Understanding immune metabolism on the single-cell and structural levels in the normal and autoimmune germinal centre reaction (360G-Wellcome-211072_Z_18_Z)

There is a growing understanding that metabolic state can profoundly influence the outcome of the immune response, through mechanisms still under exploration. However, how immune metabolism varies at the single-cell level, in time and space, in vivo, and in disease, is almost unknown. The germinal centre (GC) reaction is tightly spatially organised and, critical for the production of high-affinity antibodies. The GC reaction is dysfunctional in lupus, because self-reactive antibody specificities escape deletion. The metabolic demands on B cells undergoing the GC reaction are expected to be considerable. There is evidence that proteins with links to metabolism have important effects on GC B cells. However, there has been no measurement of the metabolome of the GC. I hypothesise that metabolism is organised in space and time in the GC. To understand metabolism on the structural level, I will use imaging mass spectrometry to study normal and autoimmune GCs from patients. To determine dynamic changes, I will use biosensors to image metabolite levels in vivo. I will genetically disrupt key metabolism pathways in the GC in mice, and I will also examine how the glycogen synthase kinase-3 signalling pathway affects B cell responses, and its potential as a therapeutic target.