De novo pyrimidine synthesis controls germinal center B cell and plasma cell fates and systemic autoimmunity

Whether and how pyrimidine metabolites promote systemic autoimmunity is unknown. Here, metabolomics and 15N-amide glutamine tracing show enhanced flux through de novo pyrimidine synthesis in SLE-prone B cells. Temporal inhibition of pyrimidine synthesis dampened SLE-prone but not foreign antigen-specific germinal center (GC), plasma cell (PC) and antibody responses. UMPS conditional deletion, however, revealed a B cell-intrinsic requirement of de novo pyrimidine synthesis in foreign antigen-driven and SLE-prone GC, PC and antibody responses, and kidney immune complex deposition. Metabolomics, mitochondrial stress-test, metabolic flow cytometry, glycolytic rate assay, and RNA sequencing highlight the importance of pyrimidine synthesis in promoting aerobic glycolysis and oxidative phosphorylation in SLE-prone B cells. De novo pyrimidine synthesis helps SLE-prone B cells maintain heightened metabolic state and expression of metabolic regulator, cMYC. Mechanistically, mTORC1 and S6K1 downstream of TLR7 and CD40 signaling in B cells promotes pyrimidine synthesis by activating CAD, a rate-limiting enzyme of this pathway.