Lack of IRF-1 accelerates development of tubulointerstitial nephritis and pulmonary granulomas with predominant Th2 polarity in lupus-prone MRL/lpr mice
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1
Fukushima Medical University, Department of Immunology, Japan
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2
Medical University of South Carolina, Department of Medicine, United States
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3
Virginia Polytechnic Institute and State University, Department of Biomedical Sciences and Pathobiology, United States
The transcription factors Interferon Regulatory Factor-4 (IRF-4) and IRF-1 are involved in the differentiation of naïve CD4+ T cells into Th2/Th9/Th17 and Th1 cells, respectively. At the 14th ICI, we reported that Irf4-/- lupus-prone MRL/lpr mice lacked serum autoantibodies and Th17 cells but developed proliferative glomerulonephritis (GN) and granulomas containing Langhans-type multinucleated giant cells (MGCs) in multiple organs with significant increase in serum IFN-γ and IFN-γ-producing CD4+ T cells; suggesting autoreactive Th1 cell-mediated mechanism for their pathogenesis. To further investigate the roles of autoreactive CD4+ T cells in murine lupus, we analyzed disease phenotype of Irf1-/- MRL/lpr mice in the present study. By 18 weeks of age, unlike wild-type MRL/lpr mice, all Irf1-/- MRL/lpr mice showed minimal to no GN but developed severe diffuse tubulointerstitial nephritis characterized by predominant infiltration of CD4+ T cells. They also developed pulmonary granulomas with severe infiltrations of CD68+ macrophages/epithelioid cells and frequent formation of foreign-body-type MGCs. Intracellular cytokine staining showed significantly increased numbers of IL-4-producing CD4+ T cells in the spleens, peritoneal lymph nodes, and kidneys of 18-week-old Irf1-/- MRL/lpr compared to wild-type littermates. Age-matched Irf1-/- C57BL/6 mice also showed significantly increased numbers of IL-4-producing splenic CD4+ T cells; however none of Irf1-/- C57BL/6 mice developed renal or pulmonary disease.
In conclusion, these results indicate that IRF-1 plays a role in the regulation of Th2 polarity in MRL/lpr and C57BL/6 mice. Our results suggest that their pathogenesis, in Irf1-/- MRL/lpr mice, is most likely caused by autoreactive Th2 cell-mediated mechanisms.
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-1,
tubulointerstitial nephritis,
pulmonary granuloma,
autoreactive CD4+ T cells,
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,
Suzuki
E,
Zhang
X,
Reilly
CM,
Gilkeson
GS and
Sekine
H
(2013). Lack of IRF-1 accelerates development of tubulointerstitial nephritis and pulmonary granulomas with predominant Th2 polarity in lupus-prone MRL/lpr mice.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00862
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Received:
21 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Prof. Hideharu Sekine, Fukushima Medical University, Department of Immunology, Fukushima, Japan, sekine@fmu.ac.jp