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Marlene Wang, Qun Zeng, Aliaa Abdelhakim, Jeffrey M Liebmann, Gulgun Tezel, Tongalp H Tezel; ACTIVATION OF COMPLEMENT SYSTEM IN THE TRABECULAR MESHWORK AND SCHLEMM’S CANAL AFTER ANTI-VEGF INJECTIONS. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1229.
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To test the hypothesis whether intraocular pressure increases after repeated injections of anti-VEGF drugs is due to cell death at trabecular meshwork (TM) and Schlemm’s canal (SC) via activation of the complement system.
Surgical trabeculectomy specimens were obtained from 8 patients, 2 of whom had been receiving repeated anti-VEGF (aflibercept and bevacizumab) injections for the treatment of exudative macular degeneration for more than a year. Tissue samples were fixed in 4% paraformaldehyde overnight and processed for immunostaining with complement activation markers (c3b, c4d, c5b-9, C3a). Co-staining with von Willebrand factor and neuron-specific enolase was done to identify the SC endothelia and TM cells targeted by complement activation. Apoptosis was determined using TUNEL staining. Ratio of SC endothelia and TM cells revealing complement activation and apoptotic cell death was estimated by counting a standard field under 400x magnification. Data obtained from patients receiving anti-VEGF drugs and the ones that had never received anti-VEGF injections were compared.
A low-grade complement activation (6.1±2.4%) was detected at the TM of patients with open angle glaucoma undergoing filtering surgery. Complement activation significantly increased (15.7±6.4%, p<0.05) after repeated intravitreal anti-VEGF injections and involve both TM cells and SC endothelium. Comparable low-grade staining of tissue samples for c4d suggest the alternate pathway involvement in complement activation. Anti-VEGF treated eyes also reveal upregulation of C3a receptor (6.3±5.7% vs 3.0±2.7%, p<0.05). No difference was found in TUNEL (+) cells between groups (2.8±1.1% vs 2.2 ±2.1%, p>0.05) suggesting that increase complement activation with anti-VEGF injection is not a part of physiological scavenging task of the complement system.
Patients receiving anti-VEGF injection reveal increased complement activation at the TM and SC. Increased activation of the complement system can directly cause cell death through the formation of membrane attack complex (MAC) and may induce inflammation through C3a receptor upregulation. The most possible cause of complement activation is the formation of immune complexes through the interaction of the anti-VEGF drugs with VEGF in the aqueous and then bind to either Fc or VEGF receptors on the cell membrane.
This is a 2020 ARVO Annual Meeting abstract.
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