Development of Murine Systemic Lupus Erythematosus in the Absence of BAFF

Abstract

Objective To determine whether SLE can develop in the absence of BAFF in a SLE‐prone host. Methods Starting with C57BL/6 mice that express a human Bcl2 transgene (Tg) in their B cells (thereby rendering B cell survival largely independent of BAFF‐triggered signals), we introgressed this Tg into NZM 2328 mice genetically deficient in BAFF (NZM.Baff^‐/‐) to generate NZM.Baff^‐/‐.Bcl2^Tg mice. Expression of human BCL2 and lymphocyte profiles were assessed by FACS; serologic profiles were assessed by ELISA; renal immunopathology was assessed by immunofluorescence and histology; and clinical disease was assessed by development of severe proteinuria and death. Results In comparison to their non‐Tg NZM.Baff^‐/‐ littermates, NZM.Baff^‐/‐.Bcl2^Tg mice over‐expressed BCL2 in their B cells and developed increased percentages and numbers of B cells and plasma cells, increased serum levels of IgG autoantibodies, increased glomerular deposition of IgG and C3, and increased glomerular and tubulointerstitial pathology, culminating in severe proteinuria and death. The time course for development of SLE features in NZM.Baff^‐/‐.Bcl2^Tg mice was more rapid than that previously observed in NZM 2328 wild‐type mice (median mortality 4.5 months vs 7.5 months). NZM.Baff^‐/‐.Bcl2^Tg mice remained responsive to BAFF, since re‐introduction of the Baff gene into these mice further accelerated the course of disease (median mortality 3 months). Conclusions BAFF may be dispensable to development of disease as long as B cell survival is preserved via a BAFF‐independent pathway. This may help explain the limited and variable clinical success with BAFF antagonists in human SLE. In addition, NZM.Baff^‐/‐.Bcl2^Tg mice may serve as a powerful murine model for the study of BAFF‐independent SLE.