A Perspective of AMD Through the Eyes of Immunology

Abstract

Despite strong genetic associations, compelling human histological data and numerous hypotheses generated with supportive animal data, the mechanisms of inflammation or inflammatory control of cell health during progression of age-related macular degeneration arguably remain elusive. This perspective delivers a view that maintaining tissue health requires active immune cellular and tissue pathways, but when responses are perturbed or exaggerated, chronic inflammation is destructive. There are potential pathways and processes to enable understanding and determine how potential causative factors including altered cellular metabolism, senescence, oxidative stress disrupt tissue homeostasis are engaged. Establishing differences in the immune phenotype between normal aging and AMD, and how the inter-relatedness of these triggers contribute to pathobiology is integral for future therapeutic success.

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

“…Despite the fact that clinical and genetic data support an association of a chronic, low-grade inflammatory response in the outer retina during the development of AMD, the exact underlying mechanisms and triggers of inflammation remain elusive (5). Genetic studies point to a central role of the innate immune response and particularly the complement cascade in the development and progression of AMD [for review see (6)]. However, we do not yet understand exactly what causes the earliest signs of inflammation in the retina.…”

Photoreceptor degeneration and choroidal neovascularization in aged BALB/c mice following systemic neonatal murine cytomegalovirus infection

“…Many patholgies and abnormalities observed following prolonged MCMV ocular latency are similar to those observed in AMD, a progressive degenerative disease and the leading cause of severe, permanent vision loss in people over age 60 [1][2][3] . Although the exact events which contribute to the development of AMD remain uncertain, studies have implicated immunological and in ammatory mechanisms [53][54][55] with various clinical and genetic data supporting a tight association between chronic low-grade in ammation and the pathogenesis of AMD 56,57 . Although AMD models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of the disease and provided much insight into its underlying pathological mechanisms; there is currently no single animal model in which all of the characteristics of AMD develop in a progressive manner 53,54,58 .…”

Functionally validated imaging endpoints in the Alabama study on early age-related macular degeneration 2 (ALSTAR2): design and methods

“…Our vascular-metabolic model, because it is linked to the topography of retinal neurons, can be contrasted with (but does not exclude) mechanisms of AMD progression that have a pan-retinal or systemic basis (e.g., oxidative stress, inflammation, complement activation) [55,56]. If our hypotheses withstand rigorous testing, strategies to maintain or restore health of ChC endothelium and/or BrM may have merit in protecting neurons, a winning strategy for tackling cerebrovascular disease and stroke.…”