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.

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.

• Authors: Chaim O Jacob, Ning Yu, Shunhua Guo, Noam Jacob, William J Quinn 3rd, Vishal Sindhava, Michael P Cancro, Beatrice Goilav, Chaim Putterman, Thi-Sau Migone, William Stohl
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 65 Issue 4 Pg. 1043-54 (Apr 2013) ISSN: 1529-0131 [Electronic] United States
• PMID: 23334904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 by the American College of Rheumatology.

Chemical References

• 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

Topics

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