Proposed Mechanisms of Age Related Macular Degeneration

Abstract

Age related macular degeneration (AMD) is currently the leading cause of blindness in the United States and its prevalence will continue to increase in the coming decades unless new prevention strategies can be developed. This provides a new approach to understanding the development and potentially the treatment of this disease. The mechanisms leading to the development of both the early and late lesions of AMD remain largely unknown but recent studies reported endoplasmic reticulum stress as a primary pathogenic mechanism leading to age related macular degeneration. Recent information supports the notion that immune mechanisms play an important and perhaps central role in AMD. The method of this study is Literature review and interpretation. We searched a database of systematic (internet) reviews in eyes and vision without language or date restrictions to review publications on the role of the immune system in age related macular degeneration, advanced AMD and therapy. We mapped treatment recommendations from the American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPPs) for AMD and citations of reliable systematic reviews to support each treatment recommendation. The result of this study shows that an ever growing body of evidence is gathering concerning the role of the immune system in AMD. Evidence to date suggests that the underlying mechanism leading to AMD is the decline of the ocular down regulatory immune environment (DIE). The subsequent activation of the immune system would lead to T cell sensitization. When combined with local anti‐angiogenic therapy, several existing immuno‐therapies could be used to downregulate the immune response and potentially leading to a more efficient inhibition of choroidal neovascularization. Five general concepts relevant to the cell biology of AMD have been described as follows (1) AMD involves aging changes plus additional pathological changes;(2) in aging and AMD, oxidative stress causes Retinal pigment epithelial(RPE) and, possibly, choriocapillaris injury;(3) in AMD RPE and choriocapillaris injury results in a chronic inflammatory response in the Bruch membrane and the choroid;(4) in AMD, RPE and choriocapillaris injury and inflammation lead to formation of an abnormal extracellular matrix(ECM), to the retina and RPE; 5) the abnormal ECM results in altered RPE‐choriocapillaris behavior leading ultimately to atrophy of the retina, RPE, and choriocapillaris and/or to choroidal new vessel (CNV)growth. In conclusion, we believe there is strong evidence for an immunologic mechanism resulting in the development of advanced AMD. The hypothesis is as follows. Debris gradually accumulates in the RPE for decades. Eventually, when this buildup reaches a critical point, this debris is extruded and accumulates as small Drusen. These small drusen serve as a potential antigenic stimulus, especially in persons with relative immune dysfunctionSupport or Funding InformationSupported by Institutional Resources of USAT Montserrat and the Einstein Medical Instiute, N. Palm Beach, FL. USAThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.