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

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 Fc gamma RIIB(-/-)Yaa and Fc gamma RIIB-/- lupus models. In contrast to IRF5-sufficient Fc gamma RIIB(-/-)Yaa mice, IRF5-deficient Fc gamma RIIB(-/-)Yaa mice do not develop lupus manifestations and have a phenotype comparable to wild-type mice. 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-alpha, a cytokine implicated in lupus pathogenesis. To address the mechanism by which IRF5 promotes disease, we evaluated Fc gamma RIIB(-/-)Yaa mice lacking the type I IFN receptor subunit 1. Unlike the tRF5-deficient and IRF5-heterozygotts Fc gamma RIIB(-/-)Yaa mice, type I IFN receptor subunit 1-deficient Fc gamma RIIB(-/-)Yaa mice maintained a substantial level of residual disease. Furthermore, in Fc gamma RIIB-/- mice lacking Yaa, IPF5-deficiency also markedly reduced disease manifestations, indicating that the beneficial effects of IRF5 deficiency in Fc gamma RIIB(-/-)Yaa mice are not due only to inhibition of the enhanced 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.