Publication in detail

Genes and immunity 2012 Apr 26. doi: 10.1038/gene.2012.10. [Epub ahead of print]

Unique contribution of IRF-5-Ikaros axis to the B-cell IgG2a response.

Fang, CM; Roy, S; Nielsen, E; Paul, M; Maul, R; Paun, A; Koentgen, F; Raval, FM; Szomolanyi-Tsuda, E; Pitha, PM

Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.

Abstract:
IRF-5 is a transcription factor activated by toll like receptor (TLR)7 and TLR9 during innate immune responses. IRF-5 activates not only Type I IFN, but also inflammatory cytokines. Most importantly, a genetic variation in the IRF-5 gene shows a strong association with autoimmune diseases such as Lupus. Here, we report that IRF5-deficient mice have attenuated IgG2a/c responses to T-cell-dependent and -independent antigens and to polyoma virus infection. This defect is due to the intrinsic deletion of IRF-5 in B cells, as SCID mice reconstituted with Irf5-/- B cells show a decrease in IgG2a/c expression after viral infection compared with mice that received wild-type B cells. Irf5-/-B cells in vitro have diminished TLR and cytokine-induced class switching to IgG2a/c. Addressing the molecular mechanism, we show that IRF-5 regulates IgG2a/c expression by decreasing Ikaros expression; reconstitution of IRF-5 in Irf5-/- B cells downregulates Ikaros levels and increases switching to IgG2a/c. The IRF site in ikzf1 promoter binds IRF-5, IRF-4 and IRF-8. We show that IRF-8 but not IRF-4 activates the ikzf1 promoter, and IRF-5 inhibits the transcriptional activity of IRF-8. Collectively, these results identify the IRF-5-Ikaros axis as a critical modulator of IgG2a/c class switching.Genes and Immunity advance online publication, 26 April 2012; doi:10.1038/gene.2012.10.

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