Bis-retinoid-mediated complement activation on retinal pigment epithelial cells is dependent on complement factor H haplotype [Cell Biology]

February 18th, 2014 by Radu, R. A., Hu, J., Jiang, Z., Bok, D.

Age-related macular degeneration (AMD) is a common central-blinding disease of the elderly. Homozygosity for a sequence variant causing Y402H- and I62V-substitutions in the gene for complement factor H (CFH) is strongly associated with risk of AMD. CFH, secreted by many cell types including those of the retinal pigment epithelium (RPE), is a regulatory protein that inhibits complement activation. Recessive Stargardt maculopathy (STGD1) is another central-blinding disease caused by mutations in the gene for ABCA4, a transporter in photoreceptor outer-segments (OS) that clears retinaldehyde and prevents formation of toxic bis-retinoids. Photoreceptors shed their distal OS daily, which are phagocytosed by the RPE cells. Here, we investigated the relationship between the CFH haplotype of human RPE (hRPE) cells, exposure to OS containing bis-retinoids, and complement activation. We show that hRPE cells of the AMD-predisposing CFH haplotype (HH402/VV62) are attacked by complement following exposure to bis-retinoid-containing Abca4-/- OS. This activation was dependent on factor B, indicating involvement of the alternative pathway. In contrast, hRPE cells of the AMD-protective CFH haplotype (YY402/II62) showed no complement activation following exposure to either Abca4-/- or wild-type OS. The AMD-protective YY402/II62 hRPE cells were more resistant to the membrane attack complex (MAC), while HH402/VV62 hRPE cells showed significant MAC deposition following ingestion of Abca4-/- OS. These results suggest that bis-retinoid accumulation in hRPE cells stimulates activation and dysregulation of complement. Cells with an intact complement negative-regulatory system are protected from complement attack, while cells with reduced CFH synthesis due to the Y402H- and I62V-substitutions are vulnerable to disease.