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David New, TJ Hollingsworth, Francesco Giorgianni, Nataliya Lenchik, Ivan Gerling, Sarka Beranova-Giorgianni, Marko Radic, Alessandro Iannaccone; The Cu/Zn+ superoxide dismutase knockout mouse (Sod1-/-), a model of age-related macular degeneration (AMD), exhibits anti-retinal autoantibodies (AAbs) and marked signs of intraretinal inflammation prior to onset of an AMD-like phenotype. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3986.
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To understand the potential role of anti-retinal AAbs and intraretinal inflammation in the Sod1-/- mouse model of AMD, and to test the hypothesis that anti-retinal AAbs and intraretinal inflammation could develop early in the disease and precede the onset of the overt phenotype exhibited by these mice, typically at or after 12 mo. of age.
We examined differences between 6-9 mo. old Sod1-/- and wild type (WT, C57BL/6J) mice at the serological, molecular, cellular and tissue by several methods: retinal immunohistochemistry (IHC) for markers of inflammation and oxidative stress (carbonylation), Western blots (WB) and IHC for serum AAb binding.
Before the onset of visible retinal disease, Sod1-/- mice show marked upregulation of the glial fibrillary acidic protein (GFAP) and glutamine synthase (GS) Müller cell reactivity (Fig. 1A), increased protein carbonylation (Fig. 1B). and serum AAbs that bind multiple retinal targets (Fig. 2).<br />
Sod1-/- mice exhibit signs of intraretinal inflammation and oxidation and display anti-retinal serum AAbs well in advance of developing a retinal degenerative phenotype. These findings strongly suggest that inflammation and an autoimmune component can play at least a con-causal role in the pathogenesis of the phenotype observed in Sod1-/- mice, feeding forward into the late-onset retinal degeneration of this mouse model of AMD. Since AAbs recognizing macular tissue antigens are found also in patients with early stage AMD, our findings support the notion that similar mechanisms may be at play early on, and thus be a target for intervention, in human disease.
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