Estimation of Systemic Complement C3 Activity in Age-Related Macular Degeneration

Abstract

Objectives: To determine the role of systemic complement activation in the pathogenesis of age-related macular degeneration and to examine whether serum C3a des Arg reflects systemic complement activation, independent of individual complement component levels.Methods: Plasma complement C3a des Arg levels and a single nucleotide polymorphism at position 402 of the complement factor H gene (CFH) were determined in 3 groups of subjects: 42 subjects with early age-related maculopathy, 42 subjects with neovascular (wet) agerelated macular degeneration, and a control group of 38 subjects with no clinical evidence of age-related changes at the macula. Results:The median (range) of plasma complement C3a des Arg levels in the age-related maculopathy and neovascular age-related macular degeneration groups were 52.6 (2.8-198.1) ng/mL and 60.9 (3.1-173.1) ng/mL, re-spectively. The levels were significantly raised compared with the control group (n=38), which had a median (range) plasma complement C3a des Arg level of 40.3 (6.1-81.7) ng/mL (analysis of variance, P=.02). The concentration of plasma C3a des Arg did not differ significantly between those with different CFH genotypes (P =.07). Conclusion:Systemic activation of the complement system may contribute to the pathogenesis of age-related macular degeneration independent of CFH polymorphism. Clinical Relevance:The results of this study may be relevant to aiming new treatment strategies toward reducing systemic low-grade inflammation.

Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B

“…The reasons for disease specificity are unclear. Several studies have demonstrated elevated plasma levels of complement activation products (including C3a, C3d, Ba, and SC5b-9) in AMD compared with controls, indicating systemic dysregulation of complement, and implying that AMD is a systemic disease with local manifestation in the retina (38,39). This systemic component may amplify the effects of the fB polymorphism, explaining the disease specificity.…”

“…This systemic component may amplify the effects of the fB polymorphism, explaining the disease specificity. Comparative expression levels from the fB alleles in controls and AMD are not yet available; early studies using crossed immunoelectrophoresis and radial immunodiffusion assays demonstrated a trend for higher expression from the fB 32Q allele in normal individuals (38,39) although, as with many complement components, the range around the mean was large. Decreased plasma levels of the fB 32R allele product may indicate decreased expression, or increased catabolism due to AP tickover or chronic inflammatory processes.…”

Complement factor H deficiency in aged mice causes retinal abnormalities and visual dysfunction

“…The authors speculate that the Arg80Gly polymorphism may weaken a potential interaction with CFH that, in turn, would lead to impaired regulation of C3 activation. A role for C3 activation in AMD has also been suggested because increased plasma C3a des Arg levels, a surrogate marker of complement activation, have been reported in AMD patients but without correlation to the at-risk CFH haplotypes (37).…”

The role of complement system in ocular diseases including uveitis and macular degeneration

“…Complement C3adesArg concentration has been found to increase in the plasma of patients with AMD compared to the age-matched controls (Sivaprasad et al, 2007). The presence of C3adesArg is an indicator of complement activation.…”