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Systemic complement activation in age-related macular degeneration
Hendrik P N Scholl1, Peter Charbel Issa, Maja Walier
1Department of Ophthalmology, University of Bonn, Bonn, Germany.
Insights
Systemic complement activation, particularly of the alternative pathway, is elevated in age-related macular degeneration (AMD) patients. This suggests AMD is a systemic disease linked to genetic factors like CFH.
Area of Science:
- Ophthalmology
- Immunology
- Genetics
Background:
- Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly.
- Dysregulation of the alternative pathway (AP) of the complement cascade is implicated in AMD pathogenesis.
- The hypothesis tested is that defective complement activation control underlies AMD.
Purpose of the Study:
- To determine parameters of complement activation in blood plasma of AMD patients and controls.
- To correlate complement activation markers with disease-associated genetic markers in AMD.
- To investigate the systemic nature of complement activation in AMD.
Main Methods:
- Quantified plasma concentrations of complement activation products (C3d, Ba, C3a, C5a, SC5b-9) and proteins (C3, C4, factor B, factor H, factor D) in 112 AMD patients and 67 controls.
- Analyzed single nucleotide polymorphisms (SNPs) in complement genes: factor H (CFH), factor B-C2 (BF-C2), and complement C3 (C3).
- Used logistic regression to compare the discriminative accuracy of complement activation markers versus genetic markers.
Main Results:
- Significantly elevated levels of all complement activation products, especially Ba and C3d, were observed in AMD patients (p<0.001).
- Factor D levels were also altered in AMD patients, unlike C3, C4, or factor H.
- A model using complement activation markers (Ba, C3d, factor D) showed better discriminative accuracy for AMD than a model based on genetic markers.
Conclusions:
- This study provides the first evidence of systemic complement activation in AMD patients, suggesting AMD is a systemic disease.
- Systemic activation of the alternative complement pathway is associated with genetic variants of CFH previously linked to AMD susceptibility.
- The findings highlight the role of complement dysregulation in AMD pathogenesis and suggest potential therapeutic targets.
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.
