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

Martina Severa, Fabiana Rizzo, Sundararajan Srinivasan, Marco Di Dario, Elena Giacomini, Maria Chiara Buscarinu, Melania Cruciani, Marilena P Etna, Silvia Sandini, Rosella Mechelli, Antonella Farina, Pankaj Trivedi, Paul J Hertzog, Marco Salvetti, Cinthia Farina, Eliana M Coccia

Research output: Contribution to journalArticlepeer-review

Abstract

Alteration in endogenous Interferon (IFN) system may profoundly impact immune cell function in autoimmune diseases. Here, we provide evidence that dysregulation in IFN-regulated genes and pathways are involved in B cell- and monocyte-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 MS patients that may arise from their chronic activation and persistent stimulation by activated T cells. Ongoing caspase-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 cell migration. 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 revealed pathogenic contribution of endogenous IFN signaling and IFN-regulated cell processes to MS pathogenesis with implications on fate and functions of B cells and monocytes that may hold therapeutic potential.

Original languageEnglish
Pages (from-to)1-16
Number of pages16
JournalJournal of Autoimmunity
Volume101
DOIs
Publication statusPublished - Jul 2019

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