration
Inflammatory Mechanisms of Age-Related Macular Degeneration
Late age-related macular degeneration (AMD), specifically central geographic atrophy (GA) and choroidal neovascularization (CNV), is the leading cause of irreversible vision loss in the elderly in the developed world. AMD is categorized as either (i) non-neovascular, or dry, when CNV is not present, or (ii) neovascular, or wet, when CNV is present. Increasing age is the most significant risk factor for AMD development. In the United States, AMD is more common in whites, and smoking is strongly associated. The hallmark of AMD clinically is the presence of drusen situated under the retinal pigment epithelium (RPE). Drusen size is categorized as small (≤62 μm), medium (63 to 124 μm), or large (≥125 μm), with presence of large drusen being a significant predictor of progression to late AMD and associated vision loss. The Age-Related Eye Disease Studies (AREDS and AREDS2) have shown that high-dose antioxidant and zinc supplementation delay the progression of AMD in moderate-risk and high-risk patients. Antivascular endothelial growth factor (VEGF) treatment is the mainstay of therapy for wet AMD. Currently, there is no treatment for GA.
While AMD pathogenesis is undoubtedly multifactorial, including the effects of aging and oxidative stress as well as genetic and environmental factors, significant evidence has emerged implicating inflammation and the immune system. The major role of the immune system is to identify and respond to physiological insults, such as infection, malignancy, and tissue damage. Often this takes the form of robust inflammatory responses, such as those seen in various forms of uveitis, despite the potent downregulatory immune environment within the eye. In AMD, immune dysregulation in the form of overt intraocular inflammation is not clinically apparent. It has been proposed that the role of inflammation is not always negative. The concept of parainflammation has been suggested to describe inflammatory responses to tissue stress that are intermediate between basal and robust inflammatory states and function in a reparative manner. As AMD is not accompanied by an intense inflammatory reaction, it is possible that dysregulation of reparative parainflammatory mechanisms, in the context of the aging eye, lead to a low-grade chronic inflammatory response and subsequent AMD pathology. This review will focus on the potential inflammatory mechanisms of AMD pathogenesis based on evidence from human studies.
Introduction
Late age-related macular degeneration (AMD), specifically central geographic atrophy (GA) and choroidal neovascularization (CNV), is the leading cause of irreversible vision loss in the elderly in the developed world. AMD is categorized as either (i) non-neovascular, or dry, when CNV is not present, or (ii) neovascular, or wet, when CNV is present. Increasing age is the most significant risk factor for AMD development. In the United States, AMD is more common in whites, and smoking is strongly associated. The hallmark of AMD clinically is the presence of drusen situated under the retinal pigment epithelium (RPE). Drusen size is categorized as small (≤62 μm), medium (63 to 124 μm), or large (≥125 μm), with presence of large drusen being a significant predictor of progression to late AMD and associated vision loss. The Age-Related Eye Disease Studies (AREDS and AREDS2) have shown that high-dose antioxidant and zinc supplementation delay the progression of AMD in moderate-risk and high-risk patients. Antivascular endothelial growth factor (VEGF) treatment is the mainstay of therapy for wet AMD. Currently, there is no treatment for GA.
While AMD pathogenesis is undoubtedly multifactorial, including the effects of aging and oxidative stress as well as genetic and environmental factors, significant evidence has emerged implicating inflammation and the immune system. The major role of the immune system is to identify and respond to physiological insults, such as infection, malignancy, and tissue damage. Often this takes the form of robust inflammatory responses, such as those seen in various forms of uveitis, despite the potent downregulatory immune environment within the eye. In AMD, immune dysregulation in the form of overt intraocular inflammation is not clinically apparent. It has been proposed that the role of inflammation is not always negative. The concept of parainflammation has been suggested to describe inflammatory responses to tissue stress that are intermediate between basal and robust inflammatory states and function in a reparative manner. As AMD is not accompanied by an intense inflammatory reaction, it is possible that dysregulation of reparative parainflammatory mechanisms, in the context of the aging eye, lead to a low-grade chronic inflammatory response and subsequent AMD pathology. This review will focus on the potential inflammatory mechanisms of AMD pathogenesis based on evidence from human studies.
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