About our research interests
Our research interests are focused on immune regulation in human disease. In a healthy immune system there is a balance between the pro-inflammatory responses necessary to fight infection and regulatory responses which keep these in check and maintain tolerance. Regulatory T (Treg) cells play a crucial role in maintaining peripheral tolerance, and depletion of these cells in mice results in autoimmunity. In recent years there has been much interest in Th17 cells, which are thought to play an important role in autoimmunity. The regulation of Th17 cells by Treg cells, metabolism and immunomodulatory therapies is a key area of our research interest.
Dysregulation of immune responses in human disease
We are interested in understanding how immune responses are dysregulated in autoimmune diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA) and psoriasis, and also in cancer. We have investigated the regulation of Th17 cells by natural Treg cells in MS, showing that a particular subset of Treg cells expressing the CD39 marker could suppress Th17 cells, while in contrast CD39- Treg cells actually produced IL-17. These findings highlighted an important theme in immunology, namely that considerable plasticity exists within the T helper and Treg CD4 T cell subsets. Th17 cells can convert to Th1/Th17 cells or Th17 cells, and Treg cells can switch to Th17 cells under inflammatory conditions. Furthermore, we showed that both the frequency and function of CD39+ Treg cells was impaired in MS. This research is part of a longstanding collaboration with Prof. Niall Tubridy and his team at SVUH.
Recently metabolism and hypoxia have emerged as key regulators of T cells. We are interested in investigating the role of hypoxia and metabolic pathways in regulating human Th17 cell subsets. We are also investigating the plasticity of Treg and Th17 cells and how this might contribute to autoimmune inflammation in the RA joint. Since the RA joint is hypoxic and is highly glycolytic, we are investigating how these conditions impact on T cell regulation. This research is in collaboration with Dr Ursula Fearon and Prof. Doug Veale at SVUH. The role of CD39+ Treg cells in colorectal cancer is also being investigated in collaboration with Dr Liz Ryan, SVUH. The role of T cell subsets in psoriasis and hidradenitis suppurativa is under investigation in collaboration with Prof. Brian Kirby and Dr Cheryl Sweeney at SVUH.
Immune modulation by therapies
We also have a research interest in investigating the immunomodulatory effects of various therapies for autoimmune disease. The role of endogenous and exogenous IFN-beta in MS is one area of interest. We have previously shown that IFN-beta exerts various immunomodulatory effects on Th17-related cytokines and specifically induced IL-27 which inhibits Th17 cells. Furthermore, the clinical response to IFN-beta treatment correlated with the induction of IL-27 by IFN-beta in vitro.
It is well known that Vitamin D has a number of immunomodulatory effects, and it is used therapeutically to treat psoriasis. Furthermore, low vitamin D levels have been associated with MS and an increased risk of relapse. As part of a clinical trial to assess the effects of vitamin D supplementation in MS, we are analyzing the effects of vitamin D supplementation on both innate and adaptive immunity.
Fumarate is a therapy that has been utilised for a number of years in psoriasis and more recently in webMS; however its mechanism of action is still unclear. We are investigating the mechanism of action of fumarate in both psoriasis and MS.