title: Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor.
abstract: OBJECTIVE
  To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE).
  
  
  METHODS
  Bcma-, Taci-, and Br3-null mutations were introgressed into NZM 2328 mice. NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice were evaluated for lymphocyte phenotype and BAFF receptor expression by flow cytometry; for B cell responsiveness to BAFF by in vitro culture; for serum levels of BAFF and total IgG and IgG anti-double-stranded DNA (anti-dsDNA) by enzyme-linked immunosorbent assay; for renal immunopathology by immunofluorescence and histopathology; and for clinical disease.
  
  
  RESULTS
  BCMA, TACI, and B lymphocyte stimulator receptor 3 (BR3) were not surface-expressed in NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice, respectively. Transitional and follicular B cells from NZM.Br3-/- mice were much less responsive to BAFF than were the corresponding cells from wild-type, NZM.Bcma-/-, or NZM.Taci-/- mice. In comparison with wild-type mice, NZM.Bcma-/- and NZM.Taci-/- mice harbored an increased number of spleen B cells, T cells, and plasma cells, whereas serum levels of total IgG and IgG anti-dsDNA were similar to those in wild-type mice. Despite their paucity of B cells, NZM.Br3-/- mice had an increased number of T cells, and the numbers of plasma cells and levels of IgG anti-dsDNA were similar to those in wild-type mice. Serum levels of BAFF were increased in NZM.Taci-/- and NZM.Br3-/- mice but were decreased in NZM.Bcma-/- mice. Despite their phenotypic differences, NZM.Bcma-/-, NZM.Taci-/-, and NZM.Br3-/- mice had renal immunopathology and clinical disease that were at least as severe as that in wild-type mice.
  
  
  CONCLUSIONS
  Any single BAFF receptor, including BR3, is dispensable for the development of SLE in NZM mice. Development of disease in NZM.Br3-/- mice demonstrates that BAFF-BCMA and/or BAFF-TACI interactions contribute to SLE, and that a profound, life-long reduction in the numbers of B cells does not guarantee protection against SLE.
authors: University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. jacob@usc.edu
authors: Chaim O
authors: CO
authors: Jacob
authors: Ning
authors: N
authors: Yu
authors: Shunhua
authors: S
authors: Guo
authors: Noam
authors: N
authors: Jacob
authors: William J
authors: WJ
authors: Quinn
authors: Vishal
authors: V
authors: Sindhava
authors: Michael P
authors: MP
authors: Cancro
authors: Beatrice
authors: B
authors: Goilav
authors: Chaim
authors: C
authors: Putterman
authors: Thi-Sau
authors: TS
authors: Migone
authors: William
authors: W
authors: Stohl
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear; D053264:B-Cell Activating Factor / Q000494:pharmacology; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000378:metabolism; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000378:metabolism*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007075:Immunoglobulin M / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D020297:Mice, Congenic; D053303:Transmembrane Activator and CAML Interactor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000974:Antibodies, Antinuclear; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C486361:Tnfrsf13b protein, mouse; C486662:Tnfrsf13c protein, mouse; C490176:Tnfrsf17 protein, mouse; C505720:Tnfsf13b protein, mouse; D053303:Transmembrane Activator and CAML Interactor Protein