IFN Regulatory Factor 5 Is Required for Disease Development in the <i>FcγRIIB−/−Yaa</i> and <i>FcγRIIB−/−</i> Mouse Models of Systemic Lupus Erythematosus

Richez, Christophe; Yasuda, Kei; Bonegio, Ramon; Watkins, Amanda A.; Aprahamian, Tamar; Busto, Patricia; Richards, Rocco J.; Liu, Chih Long; Cheung, Regina; Utz, Paul J.; Marshak‐Rothstein, Ann; Rifkin, Ian R.

doi:10.4049/jimmunol.0901748

Cited by 89 publications

(117 citation statements)

References 88 publications

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“…Indeed, this is supported by the demonstration that autoreactive B cells are distinctly capable of internalizing, via BCR endocytosis, and responding to autoantigens in the absence of prior autoantibody production (42). Consistent with our data, more convincing data are provided by Richez et al, who found that type I IFN receptordeficient mice are not protected from SLE on an autoimmuneprone background (26).…”

Section: Discussionsupporting

confidence: 91%

“…1B). These data demonstrate that IRF5 is required for nephritisrelated IgG deposits in glomeruli induced to develop by pristane treatment and are consistent with those by Richez et al (26).…”

Section: Irf5supporting

confidence: 92%

“…Recently, IRF5 was demonstrated to be required for murine lupus in autoimmune-prone FcγRIIb −/− Yaa mice, although no mechanism was described (26). Whereas type I IFN production induced in murine dendritic cells (DCs) by stimulation with human IC is IRF5-dependent, albeit partially, it is unclear whether this is a mechanism by which IRF5 contributes to SLE disease development (27).…”

mentioning

confidence: 99%

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Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Savitsky

Yanai

Tamura

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Interferon regulatory factor (IRF) 5 is a key transcription factor for the activation of innate immune responses downstream of Tolllike receptor signaling. Based on recent genetic analyses, IRF5 is a focus for its potential involvement in systemic lupus erythematosus (SLE), although how IRF5 contributes to SLE is uncertain. In this study, we demonstrate a requirement for IRF5 in the development of murine SLE via its role in B lymphocytes. We show that antinuclear autoantibodies and Ig glomerular deposits, hallmarks of SLE, are absent in Irf5 −/− mice challenged to develop SLE by pristane injection. In particular, production of autoantibodies of the IgG2a subtype, the most prominent isotype in inducing autoimmunity, requires IRF5. Finally, we provide evidence for the critical role of this transcription factor in the secretion of pathogenic antibodies through its direct control of class switch recombination of the γ2a locus. By demonstrating a B-cell-intrinsic role, this study places IRF5 in a context that may have implications for understanding the pathogenesis of human SLE.autoimmunity | B lymphocytes | TLR signaling

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Section: Discussionsupporting

confidence: 91%

Section: Irf5supporting

confidence: 92%

mentioning

confidence: 99%

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Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Savitsky

Yanai

Tamura

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, treating these mice with interferon accelerates disease in a T-cell like manner (Z. Liu, et al, 2010;Mathian, et al, 2005), while knocking out or inhibiting interferon-related genes slows or eliminates the development of lupus-like symptoms (Jorgensen, et al, 2007;Sharma, et al, 2005). These mice have been used to clarify the interactions between sex hormones and www.intechopen.com interferon in lupus etiology (Bynote, et al, 2008;Panchanathan, et al, 2009;Panchanathan, et al, 2010), and they serve as an excellent all-around model for spontaneous development of lupus.…”

Section: Mouse Models Allow the Study Of Ifn And Apoptosis Pathwaysmentioning

confidence: 99%

“…This gene is an interferon-regulating gene which will be described in section 5.2 below. It was discovered that knockout of IRF5 prevents or inhibits the development of lupus in MRL/lpr mice, Fc -/-Yaa mice, and pristine-injected mice (Richez, et al, 2010;Savitsky, et al, 2010;Tada, et al, 2011). Mouse models for lupus represent a powerful and flexible mechanism for investigating the role of multiple aspects of lupus.…”

Section: Mouse Models Allow the Study Of Ifn And Apoptosis Pathwaysmentioning

confidence: 99%

Interferon and Apoptosis in Systemic Lupus Erythematosus

Clark¹,

Poole²

2012

Systemic Lupus Erythematosus

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Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice

Tada¹,

Kondo²,

Aoki³

et al. 2011

Arthritis & Rheumatism

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Objective. Interferon regulatory factor 5 (IRF-5) is a transcription factor that mediates intracellular signals activated by engagement of Toll-like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus.Methods. We crossed gene-targeted IRF5-deficient (IRF5 ؊/؊ ) mice with MRL/MpJ-lpr/lpr (MRL/ lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function.Results. IRF5 ؊/؊ MRL/lpr mice survived longer than control IRF5 ؉/؉ MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLErelated nuclear antigens were lower in IRF5 ؊/؊ MRL/lpr mouse serum, and numbers of activated CD4؉ T cells were reduced in the spleen. Splenic DCs from IRF5 ؊/؊ MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR-7 or TLR-9 ligands or immune complexes. Interferon-␣ production in response to CpG was also decreased. Conclusion.Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients.

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IFN Regulatory Factor 5 Is Required for Disease Development in the FcγRIIB−/−Yaa and FcγRIIB−/− Mouse Models of Systemic Lupus Erythematosus

Abstract: This information is current as Lupus ErythematosusMouse Models of Systemic − / − RIIB γ Fc and

Cited by 89 publications

References 88 publications

Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus

Interferon and Apoptosis in Systemic Lupus Erythematosus

Interferon regulatory factor 5 is critical for the development of lupus in MRL/lpr mice

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