The tissue specific signature of immune cells in persistent uveitis

Project Background: Why was this research important?

Uveitis is a debilitating condition that frequently leads to severe visual impairment. It is often caused by autoimmune disease, where the immune system attacks healthy tissue and damages it. The cells that co-ordinate this attack are called T cells. Once uveitis has started,

T cells move into tissues of the eye, (from which they are usually excluded), and establish persistent changes, which make recurrence of the disease more likely.

Dr Nicholson’s team suspected that the nature of the eye tissue changes as uveitis progresses, that this process could be divided into phases, and that it might be possible for drugs to be developed that could be tailored to treat patients at different stages of the disease.

The behaviour of the T cells is controlled by many different genes, and Dr Nicholson’s team wanted to explore the theory that some of these genes are only switched on within the eye tissue. The hope was that by understanding more about the nature and function of these genes, researchers should be able to get closer to the goal of restoring the eye to normality, by eliminating infiltrating T cells.

What was the aim of the project?

Using modern gene-sequencing techniques, Dr Nicholson’s team set out to identify every gene that is switched on in cells from the eye (about 23,000), and compare them with genes in normal resting cells to understand how the eye tissue changes the T cells.

Dr Nicholson hoped that once this information had been captured and recorded, it would form the basis of a resource that could be used as a roadmap to understand how the immune cells are altered as uveitis progresses. In order to complete their analysis, his team studied cells from the eyes of mice with persistent uveitis, because it is not safe to take these cells from the eyes of patients with the disease.

What was the outcome?

The project funding allowed the team studied two types of immune cell, called CD4 and CD8, taken at different stages of the disease. This data was used to compare the similarities and differences of the cells that are in the eye in uveitis, with those obtained from other diseases such as inflammation in the skin.

How will this research help to beat sight loss faster?

The funding provided by Sight Research UK has helped to produce a rich research resource that will facilitate studies of uveitis, by the team at Bristol as well as by other groups, for several years to come. In the short-term, Dr Nicholson’s team will reanalyse the data to address further questions, including:

• looking for common patterns of gene signalling that allow immune cells to move into the eye;
• identifying genes that could be manipulated by different drugs;
• in combination with similar data on another different, important cell type, called microglia, investigate how normal mechanisms, that work to limit the damage caused by eye inflammation, could be supported with drug therapies to make them even more effective.