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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)DNA antibodies (Abs). To identify 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 autoimmune (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 splenic follicle. In the MRL genetic background, anti-dsDNA B cells are no longer developmentally arrested, suggesting an intrinsic B cell defect conferred by MRL background genes. With intact Fas, they continue to exhibit follicular exclusion; however, in the presence of the lpr/lpr mutation, anti-dsDNA B cells are now present in the follicle. Coincident with the altered localization of anti-dsDNA B cells is a follicular infiltration of CD4 T cells. Together, these data suggest that MRL mice are defective in maintaining the developmental arrest of autoreactive B cells and indicate a role for Fas in restricting entry into the follicle.

Key Words: tolerance • Fas • autoimmunity • antinuclear antibody • splenic architecture

Services provided by The Wistar Institute staff were supported by Core grant CA10815 and by grants from the National Institutes of Health (5R01 AI32137-06), the Arthritis Foundation, and the Pew Charitable Trust to J. Erikson. L. Mandik-Nayak is supported by Wistar Training grant CA-09171. S. Seo is supported by Medical Scientist Training Program grant 5T-32GM-07170.

Abbreviations used: AFC, antibody-forming cell; ANA, antinuclear antibody; AP, alkaline phosphatase; BM, bone marrow; DN, double-negative; ds, double-stranded; ELISpot, enzyme-linked immunospot assay; GC, germinal center; HEL, hen egg lysozyme; HN, homogeneous nuclear; HRP, horseradish peroxidase; HSA, heat-stable antigen; MFI, mean fluorescence intensity; MZ, marginal zone; PALS, periarteriolar lymphoid sheath; ss, single-stranded; SA, streptavidin; Tg, transgene.

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