A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis. (July 2019)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Journal of autoimmunity. Volume 101(2019)
• Page Start: 1
• Page End: 16
• Publication Date: 2019-07
• Subjects: Relapsing-remitting multiple sclerosis -- B cell -- Monocyte -- Transcriptome -- Interferome -- Apoptosis -- Antiviral state -- Type I interferon signaling; Ab antibody -- AIM2 absent in melanoma 2 gene -- CNS central nervous system -- EBER-1 Epstein-barr virus-encoded small RNA -- EBV Epstein-barr virus -- FBS fetal bovine serum -- FvDye Fixable viability dye -- GO gene ontology -- HD healthy donor -- IFNAR Interferon-α/β receptor -- IFI Interferon inducible protein -- IFN interferon -- IFNGR Interferon-γ receptor -- IL-16 Interleukin-16 -- IL-1RA interleukin-1 receptor antagonist -- IRAK3 IL-1 receptor-associated kinase 3 -- IRF Interferon regulatory factor -- IRG Interferon-regulated gene -- mAb monoclonal antibody -- MS multiple sclerosis -- Mx1 Mx dynamin-like GTPase 1 -- MyD88 myeloid differentiation primary response gene 88 -- OAS1 2′-5′ oligoadenylate synthetase 1 -- PBMC peripheral blood mononuclear cells -- RRMS relapsing-remitting multiple sclerosis -- SD standard deviation -- SP110 sp110 nuclear body protein gene -- STAT signal transducer and activator of transcription -- TBK1 TANK binding kinase 1 -- TBP TATA-box-binding protein -- TLR Toll-like receptor; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2019.04.006
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: Cell type-specific alteration in endogenous Interferon (IFN) system is characterized in Multiple Sclerosis (MS). Altered IFN-regulated genes and pathways are identified in MS B cells and monocytes by an Interferome -based approach. B cells and monocytes from MS patients display an increased susceptibility to caspase-3 dependent apoptotic cell death. Ongoing caspase-3 activation in MS monocytes drives continuous release of bio-active IL-16 amplifying CD4 + T cell migration. Impaired type I IFN-mediated signaling in MS B cells impacts on induction of anti-viral response and EBV infection control.