To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE).Methods
Bcma-,Taci-, andBr3-null mutations were introgressed into NZM 2328 mice. NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry; for B cell responsiveness to BAFF by in vitro culture; for serum levels of BAFF and total IgG and IgG anti–double-stranded DNA (anti-dsDNA) by enzyme-linked immunosorbent assay; for renal immunopathology by immunofluorescence and histopathology; and for clinical disease.Results
BCMA, TACI, and B lymphocyte stimulator receptor 3 (BR3) were not surface-expressed in NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice, respectively. Transitional and follicular B cells from NZM.Br3−/− mice were much less responsive to BAFF than were the corresponding cells from wild-type, NZM.Bcma−/−, or NZM.Taci−/− mice. In comparison with wild-type mice, NZM.Bcma−/− and NZM.Taci−/− mice harbored an increased number of spleen B cells, T cells, and plasma cells, whereas serum levels of total IgG and IgG anti-dsDNA were similar to those in wild-type mice. Despite their paucity of B cells, NZM.Br3−/− mice had an increased number of T cells, and the numbers of plasma cells and levels of IgG anti-dsDNA were similar to those in wild-type mice. Serum levels of BAFF were increased in NZM.Taci−/− and NZM.Br3−/− mice but were decreased in NZM.Bcma−/− mice. Despite their phenotypic differences, NZM.Bcma−/−, NZM.Taci−/−, and NZM.Br3−/− mice had renal immunopathology and clinical disease that were at least as severe as that in wild-type mice.Conclusion
Any single BAFF receptor, including BR3, is dispensable for the development of SLE in NZM mice. Development of disease in NZM.Br3−/− mice demonstrates that BAFF–BCMA and/or BAFF–TACI interactions contribute to SLE, and that a profound, life-long reduction in the numbers of B cells does not guarantee protection against SLE.