Williams, J.A.E.; (2012) An investigation into the role of complement factor H in the retina. Doctoral thesis , UCL (University College London).

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Abstract

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the UK. In 2005, the first publication of a genome-wide associated study identified a single nucleotide polymorphism in complement factor H (CFH) as a genetic risk factor for AMD. CFH is a secreted regulator of the alternative complement pathway and therefore key to controlling the inflammatory response. Prior to 2005, little was known about the role of CFH in the retina. This study addresses this question in order to understand how this protein could contribute towards AMD pathology. Initial experiments confirmed that retinal pigment epithelial (RPE) cells are capable of secreting detectable levels of CFH, and that RPE cells were able to enhance the secretion of CFH in response to inflammatory stimuli. The main focus of this study was to characterise the effect of loss of CFH on young and aged retina in Cfh-/- mice. Immunohistochemical studies revealed that signs of stress and re-distribution of complement proteins appear at one year of age. Genome-wide microarray analysis of the RPE and choroid or neuroretina, showed that loss of CFH has little effect on gene expression in young mice but that the impact of CFH loss increases with age. The largest group of genes to change were involved in antigen presentation and immunity suggesting that CFH has an important role in immune regulation in the eye. Analysis of visual function using electoretinograms revealed that dysfunction seen at two years was not present at one year, indicating that age-related gene expression changes are likely to be involved in the pathogenic process in these mice. This study reveals the importance of CFH in maintaining retinal health and good visual function with age.

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