An NZM2410-derived lupus susceptibility locus on murine chromosome 4, Sle2 z, has previously been noted to engender generalized B cell hyperactivity. To study how Sle2 z impacts B cell tolerance, two Ig H chain site-directed transgenes, 3H9 and 56R, with specificity for DNA were backcrossed onto the C57BL/6 background with or without Sle2 z. Interestingly, the presence of the NZM2410 “z” allele of Sle2 on the C57BL/6 background profoundly breached B cell tolerance to DNA, apparently by thwarting receptor editing. Whereas mAbs isolated from the spleens of B6. 56R control mice demonstrated significant usage of the endogenous (ie, nontargeted) H chain locus and evidence of vigorous L chain editing; Abs isolated from B6. Sle2 z. 56R spleens were largely composed of the transgenic H chain paired with a spectrum of L chains, predominantly recombined to J k 1 or J k 2. In addition, Sle2 z-bearing B cells adopted divergent phenotypes depending on their Ag specificity. Whereas Sle2 z-bearing anti-DNA transgenic B cells were skewed toward marginal zone B cells and preplasmablasts, B cells from the same mice that did not express the transgene were skewed toward the B1a phenotype. This work illustrates that genetic loci that confer lupus susceptibility may influence B cell differentiation depending on their Ag specificity and potentially contribute to antinuclear autoantibody formation by infringing upon B cell receptor editing. Taken together with a recent report on Sle1 z, these studies suggest that dysregulated receptor-editing of nuclear Ag-reactive B cells may be a major mechanism through which antinuclear Abs arise in lupus.