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Abstract Number: 1948

A Dual Role for IFN-γ in Development of Peripheral B Cells in Lupus-Prone MRL/Lpr Mice

Takeshi Machida1, Natsumi Sakamoto1, Gary S. Gilkeson2 and Hideharu Sekine1, 1Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan, 2Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: B cells, SLE and animal models

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Session Information

Session Title: B cell Biology and Targets in Autoimmune Disease: Systemic Lupus Erythematosus and Related Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: It had been reported previously that IFN-gamma and IFN-gamma-receptor-1 (IFNGR1) were required for auto-Ab production and development of renal disease in lupus-prone MRL/lpr mice. At ACR 2011, we reported that MRL/lpr mice deficient for the transcription factor IFN regulatory factor-4 (IRF-4), that is required for Th2/Th17 differentiation, developed granulomas in multiple organs with significantly increased numbers of IFN-gamma-producing CD4+ T cells (Th1 cells) and high serum IFN-gamma levels after 12 weeks of age (Fig. 1A). Strikingly, unlike their WT littermates, they also exhibited total loss of splenic CD19+IgM+ B cells by 12 weeks of age. Similar B cell loss was observed in Irf4-/- MRL+/+ mice but not in Irf4-/- C57BL/6 mice, suggesting a role for IFN-gamma in survival of peripheral B cells in mice with an MRL background. This study aimed to further define roles for IFN-gamma in survival of peripheral B cells and in development of autoreactive B cells in MRL/lpr mice.

Methods: Irf4/Ifng or Irf4/Ifngr1 double-gene knockout MRL/lpr mice were generated by backcrossing with C57BL/6 mice lacking corresponding genes for 8 generations. Expression levels of CD19, IgM, CD21, CD23, and IFNGR1 on splenic B cells were analyzed by flow. Splenic follicular (FO)- and marginal zone (MZ)-B cells were isolated by cell sorting and frequency of anti-dsDNA Ab-secreting cells was quantified by ELISPOT assay.

Results: The splenic B cell loss observed in Irf4-/- MRL/lpr mice was restored in Irf4-/-Ifng-/- and Irf4-/-Ifngr1-/- MRL/lpr mice even after 12 weeks of age (Fig. 1B).

�à–¾: Macintosh HD:Users:machidatakeshi:Desktop:Fig1(140624).png
CD21hiCD23lo MZ-B cells of WT MRL/lpr and MRL+/+ mice showed high IFNGR1 expression levels compared to their CD21loCD23hi FO-B cells. In contrast, MZ- and FO-B cells of C57BL/6 mice showed minimal IFNGR1 expression (Fig. 2A). MZ-B cells of MRL/lpr mice showed significantly increased frequency of anti-dsDNA IgM-secreting cells compared to their FO-B cells or MZ/FO-B cells of C57BL/6 mice (Fig. 2B).

�à–¾: Macintosh HD:Users:machidatakeshi:Desktop:Fig2(140624).png
Conclusion: Our results suggest a dual role for IFN-gamma in peripheral B-cell development in murine lupus: expression of IFNGR1 on splenic B cells, especially on MZ-B cells, is required for development of autoreactive B cells whereas high levels of serum IFN-gamma impact on their survival.


Disclosure:

T. Machida,
None;

N. Sakamoto,
None;

G. S. Gilkeson,
None;

H. Sekine,
None.

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