Cardinal features of lupus include elevated B cell activation and autoantibody production with a female sex preponderance. We quantified interactions of sex and genetic variation on the development of autoimmune B-cell phenotypes and autoantibodies in the BXD2 murine model of lupus using a cohort of backcrossed progeny (BXD2 x C57BL/6 J) x BXD2. Sex was the key factor leading to increased total IgG, IgG2b, and autoantibodies. The percentage of T-betCD11c IgD activated naive B cells (aNAV) was higher in females and was associated with increased T-betCD11c IgD age-related B cells, FasGL7 germinal center B cells, Cxcr5Icos peripheral T-helper cells, and T-and Cxcr5Icos follicular T-helper cells. IFN-β was elevated in females. Variation in aNAV cells was mapped to Chr 7 in a locus that shows significant interactions between the female sex and heterozygous B/D variant. Our results suggest that activation of naive B cells forms the basis for the female-predominant development of autoantibodies in lupus-susceptible BXD2 mice.Copyright © 2023. Published by Elsevier Inc.