Investigating how neutrophil-derived oxidised mitochondrial DNA impairs B-cell differentiation via mitochondrial and lipid metabolism in lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that disproportionately affects young women from minority ethnic groups. 50% of patients develop lupus-nephritis, a severe manifestation that often progresses to kidney failure despite current immunosuppression. The mechanisms underlying treatment resistance remain poorly understood, particularly how innate immune activation reshapes adaptive immunity. My preliminary work shows that neutrophils in lupus-nephritis release oxidised mitochondrial DNA (ox-mtDNA) within extracellular traps that disrupt B-cell metabolism. Exposure to ox-mtDNA impairs B-cell oxidative phosphorylation, blocking differentiation of IL-10–producing regulatory B-cells (Bregs) and instead promoting pro-inflammatory plasma cells that drive tissue damage. Transcriptomic and spatial analyses of kidney biopsies corroborate Breg loss, expansion of pathogenic B-cell subsets, and disruption of redox and lipid metabolic pathways involving NADPH. Building on these findings, I will integrate single-cell profiling of paired neutrophils and B-cells, spatial proteomics of kidney biopsies, and metabolic assays in patient cohorts pre and post-treatment, stratified by clinical response. I aim to: (1) define how neutrophil ox-mtDNA causally reprogrammes B-cell metabolism and differentiation, (2) map neutrophil–B-cell interactions across disease activity and (3) test metabolic interventions that restore regulatory B-cell function. This work will identify new strategies to rebalance immunity and improve outcomes in SLE. lupus-nephritis, B-cells, mitochondrial DNA