Helios-dependent chromatin remodeling drives IFN-α–responsive plasmablast differentiation in NMOSD naïve B cells

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system driven by pathogenic antibodies against aquaporin-4. Aberrant differentiation of B cells into plasmablasts drives autoantibody production, yet the molecular and epigenetic mechanisms behind this aberrant differentiation remain unclear. We focused on a CD25 hi naïve B (NB) cell subset with a high differentiation potential that is expanded in NMOSD. Transcriptomic analysis showed that CD25 hi NB cells from NMOSD patients exhibited increased expression of interferon (IFN)-stimulated genes and PRDM1 , a master regulator of plasmablast differentiation. These cells had reduced expression of IKZF2 (Helios), a transcription factor that normally restrains gene activation. Experimental reduction of IKZF2 (Helios) expression enhanced IFN-α–dependent PRDM1 expression and plasmablast differentiation. Chromatin accessibility analysis revealed increased accessibility at regulatory regions of interferon-responsive genes and the PRDM1 locus following Helios reduction. CUT&RUN analysis identified Helios binding at the PRDM1 enhancer. Reduced Helios expression is associated with increased chromatin accessibility at the PRDM1 locus and enhanced type I interferon responsiveness, thereby contributing to dysregulated B-cell differentiation in NMOSD. These findings provide new insights into the molecular mechanisms underlying dysregulated B-cell differentiation in NMOSD and suggest type I interferon signaling as a potential therapeutic target.