IFN-β induces IL-6 production by B cells to promote TH17-mediated neuroinflammation

Abstract Both type I interferon (IFN-I) and T helper 17 (TH17) drive pathology in neuromyelitis optica spectrum disorder (NMOSD) and TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE). This is paradoxical because the prevalent theory is that IFN-I inhibits TH17 function. Here, we identify that IFN-I promotes IL-6 production from B-cells to exacerbate TH17-mediated disease in NMOSD and TH17-EAE. We identified that high levels of IL-17, IFN-I chemokines and IL-6 correlate with severe disability in NMOSD. Furthermore, IL-6 levels were significantly lower in patients treated with anti-CD20 antibody therapy. In mice, IFN-I treatment elevated IL-6 and exacerbated TH17-EAE. Strikingly, therapeutic blockade of IL-6 attenuated disease in IFN-I treated mice. We further demonstrate that IFN-I stimulates B cells to produce IL-6 which in turn drives pathogenic TH17 differentiation. These findings identify potential prognostic biomarkers for NMOSD, define molecular processes behind NMOSD pathogenesis and clarify the paradox surrounding IFN-I and TH17-induced disease.