Type IIFN is essential for viral clearance but also contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), via aberrant nucleic acid-sensing pathways, leading to autoantibody production. Type III IFN (IFN-X) is now appreciated to have a nonredundant role in viral infection, but few studies have addressed the effects of IFN-X on immune cells given the more restricted expression of its receptor primarily to the epithelium. In this study, we demonstrate that B cells display a prominent IFN gene expression profile in patients with lupus. Serum levels of IFN-X are elevated in SLE and positively correlate with B cell subsets associated with autoimmune plasma cell development, including CDllc+T-bet+CD21“ B cells. Although B cell subsets express all IFN receptors, IFNLR1 strongly correlates with the CDllc+CD21- B cell expansion, suggesting that IFN-X may be an unappreciated driver of the SLE IFN signature and B cell abnormalities. We show that IFN-X potentiates gene transcription in human B cells typically attributed to type I IFN as well as expansion of T-bet-expressing B cells after BCR and TLR7/8 stimulation. Further, IFN-X promotes TLR7/8-mediated plasmablast differentiation and increased IgM production. CDllc+ B cells demonstrate IFN-X hyp er responsive signaling compared with other B cell subsets, suggesting that IFN-X accelerates plasma cell differentiation through this putative extrafollicular pathway. In summary, our data support type III IFN-X as a cytokine promoting the Ab-secreting cell pool in human viral and autoimmune disease.
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