Understanding immune responses in the retina’s support cells and Bruch’s membrane
- Type of funding: Project Grant
- Grant Holder: Dr Simon Clark
- Institute: University of Manchester
- Region: North West
- Start date: September 2016
- End Date: August 2018
- Priority: Causes
- Eye Category: AMD
Most sight loss in age-related macular degeneration (AMD) happens during the late stage of the condition. Late stage AMD is either ‘wet’ or ‘dry’.
In early AMD, changes start to happen in the macula – the central part of the light-sensitive tissue at the back of the eye. Deposits build-up on what’s known as Bruch’s membrane. This membrane supports a blanket of cells called retinal pigment epithelium cells. In turn, these cells support the light-detecting photoreceptor cells.
As the deposits on Bruch’s membrane build-up, they change the way membrane and the cells work together. The cells become sick and die, which then leads to the photoreceptors becoming sick and dying.The research team has recently discovered that a substance that protects Bruch’s membrane from attack by the immune system can also interact with retinal pigment epithelium cells directly. We already knew that genetic faults that increase the risk of getting AMD affect Bruch’s membrane and may increase inflammation. Now it seems as though the changes are more widespread. So in this project the team is aiming to get a better understanding of these interactions. They are looking at how well cells can grow and survive on Bruch’s membrane under various conditions. The knowledge will feed into developing future treatments to stop AMD before sight loss occurs.
Influence of factor H and factor H-like protein 1 on retinal pigment epithelial cell interactions with Bruch’s membraneChanges to the morphology of Bruch’s membrane (BM), such as the formation of basal laminar deposits or large soft drusen, precede the early stages of age-related macular degeneration (AMD). These changes likely alter the interaction of the retinal pigment epithelium (RPE) with this extracellular matrix: an interaction mediated by integrins expressed on the RPE cell surface. The research team recently identified the main regulator of complement activation, part of the innate immune response, protecting BM as factor H-like protein 1 (FHL-1). Indeed, mutations in the CFH gene that are strongly associated with increased risk of AMD, affect the ability of FHL-1 to bind BM. It is believed that the resulting poor regulation of complement turnover leads to a chronic local inflammatory response that contributes to disease pathogenesis.
However, the team has discovered that primary RPE cells from human donor eyes can adhere and spread directly onto the FHL-1 protein. This implies that FHL-1 not only dampens down an immune response, but also contributes directly to the communication between RPE cells and BM. They will test this hypothesis by examining cultured primary RPE cell adhesion and spreading on enriched BM with and without FHL-1 supplementation. Furthermore, they will use a series of integrin-specific blocking antibodies to identify the integrin responsible for this interaction and will perform RNAseq experiments on RPE cells ± FHL-1 binding to see which cellular pathways are altered. Understanding this novel interaction will likely be important for future design of therapeutics and RPE cell transplantation techniques to help treat AMD.