Development of Murine Systemic Lupus Erythematosus in the Absence of BAFF

William Stohl, Ning Yu, Samantha Chalmers, Chaim Putterman, Chaim O. Jacob

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Abstract

Objective: To determine whether systemic lupus erythematosus (SLE) can develop in the absence of BAFF in an 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−/−.Bcl2Tg mice. Expression of human Bcl-2 and lymphocyte profiles were assessed by fluorescence-activated cell sorting, and serologic profiles were determined by enzyme-linked immunosorbent assay. Immunofluorescence and histologic analyses were performed to assess renal immunopathologic features in the mice, and clinical disease was assessed according to the outcomes of severe proteinuria and death. Results: In comparison to their non-Tg NZM.Baff−/− littermates (n ≥ 7), NZM.Baff−/−.Bcl2Tg mice (n ≥ 8) overexpressed Bcl-2 in their B cells and developed significantly increased percentages and numbers of B cells and plasma cells, serum levels of IgG autoantibodies, glomerular deposition of IgG and C3, and severity of glomerular and tubulointerstitial inflammation, culminating in severe proteinuria and death (all P < 0.05 versus NZM.Baff−/− littermates). The time course for development of SLE-like features in NZM.Baff−/−.Bcl2Tg mice was more rapid than has been previously observed in NZM 2328 wild-type mice (median age at death 4.5 months versus 7.5 months). NZM.Baff−/−.Bcl2Tg mice remained responsive to BAFF, since reintroduction of the Baff gene into these mice further accelerated the course of disease (median age at death 3 months). Conclusion: The role of BAFF in the development of SLE-like disease may be dispensable 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. Thus, NZM.Baff−/−.Bcl2Tg mice may serve as a powerful murine model for the study of BAFF-independent SLE.

Original languageEnglish (US)
Pages (from-to)292-302
Number of pages11
JournalArthritis and Rheumatology
Volume72
Issue number2
DOIs
StatePublished - Feb 1 2020

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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