@article{10.1172/jci.insight.141395, author = {Alex Pellerin AND Kei Yasuda AND Abraham Cohen-Bucay AND Vanessa Sandra AND Prachi Shukla AND Barry K. Horne Jr AND Kerstin Nündel AND Gregory A. Viglianti AND Yao Xie AND Ulf Klein AND Ying Tan AND Ramon G. Bonegio AND Ian R. Rifkin}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Monoallelic IRF5 deficiency in B cells prevents murine lupus}, year = {2021}, month = {8}, volume = {6}, url = {https://insight.jci.org/articles/view/141395}, abstract = {Gain-of-function polymorphisms in the transcription factor IFN regulatory factor 5 (IRF5) are associated with an increased risk of developing systemic lupus erythematosus. However, the IRF5-expressing cell type(s) responsible for lupus pathogenesis in vivo is not known. We now show that monoallelic IRF5 deficiency in B cells markedly reduced disease in a murine lupus model. In contrast, similar reduction of IRF5 expression in macrophages, monocytes, and neutrophils did not reduce disease severity. B cell receptor and TLR7 signaling synergized to promote IRF5 phosphorylation and increase IRF5 protein expression, with these processes being independently regulated. This synergy increased B cell–intrinsic IL-6 and TNF-α production, both key requirements for germinal center (GC) responses, with IL-6 and TNF-α production in vitro and in vivo being substantially lower with loss of 1 allele of IRF5. Mechanistically, TLR7-dependent IRF5 nuclear translocation was reduced in B cells from IRF5-heterozygous mice. In addition, we show in multiple lupus models that IRF5 expression was dynamically regulated in vivo with increased expression in GC B cells compared with non-GC B cells and with further sequential increases during progression to plasmablasts and long-lived plasma cells. Overall, a critical threshold level of IRF5 in B cells was required to promote disease in murine lupus.}, number = {15}, doi = {10.1172/jci.insight.141395}, url = {https://doi.org/10.1172/jci.insight.141395}, }