Background/Purpose:  BAFF is a vital survival and differentiation factor for B cells. In human SLE, clinical efficacy with any of 4 different BAFF antagonists is modest at best. This limited ability of BAFF antagonists to control disease activity in human SLE points to a substantial BAFF-independent component. In stark contrast to this substantial BAFF-independent component to human SLE, disease in currently utilized murine SLE models is highly BAFF-dependent. To investigate the in vivo BAFF-independent component to SLE, we generated a murine model in which SLE clinical disease develops in the absence of BAFF.

Methods:  Starting with C57BL/6 mice that express a human Bcl2 transgene (Tg) in their B cells (thereby permitting B cell survival even in the absence of BAFF), we introgressed this Tg into NZM 2328 (NZM) 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 testing for severe proteinuria and death. To determine whether NZM.Baff^-/-.Bcl2^Tg mice are sensitive to restoration of BAFF, NZM.Baff^-/-.Bcl2^Tg mice were crossed with NZM wild-type (WT) mice to yield BAFF-expressing NZM.Baff^+/-.Bcl2^Tg mice.

Results: Since SLE in NZM WT mice (and in humans) is predominantly a disease of females, only female mice were studied. In comparison to their NZM.Baff^-/- littermates and to age-matched NZM WT mice, NZM.Baff^-/-.Bcl2^Tg mice selectively over-expressed BCL2 in their B cells. Whereas NZM.Baff^-/- mice harbored decreased percentages and numbers of total B cells, follicular B cells, marginal zone (MZ) B cells, and plasma cells in comparison to NZM WT mice, these (other than MZ B cells) were restored in NZM.Baff^-/-.Bcl2^Tg mice to at least WT levels. NZM.Baff^-/-.Bcl2^Tg mice developed increased serum levels of IgG autoantibodies (anti-chromatin and anti-dsDNA), 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 even more rapid than that in NZM WT mice. Whereas NZM WT mice start to develop severe proteinuria at 5-6 months of age, with 50% being affected by 7 months, NZM.Baff^-/-.Bcl2^Tg mice develop severe proteinuria as early as 3 months of age, with 50% of the mice being affected by 4 months. Whereas NZM WT mice begin dying at 6 months of age, with 50% mortality at 7-8 months, NZM.Baff^-/-.Bcl2^Tg mice die as early as 3 months of age, with 50% mortality at 4.5 months. SLE disease in NZM.Baff^+/-.Bcl2^Tg mice is even more severe, with 100% mortality at 5 months, thereby pointing to both BAFF-dependent and BAFF-independent components to disease in NZM.Baff^+/-.Bcl2^Tgmice.

Conclusion: 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 should serve as a powerful murine model for the study of BAFF-independent SLE.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-murine-sle-in-the-absence-of-baff/