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 -