Enhanced mitochondrial biogenesis in B cells from females is required to drive increased T-bet induction by TLR7 in lupus 2317

Abstract Description The development of T-bet+ B cells, driven by aberrant TLR7 and interferon (IFN) signaling, is a key pathogenic feature of systemic lupus erythematosus (SLE), a disease that predominantly affects women. We analyzed the transcriptomic profiles of naïve B cells (IGHM+IGHD+IGHG-) from 11 female (4 SLE patients and 7 healthy) and 11 male donors. While upregulation of IFN-stimulated genes was specific to SLE patients, a distinctive upregulation of mitochondrial complex genes was observed in naïve B cells from all female donors. In vitro stimulation of B cells from lupus prone BXD2 mice with TLR7 and IFNβ showed comparable early CD69 induction but significantly higher expression of mitochondrial complex I genes (Ndufa1, Ndufb1, and Ndufa3) at 24 hours, along with increased mitochondrial mass at 48 and 72 hours in females compared to males. This was associated with greater T-bet and IRF7 expression in females compared to males at 72 hours. Inhibition of the electron transport chain with IM-156 reduced T-bet and IRF7 induction in both sexes. Interestingly, complex I gene expression was higher in female versus male BXD2-Ifnar1−/− mice following TLR7 and IFNβ stimulation. These results suggest that female-biased mitochondrial biogenesis, albeit independent of IFN responses, supports the energy demands for TLR7 and IFNβ responses to promote T-bet+ B cell development, and potentially contributes to SLE pathogenesis in women. Funding Sources This study was supported by grants from VA Merit Review grant (1I01BX006099 and I01BX004049), NIH R01 AI134023 to J.D.M., and Lupus Research Alliance - Target Identification in Lupus Award to H-C.H. NIH/NIAMS Rheumatology T32 Training for pre-doctoral student (T32AR069516) and Lupus Foundation of America Gina M. Finzi Fellowship Award to K.A.S. Topic Categories Basic Autoimmunity (BA)