title: Differential Development of Systemic Lupus Erythematosus in NZM 2328 Mice Deficient in Discrete Pairs of BAFF Receptors.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles.
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles.
authors.forename: Ning
authors.initials: N
authors.lastname: Yu
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Vishal
authors.initials: V
authors.lastname: Sindhava
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cancro
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Rahul D
authors.initials: RD
authors.lastname: Pawar
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
authors.affiliation: University of Southern California Keck School of Medicine, Los Angeles.
authors.forename: William
authors.initials: W
authors.lastname: Stohl
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D053265:B-Cell Activation Factor Receptor / Q000235:genetics*; D053301:B-Cell Maturation Antigen / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; C486361:Tnfrsf13b protein, mouse; C490176:Tnfrsf17 protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein