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Inflammation Gone Wild Can Lead To Macular Degeneration: A Breakthrough by Wilmer Researchers

October 6, 2011

As featured in a release by the American Health Assistance Foundation, clinical investigators from the Wilmer Eye Institute helped lead a research breakthrough in age-related macular degeneration (AMD) - the leading cause of blindness in Western societies. James Handa, M.D. and Hendrik Scholl, M.D., M.A., along with Wilmer researcher Marisol Cano, Ph.D. and a consortium of investigators from other institutions; linked immunological response and the onset of AMD with a single mutation in the complement factor H (CFH) protein- CFH polymorphism H402.

Inflammation in the body is a reaction to protect against oxidative damage brought about by pathogens, chemical exposure, radiation, and other stressors. Normally, CFH regulates this inflammatory response by binding to malondialdehyde (MDA), a lipid peroxidation product. However, a specific mutation inhibits the ability of CFH to behave in this manner, preventing reuptake of MDA, and leading to excessive inflammation and tissue damage. This has been associated with the onset of multiple disease processes, including atherosclerosis in cardiovascular disease and stroke. In the eye, the mutation is linked to retinal drusen deposits and increased risk of AMD.

In lab studies, CFH was identified in normal cells as the protein in plasma that most commonly adhered to MDA. By studying fragments of the protein, researchers discovered that the MDA binding site was located in the same region as the genetic abnormality associated with AMD. In cultured retinal pigment epithelial cells and in macrophages, treatment with both MDA and CFH neutralized the production of inflammatory molecules; whereas treatment with MDA alone elicited a harmful inflammatory response. In human donor eyes with AMD, the CFH protein and MDA were located in the macula in the same area, suggesting that CFH was trying to act protectively against the toxic effects of MDA. In the presence of the genetic abnormality, however, CFH was unable to bind to MDA and remove it; leading to a harmful acumulation of MDA in the macula.

While genetic abnormalities in CFH have been linked with risk of AMD in the past, the mechanism by which these abnormalities caused AMD had previously eluded researchers. These new findings may potentially support breakthroughs in the diagnosis, treatment, and possibly the prevention of age-related macular degeneration. With these results, the researchers hope to test this new function of CFH in an expanded series of experiments using state-of-the-art models of AMD and atherosclerosis. This work will be performed in conjunction with investigators from UC San Diego, the University of Vienna, and Liebnitz Institute, Germany.

Original Publication:

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