Robinson, George Anthony; (2018) The role of lipid metabolism in the immunopathogenesis of juvenile-onset systemic lupus erythematosus. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Juvenile-onset systemic lupus erythematosus (JSLE) is a complex autoimmune disorder characterised by chronic inflammation, multiple organ damage and increased risk of cardiovascular disease (CVD). Disease onset in JSLE is more common during puberty and the female to male ratio is 4.5:1, suggesting a hormonal importance in disease pathogenesis. Work by the Jury lab in adult-onset SLE links immune cell dysregulation with defects in plasma membrane lipids rafts; signalling platforms that facilitate immune cell activation and effector function. 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 available to the adults are relevant for this younger group of patients. My hypothesis is that altered lipid metabolism leads to changes in immune cell function; differences in lipid metabolism exist between males and females and defects in these pathways contribute to JSLE pathogenesis. My aims were to 1) investigate sex differences in immune and metabolic phenotype in healthy individuals and JSLE patients, 2) assess the relationship between immune cells and serum lipids and 3) identify predictive biomarkers for CVD risk in JSLE. Using in depth immunophenotyping by flow cytometry and metabolomic analysis, this study has identified fundamental differences between healthy adolescent males and females. Males had increased regulatory T-cell (Treg) frequencies, altered lipid raft profiles and functional differences including an increased IL-4 production and suppressive capacity compared to females. These Treg phenotypic differences were associated with the very low density lipoprotein (VLDL) signature connected with males. In a chronic inflammatory setting (JSLE), these differences were lost between males and females. I also found that JSLE patients could be stratified according to their serum lipoprotein profile allowing potential identification of patients with increased CVD risk. This work provides evidence that a combination of pubertal development, immune cell defects and dyslipidemia may contribute to JSLE pathogenesis. Patient stratification has identified a unique group of patients that could benefit from lipid modification therapy, reducing both CVD risk and immune cell activity.

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