Background/Purpose: The transcription factor interferon regulatory factor-4 (IRF-4) and -1 (IRF-1) are members of the IRF family of transcription regulators and involved in the development of Th2/Th17 and Th1 cells, respectively. MRL/lpr mice, a murine model of human SLE, spontaneously develop lupus-like disease. At ACR 2011, we reported that Irf4^-/- MRL/lpr mice, which lacked serum autoantibodies and Th17 cells, developed proliferative glomerulonephritis but minimal to no interstitial nephritis or renal vasculitis. Irf4^-/- MRL/lpr mice also developed granulomas containing Langhans-type multinucleated giant cells (MGCs) in multiple organs with significantly increased numbers of IFN-γ producing CD4⁺ T cells, suggesting autoreactive Th1 cell-mediated mechanisms for their pathogenesis. To further define the role of autoreactive CD4⁺ T cells in murine lupus, we generated Irf1^-/- MRL/lpr mice and assessed their disease.

Methods: Irf1^-/- MRL/lpr mice were generated by backcrossing Irf1–KO C57BL/6 mice onto MRL/lpr background for 7 generations by using speed congenic strategy. Mice were sacrificed at 18 weeks of age and histopathological analysis in multiple organs was performed. Infiltration of CD4⁺ T cells and CD68⁺ macrophages/monocytes in tissues was detected by immunofluorescence or immunohistochemical staining. Splenic immune cell populations were analyzed by flow. To determine Th1/Th2/Th17 cell numbers, splenic CD4⁺T cells were cultured with PMA/ionomycin, and IFN-γ, IL-4 or IL-17 production was detected by intracellular staining and flow analysis.

Results: Unlike WT or Irf4^-/- MRL/lpr mice, Irf1^-/- MRL/lpr mice showed severe inflammation in their renal intersititum and blood vessels characterized by predominant infiltration of CD4⁺ T cells. In contrast, minimal to no inflammation was observed in their glomeruli, suggesting independent mechanisms for development of interstitial nephritis and renal vasculitis. Irf1^-/- MRL/lpr mice also developed pulmonary granulomas characterized by predominant infiltration of CD68⁺ macrophages/epithelioid cells with formation of foreign body-type and Langhans-type MGCs. No granuloma was observed in age-matched WT MRL/lpr or Irf1^-/- C57BL/6 mice. Different appearances of renal disease and granulomas between Irf4^-/- and Irf1^-/- MRL/lpr mice are summarized in the table. Intracellular cytokine analysis showed that there was significantly increased population of IL-4-producing CD4⁺ T cells in the spleens of Irf1^-/- MRL/lpr and C57BL/6 mice than their WT controls.     

Conclusion: Our results indicate that IRF-1 plays an important role in the regulation of Th2 polarity in MRL/lpr and C57BL/6 mice. Development of inflammatory renal disease and pulmonary granulomas not in Irf1^-/- C57BL/6 mice but in lupus-prone Irf1^-/- MRL/lpr mice with significantly increased numbers of IL-4 producing CD4⁺ T cells suggests autoreactive Th2 cell-mediated mechanisms for their pathogenesis.

	CD4+ T cell polarity	Renal disease			Granulomas
Mouse		Glomerular change	Interstitial inflamation	Vasculitis	Lung	Liver	Spleen	Lymph node
Irf4-/- MRL/lpr	Th1	±~++(Proliferative GN)	−~±	None	CD4+ T cell predominant infiltration with formation of Langhans-type MGCs	CD4+ T cell predominant infiltration with formation of Langhans-type MGCs	CD4+ T cell predominant infiltration with formation of few Langhans-type MGCs	CD4+ T cell predominant infiltration with formation of few Langhans-type MGCs
Irf1-/- MRL/lpr	Th2	−~±	+++       CD4+ T cell predominant infiltration	+++       CD4+ T cell predominant infiltration	CD68+ macrophages predominant infiltration with formation of foreign body-type and Langhans-type MGCs	Focal granulomatous lesions with formation of foreign body-type MGCs	No granulomas	No granulomas

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/irf-1-deficient-lupus-prone-mrllpr-mice-show-reduced-glomerulonephritis-but-develop-severe-interstitial-nephritis-renal-vasculitis-and-pulmonary-granulomas-with-propensity-for-th2-polarity/