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.

A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in multiple sclerosis / Severa, Martina; Rizzo, Fabiana; Srinivasan, Sundararajan; Di Dario, Marco; Giacomini, Elena; Buscarinu, Maria Chiara; Cruciani, Melania; Etna, Marilena P; Sandini, Silvia; Mechelli, Rosella; Farina, Antonella; Trivedi, Pankaj; Hertzog, Paul J; Salvetti, Marco; Farina, Cinthia; Coccia, Eliana M. - In: JOURNAL OF AUTOIMMUNITY. - ISSN 0896-8411. - 101:July(2019), pp. 1-16. [10.1016/j.jaut.2019.04.006]

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

Buscarinu, Maria Chiara;Cruciani, Melania;Mechelli, Rosella;Farina, Antonella;Trivedi, Pankaj;Salvetti, Marco;
2019

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1264347
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