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J.Z. Baffi, M. Nozaki, B.J. Raisler, E. Sakurai, K. Zhang, J.D. Lambris, J.V. Sarma, A. Humbles, B.K. Ambati, J. Ambati; Activated Complement Components of Drusen Promote Choroidal Neovascularization . Invest. Ophthalmol. Vis. Sci. 2006;47(13):860.
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Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV) it is not known whether drusen contribute to the development of CNV in age–related macular degeneration (AMD). Both in human AMD and in a recently described mouse model of AMD, early sub–RPE deposition of complement components C3 and C5 has been demonstrated, suggesting a pathogenetic role for these inflammatory proteins. We examined the hypothesis that bioactive complement fragments C3a and C5a are present in human drusen and that they can promote CNV.
AMD and control human eyes were interrogated for the presence of C3a and C5a by immunostaining using antibodies specific for the neoepitopes generated upon complement activation. The effect of C3a and C5a on production of vascular endothelial growth factor (VEGF) was assessed in vivo by intravitreous injection in wild–type mice. The development of CNV (quantified by confocal imaging of Isolectin B4 stained choroidal flat mounts), leukocyte recruitment (quantified by flow cytometry), and VEGF expression and complement generation (quantified by ELISA) in RPE/choroid following laser injury was assessed in wild–type and in C3aR–/– and C5aR–/– mice. The effect of neutralizing antibodies against C3a or C5a and small molecule receptor antagonists on laser–induced CNV was studied.
C3a and C5a were identified in drusen of patients with AMD but not in control eyes. C3a and C5a were generated early in the course of experimental CNV and induced VEGF expression in vivo in RPE/choroid. Genetic ablation of receptors for C3a or C5a reduced VEGF expression (60%), leukocyte recruitment (40–50%), and CNV formation (40%). Pharmacological blockade of C3a or C5a or their receptors also reduced CNV size (50–80%) (all P’s < 0.05).
Collectively these findings, which are the first to demonstrate the presence of diffusible complement anaphylatoxins in human AMD, establish a mechanistic basis for the clinical observation that drusen predispose to CNV, both revealing a novel role for immunological phenomena in angiogenesis and providing new therapeutic targets for AMD.
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