Support cells and the immune system in AMD
- Type of funding: PhD Studentship
- Grant Holder: Professor Stephen Moss
- Institute: UCL Institute of Ophthalmology
- Region: London
- Start date: October 2011
- End Date: September 2014
- Eye Category:
Age-related macular degeneration (AMD) is linked to genetic variations that affect how part of the immune system works in at least 1 in 2 people with the condition. Some of the common variations increase risk of getting the condition but others protect against it. So a person’s overall risk of AMD depends on the balance of ‘good’ and ‘bad’ variations, together with other things that affect risk, such as smoking.The aim of this project is to find out how the proteins affected by these genetic variations change the behaviour of cells in the retinal pigment epithelium. This is a layer of cells that provides nutrition and oxygen to the light-sensitive cells in the central part of the retina (the macula). The results will improve our understanding of the links between genes, AMD and the retina.
RPE and the complement system in AMD pathologyAge-related macular degeneration (AMD) is linked, in at least 50% of individuals, to variants in genes encoding proteins of the complement pathway. Thus, complement factor H (CFH), complement factor B (CFB), C2 and C3 all have relatively common single-nucleotide polymorphisms (SNPs) associated with increased risk of AMD. However, there are also protective SNPs in these genes, so the overall disease risk for an individual is determined by the balance of ‘good’ and ‘bad’ SNPs, together with other risk factors such as smoking.
The accumulation of complement proteins in the retinas of AMD patients is a hallmark of the disease, and there is growing evidence that as we age, these proteins alter the properties and functions of the retinal pigment epithelium (RPE). Ultimately RPE cells die or become dysfunctional, leading to death of the associated photoreceptors. There is therefore a need to gain insight into how complement proteins modulate RPE function and phenotype, particularly in the pre-symptomatic years during which RPE cells are chronically exposed to a dysregulated complement system.
In this project the team is using RPE cell lines, together with primary RPE cells from control and complement-null mutant mice, to test the hypothesis that exposure to MAC and complement proteins (normal and harmful variants) alters RPE phenotype and function. Functional readouts will include outer segment phagocytosis, mitochondrial morphogenesis, barrier function and polarisation. The findings will shed new light on the cellular pathogenesis of AMD, and inform the future design of better mouse models for the development of AMD therapeutics.
The team wanted to find out how the retina copes with attack by the immune system, as this is the major cause of sight loss in AMD. The cells that seem to both start the process of degeneration and become its victims are the retinal pigment epithelial cells.The research team showed that when these cells are healthy they deal with attack by the immune system very well, by taking in and breaking down proteins that might otherwise cause damage. They also showed that if this process of taking the proteins in is blocked, then the cells quickly start to show defects similar to those seen in AMD. This suggests that some of the changes that lead to degeneration in AMD happen because the retinal pigment epithelium fails to deal with an attack by the immune system.
- Georgiannakis, A. et al. Retinal Pigment Epithelial Cells Mitigate the Effects of Complement Attack by Endocytosis of C5b-9. J Immunol 195, 3382–3389 (2015).