Susceptibility to systemic lupus erythematosus in the NZM2410 murine model maps to Sle1, Sle2, Sle3, and the H2 loci. To unravel how these loci contribute to the pathogenesis of lupus, individual NZM2410-derived genomic intervals bearing these loci have been successfully backcrossed onto the resistant C57BL/6 (B6) background. The focus of this study was to understand how Sle2 on murine chromosome 4 impacts the immune system. Compared with C57BL/6 (B6) mice, B6 mice congenic for Sle2 exhibit a variety of immunophenotypes affecting their B cells. They have an early, but transient, expansion of splenic, CD23(low) B cells. Thereafter, their B cells appear activated by surface phenotype and functional criteria, paralleled by elevated serum levels of polyreactive/polyclonal IgM. Importantly, Sle2 leads to a heightened B cell responsiveness to in vitro stimuli and to in vivo antigenic challenge. Finally, they exhibit increased levels of peritoneal and splenic B1 cells. Thus, Sle2 harbors a gene that leads to B cell hyperactivity and elevated B1 cell formation. However, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis. By reducing the B cell signaling threshold, Sle2 might serve to amplify an ongoing autoimmune response.