Differential development of systemic lupus erythematosus in NZM 2328 mice deficient in discrete pairs of BAFF receptors

Chaim O. Jacob, Ning Yu, Vishal Sindhava, Michael P. Cancro, Rahul D. Pawar, Chaim Putterman, William Stohl

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2523-2535
Number of pages13
JournalArthritis and Rheumatology
Volume67
Issue number9
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology

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