Metabolomics of inflammation; immune cell signalling dysregulation in chronic disease.
Stephen’s research centres on the complex processes that give rise to chronic inflammatory diseases in humans. In particular, he takes a molecular and cellular approach to understanding the factors which give rise to aberrations in signalling pathways that underlie the immune pathology associated with diseases such as rheumatoid arthritis, vasculitis and uveitis. He has been innovative in implementing and developing a number of novel technologies. These include analysis of signalling pathways at the level of the single cell, molecular interaction analysis using surface plasmon resonance and metabolite profiling using NMR-based metabolomics.
Signalling aberrations in inflammatory disease
Abnormal function of peripheral blood T lymphocytes is characteristic of rheumatoid arthritis (RA); diminished proliferation and secretion of cytokines following in vitro mitogen stimulation are observed. Stephen was the first to demonstrate that a TCR-linked signalling abnormality underlies this and since then he has further characterised these pathways and shown that extrinsic factors can lead to signalling dysregulation. In particular TNF, acting through acid sphingomyelinase, suppresses plasma membrane calcium signals and oxidation leads to inactivation of protein tyrosine phosphatases (PTP). He has also found that this occurs in the healthy elderly, partially explaining the depressed signalling and function of lymphocytes in ageing. This has led to investigations of the interactions between a variant PTP N22 gene known to associated with arrange of autoimmune disease and the extrinsic factors such as hypoxia, inflammatory mediators and cigarette smoking, as an exemplar for environmental/genetic interactions in driving autoimmune arthritis. We have also shown that neutrophils expressing the variant of the PTPN22 gene are hyperactive which may explain their important role in rheumatoid arthritis.
He has extended this work to studies on endothelial cells in an attempt to explain the increase in cardiovascular disease associated with rheumatoid arthritis. He has shown that the earliest stages of the atherosclerotic process, the induction of endothelial cell dysfunction, can be mediated by TNF-induced sphingomyelinase, which in turn can be regulated by oxidative stress.
This dysfunction in lymphocyte and endothelial function may result from a complex interaction between factors including genes, lifestyle, nutrition and infection. Metabolomics is a powerful new approach to the analysis of the overall metabolic activity of an organism, which may allow generation of a composite picture resulting from these many factors. Stephen has established NMR-based Metabolomics to study human inflammatory disease and this has proven to be a powerful tool for stratifying patients with complex diseases such as Uveitis and Rheumatoid Arthritis, and neurological diseases. He is applying these methods to analysis of rheumatoid arthritis, Lupus and Behcet’s Disease in close collaboration with the RA-MAP, RACE, ARUK Microbiome and MASTERPLANS consortia.
Click on the link below to listen to a Rheumatology Podcast where Stephen Young discusses with Prof Rob Moots, Editor of Rheumatology, a paper on antibodies formed in patients against an import therapeutic drug infliximab.