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 systemic lupus erythematosus (SLE)-prone B cells. Temporal inhibition of pyrimidine synthesis dampens SLE-prone but not foreign antigen-specific germinal center (GC), plasma cell (PC), and antibody responses. Uridine monophosphate synthase (UMPS) conditional deletion, however, reveals 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 promote pyrimidine synthesis by activating CAD, a rate-limiting enzyme of this pathway.