A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in multiple sclerosis

Alteration in endogenous Interferon (IFN) system may profoundly impact immune cell function in autoimmunediseases.Here, we provide evidence that dysregulation in IFN-regulated genes and pathways are involved in B cell- andmonocyte-driven pathogenic contribution to Multiple Sclerosis (MS) development and maintenance.In particular, by using an Interferome-based cell type-specific approach, we characterized an increased susceptibility to an IFN-linked caspase-3 dependent apoptotic cell death in both B cells and monocytes of MSpatients that may arise from their chronic activation and persistent stimulation by activated T cells. Ongoingcaspase-3 activation functionally impacts on MS monocyte properties influencing the STAT-3/IL-16 axis, thus,driving increased expression and massive release of the bio-active IL-16 triggering and perpetuating CD4+ T cellmigration.Importantly, our analysis also identified a previously unknown multi-component defect in type I IFN-mediated signaling and response to virus pathways specific of MS B cells, impacting on induction of anti-viral responses and Epstein-barr virus infection control in patients.Taking advantage of cell type-specific transcriptomics and in-depth functional validation, this study revealedpathogenic contribution of endogenous IFN signaling and IFN-regulated cell processes to MS pathogenesis withimplications on fate and functions of B cells and monocytes that may hold therapeutic potential.