Aged IRF-4-deficient lupus-prone MRL/lpr mice show peripheral B-cell deficiency with elevated serum IFN-γ levels and increased expression of IFN-γ-receptor-1 on B cells
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1
Fukushima Medical University, Department of Immunology, Japan
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2
Graduate School of Biomedical Sciences, Nagasaki University, Department of Molecular Microbiology and Immunology, Japan
The transcription factor Interferon Regulatory Factor-4 (IRF-4) is required for early B-cell development, and is also influential at these later stages of B-cell development and function in antibody somatic hypermutation, class-switch recombination and secretion. IRF-4 is also required for T-cell development in differentiation into Th2/Th9/Th17 cells. At the 14th ICI, we reported that Irf4-/- lupus-prone MRL/lpr mice developed granulomatous lesions in multiple organs with significantly increased numbers of IFN-γ-producing Th1 cells compared to wild-type littermates. In the present study, we further investigated the role of IRF-4 in B-cell development in MRL/lpr mice.
At 6 weeks of age, there was no statistically significant difference of splenic CD19+IgM+ B-cell numbers between Irf4-/- and wild-type C57BL/6 or MRL/lpr mice. Unexpectedly, Irf4-/- MRL/lpr mice showed significant loss of splenic CD19+IgM+ B cells (<1/20 of wild-type littermates) after 12 weeks of age. Similar splenic B-cell loss was observed in age-matched Irf4-/- MRL-Fas+/+ mice but not in Irf4-/- C57BL/6 mice. Multiplex cytokine analysis revealed significant increase in serum IFN-γ levels in Irf4-/- MRL/lpr mice compared to wild-type littermates and Irf4-/- C57BL/6 mice. FACS analysis showed abundant expression of IFN-γ-receptor-1 (IFNgR1) on splenic B cells of MRL/lpr and MRL-Fas+/+ mice, while minimal IFNgR1-expression was observed on those of C57BL/6 mice. Irf4-/- IFNgR1-/- MRL/lpr mice showed full restoration of splenic CD19+IgM+ B cells even after 12 weeks of age.
Our results suggest that lack of IRF-4 has a significant impact on serum IFN-γ levels and peripheral B-cell survival/maintenance likely via IFNgR1 in lupus-prone MRL background.
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific Research (no. 23591442) from the Japan Society for the Promotion of Science.
Keywords:
IRF-4,
peripheral B cell survival,
IFN-γ-receptor-1,
IFN-γ,
MRL/lpr
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Machida
T,
Sakamoto
N,
Honma
K,
Matsuyama
T,
Yui
K and
Sekine
H
(2013). Aged IRF-4-deficient lupus-prone MRL/lpr mice show peripheral B-cell deficiency with elevated serum IFN-γ levels and increased expression of IFN-γ-receptor-1 on B cells.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00861
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Received:
25 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Hideharu Sekine, Fukushima Medical University, Department of Immunology, Fukushima, Japan, sekine@fmu.ac.jp