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Abstract

Rheumatoid arthritis is an auto-immune disease affecting approximately 1 % of the adult population. It presents with stiffness and swelling of the joints, and can culminate into severe deformations if not treated early and adequately. Due to the unknown origin of rheumatoid arthritis, there is presently no cure and therapies are mainly symptomatic. On a molecular level, rheumatoid arthritis is manifested by hyper-inflammation and massive fibroblast activation and immune-cell infiltration. CD8+ T-cells are major drivers of the disease due to their cytotoxic and tissue-destructive capacities. They also make up a large fraction of joint-infiltrating immune cells. Next to their pro-inflammatory phenotype, CD8+ T-cells in rheumatoid arthritis mainly rely on aerobic glycolysis for their energy production to (initiate ? and) sustain their pro-inflammatory immune activity. Cancer cells are known to maintain a similar metabolism by epigenetically up-regulating the gene expression of pro-glycolytic enzymes and down-regulating the gene expression of TCA cycle and oxidative phosphorylation related enzymes. Further, metabolism and epigenetics are closely related as many TCA cycle intermediates are important co-factors or inhibitors of epigenetic writers and erasers. This thesis aimed to detangle the underlying mechanisms of the metabolic switch from oxidative phosphorylation to aerobic glycolysis and to introduce novel approaches to interrupt the inflammatory-glycolytic cycle by ex vivo analyses of CD8+ T-cells from rheumatoid arthritis patients in comparison with cells from healthy donors. Using state-of-the-art -omics methods and multivariate analyses combined with confirmatory in vitro assays examining the cellular metabolism and immune function, I identified an epigenetic-metabolic axis as an important driver of the rheumatoid arthritis CD8+ T-cell phenotype. The results show the accumulation of 2-hydroxyglutarate and a TET (DNA demethylase) and DNMT1 (DNA methyl-transferase) driven increase in DNA-methylation in RA CD8+ T-cells. The approach to rescue this phenotype with the supplementation of the TET co-factor α-ketoglutarate was successful and rendered the cells less inflammatory and reduced their effector functions. Thus, it is plausible that the auto-immune phenotype of CD8+ T-cells in rheumatoid arthritis is based on an altered epigenetic landscape that manifests aerobic glycolysis and the production of regulatory metabolites that stabilise on the one hand, the pro-inflammatory signalling and, on the other hand, the epigenetic remodelling. Further, this thesis introduces α-ketoglutarate as a potent modulator of CD8+ T-cell activity in rheumatoid arthritis. It inaugurates cellular metabolism as a promising therapeutic target in rheumatoid arthritis that not only alleviates the symptoms but harbours the potential to act on the foundation of the disease.