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

TY - JOUR

T1 - A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis

AU - Severa, Martina

AU - Rizzo, Fabiana

AU - Srinivasan, Sundararajan

AU - Di Dario, Marco

AU - Giacomini, Elena

AU - Buscarinu, Maria Chiara

AU - Cruciani, Melania

AU - Etna, Marilena P

AU - Sandini, Silvia

AU - Mechelli, Rosella

AU - Farina, Antonella

AU - Trivedi, Pankaj

AU - Hertzog, Paul J

AU - Salvetti, Marco

AU - Farina, Cinthia

AU - Coccia, Eliana M

N1 - This work was supported by Fondazione Italiana Sclerosi Multipla (FISM grant 2013/R/9 to EMC and CF) and in part also by grant GR-2016-02363749 from Italian Ministry of Health (to MS). Copyright © 2019 Elsevier Ltd. All rights reserved.

PY - 2019/7

Y1 - 2019/7

N2 - 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.

AB - 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.

KW - Adult

KW - Apoptosis

KW - B-Lymphocytes/immunology

KW - Biomarkers

KW - Case-Control Studies

KW - Disease Susceptibility

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Immunophenotyping

KW - Interferon Type I/genetics

KW - Interleukin-16/genetics

KW - Male

KW - Middle Aged

KW - Monocytes/immunology

KW - Multiple Sclerosis/etiology

KW - Organ Specificity/genetics

KW - Promoter Regions, Genetic

KW - Signal Transduction

KW - Transcriptome

UR - https://www.scopus.com/pages/publications/85066978627

U2 - 10.1016/j.jaut.2019.04.006

DO - 10.1016/j.jaut.2019.04.006

M3 - Article

C2 - 31047767

AN - SCOPUS:85066978627

SN - 0896-8411

VL - 101

SP - 1

EP - 16

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

ER -