Development of Systemic Lupus Erythematosus in NZM 2328 Mice in the Absence of any Single BAFF Receptor

Objective To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE). Methods Bcma-, Taci-, and Br3-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 antidouble-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 BAFFBCMA and/or BAFFTACI interactions contribute to SLE, and that a profound, life-long reduction in the numbers of B cells does not guarantee protection against SLE.