Host tissue recognition by complement factor H in the human eye: mapping changes with age and in AMD

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Over half of blindness in the UK is caused by age-related macular degeneration (AMD), with about 50 million people affected worldwide. AMD is a disease that damages the central part of the retina (called the macula) and leads to central vision loss. There is mounting evidence that the risk of developing this disease is strongly influenced by our genes. Recent studies revealed that a common variant in one particular gene (known as Complement Factor H or CFH for short) strongly increases the risk of developing AMD. This variant (called the Y402H polymorphism) is present in about 35% of people of European decent and it results in a small, but significant, change in the CFH protein that alters its functional properties. We have recently made an important discovery that the ?Y? and ?H? forms of CFH (normal and disease-causing, respectively) have different abilities to recognise carbohydrate molecules in the eye. This may influence the localisation of the CFH protein, which is likely to be important to the cause and development of AMD since CFH is part of our immune system that distinguishes healthy from diseased tissues. If the CFH protein is not present in the correct location then a disruption to the function of the immune system would lead to tissue damage. We have proposed that AMD may result from age-related changes in the carbohydrate molecules within the eye, which we believe would influence CFH location and function. One aim of this research project is to test this idea by analysing eye tissues from donors of different ages (supplied by the Manchester Eye Bank) in a wide range of experiments. In addition to normal eye tissues we will also examine AMD-affected eyes. These studies are possible due to the molecular tools we have developed that allow us to look (using microscopy) at CFH-binding sites in human tissues. Our own expertise in Manchester (for example in AMD, the CFH protein and carbohydrate chemistry) will be complemented by a network of scientific collaborators (in the UK and USA) providing access to specialised biochemicals and cutting-edge technologies.Overall these studies are likely to lead to a greater understanding of the causes of AMD and may allow the development of new therapeutic strategies for treating this disease.