Systemic Complement Activation in AMD A new study finds that patients with AMD have evidence of systemic activation of the alternative complement pathway (AP).

Two lines of evidence have implicated inflammation in the development of AMD. First, drusen contain large amounts of material associated with inflammation and immune-mediated processes. Second are genetic studies that have found that variants in the complement factor H (CFH) gene are significantly associated with an increased risk for AMD in Caucasian populations.

Genetic studies have recently found that variants in other complement genes, notably those coding for factor B-complement component C2 (BF-C2) and complement C3 (C3), are also associated with AMD. Multiple variants in the CFH and BF genes appear to influence AMD disease risk, and both disease-predisposing and protective gene variants have been identified.

Subtle differences in plasma concentrations or functional activities of complement regulatory proteins (such as factor H and factor B) could have a significant impact on the magnitude of local inflammatory response. Consequently, chronic low-level activation of the AP of complement may lead to tissue damage in the retina which may eventually result in macular degeneration.

Based on the hypothesis that defective regulation of the the alternative pathway of the complement pathway plays a role in the development of AMD, the investigators performed a comprehensive investigation of complement protein plasma concentrations in a cohort of AMD patients and controls. The findings were correlated with genetic profiles.

The researchers measured the plasma concentrations of numerous complement activation markers in 112 patients with AMD and 67 control subjects without AMD. All participants were also analyzed for their factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes, each of which has been associated with AMD.

All complement activation products were significantly elevated in AMD patients compared to controls. Logistic regression analysis revealed that complement activation markers Ba, C3d and factor D most reliably differentiated AMD patients from controls. Within both study groups (AMD and control) those individuals who carry the AMD-associated CFH genes had higher plasma concentrations of complement activation products, and conversely those individuals with protective CFH genes were associated with lower levels of activation products

The authors conclude that AMD indeed is a systemic disease with local disease manifestation in the eye as macular degeneration. This study is the first to show systemic complement activation in AMD patients. The hypothesis of AMD being a systemic disease certainly raises the possibility of manifestations of the disease elsewhere in the body that have yet to be detected.

The discriminatory ability of complement proteins appears superior or at least similar to the discriminatory ability of genetic markers of complement genes for the prediction of AMD. Additional studies will be required to determine whether plasma concentrations of complement proteins could be useful as markers of AMD, either alone or in combination with genetic markers. Recently, genetic testing for the prediction of AMD was found to be 80%, which is similar to what this study found using protein markers of the alternative pathway of complement.

The researchers suggest that AMD patients may benefit from pharmacologic therapy directed at complement control proteins. Complement inhibitors may serve as a future therapeutic option for AMD.

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PLoS ONE 3(7): e2593 (Free full text)