MRL-lpr/lpr mice exhibit a defect in maintaining developmental arrest and follicular exclusion of anti-double-stranded DNA B cells

A hallmark of systemic lupus erythematosus and the MRL murine model for lup us is the presence of anti-double-stranded (ds)DNA antibodies (Abs). To ide ntify the steps leading to the production of these Abs in autoimmune mice, we have compared the phenotype and localization of anti-dsDNA B cells in au toimmune (MRL+/+ and lpr/lpr) mice with that in nonautoimmune (BALB/c) mice . Anti-dsDNA B cells are actively regulated in BALB/c mice as indicated by their developmental arrest and accumulation at the T-B interface of the spl enic follicle. In the MRL genetic background, anti-dsDNA B cells are no lon ger developmentally arrested, suggesting an intrinsic B cell defect conferr ed by MRL background genes. With intact Fas, they continue to exhibit folli cular exclusion; however, in the presence of the lpr/lpr mutation, anti-dsD NA B cells are now present in the follicle. Coincident with the altered loc alization of anti-dsDNA B cells is a follicular infiltration of CD4 T cells . Together, these data suggest that MRL mice are defective in maintaining t he developmental arrest of autoreactive B cells and indicate a role for Fas in restricting entry into the follicle.