Differential Development of Systemic Lupus Erythematosus in NZM 2328 Mice Deficient in Discrete Pairs of BAFF Receptors

OBJECTIVE: To determine the development of systemic lupus erythematosus (SLE) in NZM 2328 (NZM) mice deficient in 2 BAFF receptors. METHODS: NZM.BR-3(-/-) .BCMA(-/-) , NZM.BR-3(-/-) .TACI(-/-) , and NZM.BCMA(-/-) .TACI(-/-) mice were evaluated on the clinical, pathologic, serologic, and cellular levels. BAFF receptor expression and lymphocyte phenotype were assessed by flow cytometry, IgG-secreting cells by enzyme-linked immunospot assay, B cell responsiveness to BAFF and generation of Treg cells by in vitro culture, serum BAFF and total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, renal immunopathology by immunofluorescence and histologic analyses, and clinical disease by assessment of proteinuria and mortality. RESULTS: Renal immunopathology and clinical disease were attenuated in NZM.BR-3(-/-) .BCMA(-/-) and NZM.BR-3(-/-) .TACI(-/-) mice but were accelerated in NZM.BCMA(-/-) .TACI(-/-) mice. Accelerated disease was associated with increases in B cells, IgG-secreting cells, serum autoantibody levels, and T cells (especially CD4+ activated memory cells), whereas attenuated disease was associated with reductions in many of these parameters. Serum BAFF levels were increased in all double-deficient NZM mice. Exogenous BAFF promoted the in vitro survival of B cells from NZM.BCMA(-/-) .TACI(-/-) or NZM wild-type mice but not those from NZM.BR-3(-/-) .BCMA(-/-) or NZM.BR-3(-/-) .TACI(-/-) mice. In vitro generation of Treg cells was reduced in NZM.BCMA(-/-) .TACI(-/-) mice, but not in NZM.BR-3(-/-) .BCMA(-/-) or NZM.BR-3(-/-) .TACI(-/-) mice. CONCLUSION: Elimination of B lymphocyte stimulator receptor 3 (BR-3) and TACI or BR-3 and BCMA inhibits the development of SLE in NZM mice. Selective targeting of BR-3 plus TACI or BR-3 plus BCMA may be an efficacious therapeutic approach in human SLE.