Local complement activation in aqueous humor in patients with age-related macular degeneration

Abstract

Purpose To investigate complement activation in aqueous humor and in plasma of patients with neovascular age-related macular degeneration (nAMD). Patients and methods Aqueous humor and EDTA-plasma of 31 nAMD patients and 30 age-matched controls was collected. The levels of the complement factor 3 (C3), the regulators factor H (FH), and factor I (FI), and of the complement activation products Ba, C3a, and the terminal complement complex (sC5b-9) were measured. Associations between complement levels and phenotype were determined using Mann-Whitney U-test. Results In plasma, no significant differences were found between the nAMD group and the control group. In aqueous humor, significantly increased levels of Ba (P = 0.002), and C3a (P = 0.002) indicate local complement activation in nAMD patients and a trend for a concomitant upregulation of the complement regulators FH (P = 0.02) and FI (P = 0.04). Conclusions Our findings provide strong evidence for a local complement dysregulation in nAMD patients.

Onset of Retinal Pigment Epithelium Atrophy Subsequent to Anti-VEGF Therapy in Patients with Neovascular Age-Related Macular Degeneration

“…Another factor, which is considered to play a key role in the development and progression of AMD, is a dysregulation of the local and systemic complement system [25, 26]. In this study, no correlation between systemic complement activation and occurrence of RPE atrophy was found.…”

“…In this study, no correlation between systemic complement activation and occurrence of RPE atrophy was found. Nevertheless, measuring complement activation in aqueous humor might be a more sensitive parameter [26]. Thus, the role of local complement activation on atrophy development in nAMD patients remains to be elucidated.…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…Consistently, studies showed that nanomolar concentrations of low molecular weight polySia with average degree of polymerization of 20 (polySia avDP20) significantly reduced proinflammatory gene transcription, abnormal phagocytosis, and oxidative burst in human macrophages challenged with LPS or amyloid-b1-42 (Shahraz et al, 2015). Furthermore, we used humanized transgenic mice expressing human SIGLEC-11, subjected them to laser injury, and treated them with intravitreal injections of polySia avDP20 (Karlstetter et al, 2017). Already low doses of polySia avDP20 significantly reduced microglial activation and vascular leakage by reducing TNF-a and VEGF-A levels as well as superoxide production (Fig 2).…”

“…Recently, we showed that A2AR antagonism also limits complement and inflammasome activation (Madeira et al, 2018). The exposure of human microglia to RPE cell debris induced activation of the complement cascade which is strongly associated with the pathogenesis of AMD (Zipfel & Skerka, 2009;Schick et al, 2017). Inhibition of A2AR prevented this change in microglial complement activation as well as inflammasome activation in (1) The purines ATP and adenosine ligate to their receptors P2X7 and A2AR, respectively, which act through PKA/PKC signaling and thereby activate IKK.…”

Mikroglia und Immuntherapien bei degenerativen Netzhauterkrankungen

“…Eine lokale Fehlregulation der alternativen Komplementfaktorkaskade in der Netzhaut gilt seither als gesicherter pathophysiologisch relevanter Mechanismus [60]. Mikroglia sind die einzigen residenten Zellen der Netzhaut, die den Komplementfaktor 3 Rezeptor exprimieren, und damit eine erhöhte Phagozytose von opsonisierten Partikeln anschalten.…”