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J. G. Hollyfield, M. E. Rayborn, X. Yang, R. Ufret, L. Liang, M. Yu, K. G. Shadrach, N. S. Peachey, R. G. Salomon, V. L. Perez; Identification of an Inflammatory Signal From the Outer Retina Causing Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2356.
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© ARVO (1962-2015); The Authors (2016-present)
AMD eye tissues contain proteins chemically modified with adducts generated by the oxidative fragmentation of the long chain polyunsaturated fatty acid, docosahexaenoic acid (DHA). Proteins modified with these adducts are found in drusen and Bruch’s membrane. Additionally, autoantibodies against a unique carboxyethylpyrrole (CEP) adduct that can only be generated from DHA are more abundant in the circulation (plasma) of individuals with AMD than in age-matched individuals without AMD. To demonstrate the linkage between oxidative modifications of proteins, their recognition by the immune system and the vulnerability of the outer retina to immune attack leading to age-related macular degeneration (AMD) we conducted the following experiment.
Normal mice were systemically immunized with CEP-adducted mouse serum albumin (MSA). We used two immunization protocols: one with multiple boosts over a three month period, and the other with a single boost and maintenance of the mice for up to one year. ERGs were used to examine overall retinal function and eye tissues were recovered and analyzed with microscopy.
In single boost animals, focal drusen deposits in the fundus were present along with thinning of the RPE. In multiple boost mice, dramatic lesions of the RPE involving lysis of individual cells were evident along with the invasion of macrophages and debris removal. The focal nature of these changes were confirmed by generally normal ERGs. None of these changes were observed in immunized rag-/- mice that are missing mature T and B cells, or in mice immunized with non-adducted MSA.
Mice immunized with CEP-MSA develop lesions in the outer retina that mimic those present in humans with AMD. The high concentration of DHA in the photoreceptor-RPE complex, coupled with the vulnerability of DHA to oxidative damage in this location results in the slow generation of CEP-adducts that accumulate over time in the outer retina. These CEP-adducts represent new epitopes foreign to the immune system. Mice immunized with CEP-MSA become sensitized to the CEP-adduct and respond to the endogenous source of CEP with an immune attack on the the outer retina and the development of AMD-like changes. This new model for AMD in the mouse is an important new resource for preclinical testing of therapeutics designed to prevent or limit the progression of AMD.
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