Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor

Arthritis Rheum. 2013 Apr;65(4):1043-54. doi: 10.1002/art.37846.

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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear
  • B-Cell Activating Factor / pharmacology
  • B-Cell Activation Factor Receptor / genetics
  • B-Cell Activation Factor Receptor / metabolism
  • B-Cell Maturation Antigen / genetics
  • B-Cell Maturation Antigen / metabolism*
  • B-Lymphocyte Subsets* / cytology
  • B-Lymphocyte Subsets* / drug effects
  • B-Lymphocyte Subsets* / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Immunoglobulin M / immunology
  • Immunoglobulin M / metabolism
  • Kidney / immunology
  • Kidney / metabolism
  • Kidney / pathology
  • Lupus Erythematosus, Systemic / etiology
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism*
  • Mice
  • Mice, Congenic
  • Transmembrane Activator and CAML Interactor Protein / genetics
  • Transmembrane Activator and CAML Interactor Protein / metabolism*

Substances

  • Antibodies, Antinuclear
  • B-Cell Activating Factor
  • B-Cell Activation Factor Receptor
  • B-Cell Maturation Antigen
  • Immunoglobulin G
  • Immunoglobulin M
  • Tnfrsf13b protein, mouse
  • Tnfrsf13c protein, mouse
  • Tnfrsf17 protein, mouse
  • Tnfsf13b protein, mouse
  • Transmembrane Activator and CAML Interactor Protein