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Philipp Herrmann, Jill Cowing, Ulrich Luhmann, Robin Ali; CD59a deficiency leads to increased age-related subretinal macrophage accumulation and elevated local C3 expression in the RPE/choroid complex of aged mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1377.
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Several polymorphisms in complement genes are associated with an increased risk to develop age-related macular degeneration (AMD), one of the most common causes for blindness in the elderly. This suggests that dysregulation of the complement system may be an important pathogenic mechanism in AMD. To investigate the consequences of altered complement regulation in the RPE/choroid and retina with age, we examined Cd59a complement regulator knockout mice between 4-15 months.
Cd59a-/- mice on a C57BL/6J background and age-matched C57BL/6J wildtype (wt) controls were assessed for increased fundus autofluorescence by in vivo scanning laser ophthalmoscopy. Fundus images were evaluated by two independent, masked graders. H&E stained paraffin sections and immunohistochemistry on RPE/choroidal flat-mounts were compared with expression analyses by quantitative RT-PCR of C3, Properdin, Ccl2 and KC in RPE/choroid and retina at 4 and 9 months (n=6 per group) in order to understand inflammatory processes on the histological, cellular and molecular level.
In vivo imaging and quantification of autofluorescent spots in the fundus of wt and Cd59a-/- mice showed a significant increase of spots from 4 to 15 months in both groups (p<0.0001, two-way ANOVA, Holm-Sidak, n(wt)=47, n(Cd59a-/-)=62). This process was significantly elevated in Cd59a-/- mice (p<0.0001), at 9 and 15 months, despite a grossly normal retinal histology. Immunohistochemistry with anti-CD45 and anti-Iba1 showed corresponding subretinal macrophages as a source of the autofluorescent spots. Relative qRT-PCR for C3 showed a significant increase in the RPE/Choroid of 9 months old Cd59a-/- mice (p=0.042) while levels in retina and 4 month old animals were not significantly altered. qRT-PCR analysis of Properdin, Ccl2 and KC showed no significant changes between the genotypes at 9 months.
This data suggest that the normal age-related accumulation of subretinal macrophages is more pronounced in Cd59a-/- mice. This may reflect a cellular inflammatory response to the local dysregulation of the complement system in the RPE/choroid of Cd59a deficient mice and supports the importance of a well regulated complement system for the maintenance of homeostasis in the ageing eye.
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