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The role of complement activation in age-related macular degeneration Cao, Sijia


Purpose: Age-related macular degeneration (AMD) is a multifactorial degenerative disease that occurs in the central part of the retina − macula. The disease affects approximately one million Canadians and constitutes the number one cause of vision loss after cataract in the elderly. The Y402H polymorphism in the complement factor H (CFH) gene and drusen load are two salient risk factors for AMD. Little is known of the detailed cellular pathway(s) shared by these two factors. Here we investigate their interactions in in vitro models of AMD and in AMD samples. Methods: The biological samples came from 44 dry AMD patients, 23 postmortem eyes and retinal pigment epithelial (RPE) cell models. Drusen load and choroidal thickness in patients were measured using spectral-domain optical coherence tomography. We used analytical techniques including genotyping, Bio-Plex suspension assays, immunohistochemistry, immunofluorescence, reverse transcription PCR, Western blot, flow cytometry and lactate dehydrogenase assay Results: In dry AMD patients, higher systemic levels of interleukin (IL)-6, IL-18, and tumor necrosis factor (TNF)-α were associated with the at-risk CC variant of CFH Y402H polymorphism. IL-1β while not significant, demonstrated a similar trend. Drusen load was inversely correlated with choroidal thickness and visual acuity. Postmortem eyes genotyped with the Y402H risk variant showed significantly increased levels of GM-CSF in vitreous and immunoreactivity for CD68, C5a, IL-18 and TNF-α in Bruch’s membrane and/or choroid. Exposure to complement activation product C5a in RPE cells promoted NF-κB activation and upregulated inflammatory cytokines and growth factors. The drusen component, Aβ, induced complement activation and downregulated the membrane bound complement inhibitor, CD55, leading to sublytic MAC formation in RPE cells, which was inhibited by aurin tricarboxylic acid complex. Conclusion: Two important risk factors for AMD, CFH Y402H polymorphism and drusen load, both promote complement activation. Complement activation can mediate downstream events associated with sublytic changes in RPE, such as proinflammatory cytokine release. These results suggest that complement activation might be the central response to multiple risk factors and the complement activation products may further inflict injury on RPE cells. Complement activation products could be potential therapeutic targets to stop chronic inflammation in AMD.

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