From lupus rare gene variants to pathogenic mechanisms

Drawing from our functional validation of disease-causing gene variants that we have identified after sequencing 200 early-onset SLE patients; the generation of bespoke mouse models of human disease; and novel tools we have generated, we plan to investigate in-depth the mechanisms that lead to disease and the cellular and molecular causes of disease heterogeneity. Our new tools will for the first time enable interrogating the cell of origin of autoantibodies (B-1 vs B-2) across the different disease pathways, as well as the route of differentiation of pathogenic B cells (follicular/germinal centre vs extrafollicular), their longevity and replenishment, and the role of somatic hypermutation in the spontaneous germinal centers seen in SLE. Importantly, we will investigate whether the four major forms of nuclear acid sensing (extracellular/endosomal DNA via TLR9; extracellular/endosomal RNA via TLR7; cytoplasmic DNA via c-Gas/STING; cytoplasmic RNA via MAVS) lead to differences in the type I/II/III IFNs produced and their receptor requirements, involvement of TLR7 signalling, and differences in the nature of self-reactive B cells involved and their responses. The salient findings and mechanisms will be investigated in non-mendelian (adult-onset) lupus that are untreated or in remission, and are expected to guide patient stratification for more effective therapies.