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Evidence for Activation of Lectin and Classical Pathway Complement Components in Aqueous Humor of Neovascular Age-Related Macular Degeneration

Purpose: The complement system is activated via 3 different pathways; the lectin pathway (LP), classical pathway (CP), and alternative pathway. To investigate the possible roles for the LP or CP in the development of neovascular age-related macular degeneration (nAMD), we compared aqueous humor levels of complement proteins of the LP and CP between eyes with nAMD and those with cataract as controls. Methods: Seventeen eyes from 17 patients with treatment-naïve nAMD and 9 eyes from 9 patients with cataract were studied. Aqueous humor samples were collected before intravitreal aflibercept or ranibizumab injection for the nAMD patients and before cataract surgery for the cataract patients. Aqueous humor levels of complement C4 of the LP and CP, complement C3 of all 3 complement pathways, and mannose-binding lectin-associated serine protease (MASP)-2 of the LP were measured by enzyme-linked immunosorbent assay. Aqueous humor levels of C4a and C3a, the activation products of C4 and C3, respectively, were measured by a bead-based immunoassay. The ratios of C4a to C4 and C3a to C3, representing the degree of C4 and C3 activation, respectively, were calculated in individual patients. Results: The aqueous humor levels of C4, C3, and MASP-2 were significantly lower in the nAMD eyes compared to the controls (p = 0.008, p = 0.011, and p = 0.018, respectively). In contrast, the aqueous humor levels of C4a and C3a, as well as the C4a/C4 and C3a/C3 ratios, were significantly higher in the nAMD eyes compared to the controls (p = 0.039, p = 0.003, p < 0.001, and p < 0.001, respectively). Conclusions: This study provides evidence for significant intraocular activation of either or both of the LP and CP in nAMD eyes that might be involved in the development of nAMD. The significantly lower levels of MASP-2 in the aqueous humor of the nAMD eyes were likely due to MASP-2 consumption by activation of the LP.