It is less well appreciated that IFNγ is also increased in some SLE patients ( Csiszár et al., 2000 Harigai et al., 2008 Pollard et al., 2013) and that a distinct IFNγ transcription signature can be detected in PBMCs from a portion of SLE patients ( Chiche et al., 2014 Welcher et al., 2015). SLE patient PBMCs often exhibit a type I interferon (IFN) transcriptional signature and systemic IFNα is elevated in many patients ( Obermoser and Pascual, 2010). Inflammatory cytokines and chemokines also contribute to SLE pathogenesis ( Apostolidis et al., 2011). Consistent with the important role for B cells and ASCs in SLE pathogenesis ( Sanz, 2014), the only new drug approved to treat SLE in decades, Belimumab, targets B cells. SLE autoAbs bound to their autoAgs form immune complexes, which are responsible for many of the clinical manifestations of SLE, particularly those associated with organ damage ( Gatto et al., 2016). The hallmark SLE autoAbs recognize nuclear proteins and nucleic acids ( Gatto et al., 2016), which are also ligands for TLR7 and TLR9 that are expressed by innate immune cells and B cells ( Avalos et al., 2010). Systemic Lupus Erythematosus (SLE) is characterized by progressive dysregulation of the innate and adaptive arms of the immune system, which ultimately leads to loss of immune tolerance in B and T lymphocytes and the production of autoantibodies (Abs) by Ab-secreting B cells (ASCs) ( Tsokos et al., 2016). Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of IL21R and PRDM1 loci. We demonstrate that naïve B cells form T-bet hi pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgD negCD27 negCD11c +CXCR5 neg (DN2) pre-antibody secreting cell (pre-ASC) subset. Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown.
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