MRL-lpr/lpr Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti-double-stranded DNA B Cells

doi:10.1084/jem.189.11.1799

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J. Exp. Med., Volume 189, Number 11, June 7, 1999 1799-1814

MRL-lpr/lpr Mice Exhibit a Defect in Maintaining Developmental Arrest and Follicular Exclusion of Anti-double-stranded DNA B Cells

By Laura Mandik-Nayak, Su-jean Seo, Caroline Sokol, Kathryn M. Potts, Anh Bui, and Jan Erikson

From The Wistar Institute, Philadelphia, Pennsylvania 19104

A hallmark of systemic lupus erythematosus and the MRL murine model for lupus is the presence of anti-double-stranded (ds)DNAantibodies (Abs). To identify the steps leading to the productionof these Abs in autoimmune mice, we have compared the phenotypeand localization of anti-dsDNA B cells in autoimmune (MRL+/+ andlpr/lpr) mice with that in nonautoimmune (BALB/c) mice. Anti-dsDNAB cells are actively regulated in BALB/c mice as indicated bytheir developmental arrest and accumulation at the T-B interfaceof the splenic follicle. In the MRL genetic background, anti-dsDNAB cells are no longer developmentally arrested, suggesting anintrinsic B cell defect conferred by MRL background genes. Withintact Fas, they continue to exhibit follicular exclusion; however,in the presence of the lpr/lpr mutation, anti-dsDNA B cells arenow present in the follicle. Coincident with the altered localizationof anti-dsDNA B cells is a follicular infiltration of CD4 T cells.Together, these data suggest that MRL mice are defective in maintainingthe developmental arrest of autoreactive B cells and indicatea role for Fas in restricting entry into thefollicle.

Key words: tolerance; Fas; autoimmunity; antinuclear antibody; splenic architecture

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