SLMS Academic Careers Office

Grand Challenges

31. Understanding the immunopathogenesis of juvenile-onset SLE: could targeting lipid biosynthesis control disease progression and reduce cardiovascular risk?

Supervisor Pair: Dr Liz Jury and Dr Despina Eleftheriou Potential Student’s Home Department: Medicine

Accelerated atherosclerosis is a serious complication of autoimmunity including patients with both adult and juvenile-onset (J) SLE. This suggests that defects in lipid homeostasis could contribute to disease pathogenesis. T-cells are implicated in the aetiology of both atherosclerosis and SLE and our previous work describes multiple defects in plasma membrane lipid rafts contributing to T-cell abnormalities in adult SLE patients. However, in patients with JSLE, the immune system is still developing and very little is known about disease pathogenesis, whether it is the same as adult disease and whether the same treatments are relevant for this group of patients. Furthermore, mechanisms controlling lipid raft homeostasis and how they affect T-cell function remain largely un-investigated in the maturing immune systems of young people.

We propose to define the phenotypic characteristics of T-cells from JSLE patients compared to age and sex-matched healthy donors, relate these results to their serum and cellular lipid profile and to the clinical features of disease in patients. We will use metabolomic and lipidomic analysis to investigate whether serum lipid levels are impaired and trigger defects in T-cell lipid metabolism and function. Finally we will explore how these abnormal interactions can be modified, potentially by clinically approved therapies. In summary, this study will provide important information about T-cell defects in JSLE patients, identify whether abnormalities in lipid biosynthesis drive some of these defects and, by relating these results to the clinical features of patients, could identify biomarkers to help to stratify JSLE patients with the greatest cardiovascular risk and pinpoint those patients that would benefit from lipid-modifying therapies.

Project supervision will be a partnership between Dr Jury, a basic scientist, and Dr Eleftheriou, a clinician scientist, within the newly established Centre for Adolescent Rheumatology. Dr Jury has well established expertise investigating the pathogenesis of patients with adult-onset SLE and has extended knowledge regarding lymphocyte function in lupus disease. In particular she has an internationally recognised track record in research aimed at understanding how changes in the lipid environment may contribute to disease pathogenesis in SLE. Dr Eleftheriou’s research interests are focused on patients with adolescent rheumatic disease including JSLE. Her primary interests are investigating endothelial injury, cardiovascular risk and the biology of the developing immune system. The newly established Centre for Adolescent Rheumatology is the only unit in the country to focus on research into young people with chronic inflammatory disease with the aim to understand the pathogenesis underlying disease progression and to improve treatment for patients. Thus this research could identify important information and have a direct impact on the treatment of patients with JSLE as well as contributing to the limited knowledge about the function of T-cells in a developing immune system in young people with and without autoimmunity.