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B. Rohrer, Z. Ablonczy, S. Tomlinson, G. Gilkeson; Light-Damage as a Model to Study Complement-Mediated Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2497.
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Age-related macular degeneration (AMD) is the leading cause of blindness for elderly persons of the Western World. It is accepted that wet AMD arises from the dry form, in part based on the discovery of common genetic risk factors, such as the variations in complement factor H (CFH) and B (CFB). CFH is an inhibitor; CFB and factor D (CFD) are activators of the alternative complement pathway. It has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis. Here we tested the involvement of the complement system in two experimental models, the light-damage mouse model, and an RPE cell-line.
Changes in gene-expression was assessed in Balb/c mouse retinas in response to constant light exposure (CLE; 115-175 ft-c for 10 days) using microarrays and real-time PCR. Susceptibility to CLE was tested in albino CFD-/- mice. Eyes were analyzed using electrophysiological (ERG), histological and immunohistochemical techniques and ELISA. Effects of complement exposure on RPE monolayers with stable barrier properties were determined by transepithelial electrical resistance (TER) measurements.
(1) Genes encoding for proteins involved in complement activation and innate immunity were significantly upregulated after CLE. The altered genes are similar to the proteins accumulated in drusen; and to those identified in both retina and RPE/choroid of AMD patients. (2) Cyclic light reared CFD-/- and CFD+/+ mice had indistinguishable rod function and number; but after light-challenge, the CFD-/- mice were found to be significantly less affected. (3) CLE increased levels of C3 in RPE. (4) ARPE-19 cells grown as a monolayer are sensitive to oxidative stress induced by H2O2, resulting in loss of TER. TER deteriorated significantly faster in the presence of source of complement, which could be inhibited by an alternative pathway-specific inhibitor.
These results suggest that rod degeneration in the light-damaged retina involves the activity of the alternative complement system, and that eliminating the amplification loop is neuroprotective. Although these results have not yet localized the site of action of the complement system, the TER results suggest that a misregulated complement system might amplify oxidative stress-induced disruption of the RPE cell barrier integrity, indirectly leading to photoreceptor cell death. Finally, the light-damage albino mouse model may be a good model to study complement-mediated photoreceptor degeneration.
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