Systemic complement activation in age-related macular degeneration

Abstract

Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.

Figure 1. The Alternative Pathway of Complement: Polymorphic Variants and Complement Proteins under Study.

Complement gene SNPs (boxed with dotted lines) and protein plasma concentrations (boxed with solid lines) were determined in all AMD patients and controls. C3, C4 and factor B are substrates (open rectangles), factor H and factor D are regulators (open ellipses), Ba, C3d and SC5b-9 are markers of chronic activation (filled rectangles), and C3a and C5a are markers of acute activation (filled ellipses) of the alternative complement pathway.

Figure 2. Receiver Operating Characteristic (ROC) Curves for the Discriminative Capability of Genetic and Protein markers of the Complement System.

Receiver operating characteristic curves for genetic markers (dotted line; A473A of CFH, IVS 10 of BF-C2 and R102G of C3) and complement protein markers (solid line; Ba, C3d, and factor D) are shown. AUC = Area under ROC curve.