The influence of mitochondrial lymphocyte metabolism on the onset of RA

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Mechanisms driving the progression of rheumatoid arthritis (RA) from early pre-symptomatic autoimmune stages to full-blown inflammatory disease remain enigmatic. During the previous funding period, we have shown that small endogenous metabolites such as acetate as well as energetic reprogramming of cells critically affect the action of T cells and the development of RA. Although energetic reprogramming and metabolic dysfunction of T cells and B cells likely impact both on the break of tolerance and the onset of inflammation, underlying mechanisms are incompletely defined, especially due to the absence of appropriate technologies. In the proposed project, we therefore aim to dissect the checkpoints controlling metabolic reprogramming of T- and B cells in the pre-clinical phase of RA using new methods allowing to study their specific contribution to the onset of RA. We will therefore use three novel technologies based on flow cytometry methods (SCENITH, Met-Flow) or microscopy (NADH-FLIM) that allow high throughput assessment of metabolism in single cells. A particular focus will be on the changes in the metabolism of B cells and T cells in the earliest stages of murine experimental arthritis and human rheumatoid arthritis. In this setting, metabolic analyses will not be confined to T- and B cell subsets only but will also specifically address the metabolism of activated autoreactive T- and B cells in experimental arthritis and human RA. Following up on these experiments, we will determine whether and how mitochondrial dysfunction controls metabolic T- and B-cell function during the transition from the pre-symptomatic to the inflammatory phase of arthritis. To achieve this aim, we will establish a surrogate premature lymphocyte aging phenotype by specific induction of mitochondrial dysfunction in T- and B cells through expression of a dominant negative mutant of the mitochondrial helicase TWINKLE. In summary, this project will provide a translational approach that defines the nature of early changes of the metabolism of activated adaptive immune cells in arthritis, in search for new possibilities for early preventive interference for disease progression.