Endogenous dsRNA and dsDNA sensing is increased in transitional B cells in BXD2 autoimmune-prone mice

Abstract

Abstract Enhanced nucleic acid-sensing (NS) pathways has been associated with development of autoimmune disease. Increased type I IFN signaling is identified in lupus prone BXD2 mouse B cells and there is a predominant production of autoantibodies against RNA binding autoantigens in BXD2 mice. Determination of the expression of Usp18 and Oasl2 in early CD93+ transitional B cells (T1 and T2) revealed a surprising finding that early transitional B cell exhibited elevated type I IFN signature gene expression, compared to CD93− mature B cells. Consistent with this, there is also elevated expression of NS pathway genes in early transitional B cells. The most highly expressed were the dsRNA sensing Rig1 and transcription factors Irf3 and Irf7, which were expressed at higher levels compared to pDCs. Interestingly, although Usp18 and Oasl2 levels were undetectable in BXD2-Ifnar−/− transitional B cells, dsRNA sensing gene expression were highly expressed suggesting an IFNAR-independent up-regulation of dsRNA NS pathway in transitional B cells. There was lower expression of Mda5 and Pkr5, and genes involved in DNA sensing including Zbp1 and Irf9. Stimulation of B cells with a RIG1 agonist, poly(I:C)-LMW/LyoVec leads to significantly elevated induction of NS pathway genes in both WT and IFNAR deficient transitional B cells from BXD2 mice. These results suggest that transitional B cells have an intrinsic enhanced nucleic acid-sensing pathway, allowing them to rapidly react to nucleic acid stimulation. Dysregulation of this pathway as a result of apoptotic cell clearance defects can act together with type I IFN stimulation to lead to survival and maturation of B cells that by-pass tolerance checkpoint 2 and produce anti-nucleic acid autoantibodies in lupus.