Lupus Model Murino

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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
Christophe Richez, Kei Yasuda, Ramon G. Bonegio, Amanda A. Watkins, Tamar Aprahamian, Patricia Busto, Rocco J. Richards, Chih Long Liu, Regina Cheung, Paul J. Utz, Ann Marshak-Rothstein and Ian R.Rifkin J Immunol 2010; 184:796-806; Prepublished online 9 December 2009; doi: 10.4049/jimmunol.0901748 http://www.jimmunol.org/content/184/2/796
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This article cites 87 articles, 34 of which you can access for free at: http://www.jimmunol.org/content/184/2/796.full#ref-list-1Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscriptions Submit copyright permission requests at: http://www.aai.org/ji/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/cgi/alerts/etoc

The Journal of Immunology is published twice each month by The American Association of Immunologists,Inc., 9650 Rockville Pike, Bethesda, MD 20814-3994. Copyright © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606.

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IFN Regulatory Factor 5 Is Required for Disease Development in the FcgRIIB2/2Yaa and FcgRIIB2/2 Mouse Models of Systemic Lupus Erythematosus
Christophe Richez,*,1,2 Kei Yasuda,*,1Ramon G. Bonegio,* Amanda A. Watkins,* Tamar Aprahamian,* Patricia Busto,† Rocco J. Richards,* Chih Long Liu,‡ Regina Cheung,‡ Paul J. Utz,‡ Ann Marshak-Rothstein,† and Ian R. Rifkin*
Polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are strongly associated in human genetic studies with an increased risk of developing the autoimmune disease systemic lupus erythematosus.However, the biological role of IRF5 in lupus pathogenesis has not previously been tested in an animal model. In this study, we show that IRF5 is absolutely required for disease development in the FcgRIIB2/2Yaa and FcgRIIB2/2 lupus models. In contrast to IRF5-sufficient FcgRIIB2/2Yaa mice, IRF5deficient FcgRIIB2/2Yaa mice do not develop lupus manifestations and have a phenotype comparable to wild-typemice. Strikingly, full expression of IRF5 is required for the development of autoimmunity, as IRF5 heterozygotes had dramatically reduced disease. One effect of IRF5 is to induce the production of the type I IFN, IFN-a, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated FcgRIIB2/2Yaa mice lacking the type I IFN receptor subunit 1. Unlikethe IRF5-deficient and IRF5-heterozygous FcgRIIB2/2Yaa mice, type I IFN receptor subunit 1-deficient FcgRIIB2/2Yaa mice maintained a substantial level of residual disease. Furthermore, in FcgRIIB2/2 mice lacking Yaa, IRF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in FcgRIIB2/2Yaa mice are not due only to inhibition of theenhanced TLR7 signaling associated with the Yaa mutation. Overall, we demonstrate that IRF5 plays an essential role in lupus pathogenesis in murine models and that this is mediated through pathways beyond that of type I IFN production. The Journal of Immunology, 2010, 184: 796–806.

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ystemic lupus erythematosus (SLE) is asystemic inflammatory autoimmune disease characterized by the production of autoantibodies and the involvement of various organ systems resulting in appreciable morbidity and mortality. The etiology of SLE is poorly understood, with disease resulting from a complex interaction between environmental and genetic factors (1–3). A large number of distinct chromosomal loci show

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