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 journalArticleResearchpeer-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 - 1 Jul 2019

Keywords

  • Antiviral state
  • Apoptosis
  • B cell
  • Interferome
  • Monocyte
  • Relapsing-remitting multiple sclerosis
  • Transcriptome
  • Type I interferon signaling

Cite this

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. / A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis. In: Journal of Autoimmunity. 2019 ; Vol. 101. pp. 1-16.
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title = "A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis",
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.",
keywords = "Antiviral state, Apoptosis, B cell, Interferome, Monocyte, Relapsing-remitting multiple sclerosis, Transcriptome, Type I interferon signaling",
author = "Martina Severa and Fabiana Rizzo and Sundararajan Srinivasan and {Di Dario}, Marco and Elena Giacomini and Buscarinu, {Maria Chiara} and Melania Cruciani and Etna, {Marilena P.} and Silvia Sandini and Rosella Mechelli and Antonella Farina and Pankaj Trivedi and Hertzog, {Paul J.} and Marco Salvetti and Cinthia Farina and Coccia, {Eliana M.}",
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Severa, M, Rizzo, F, Srinivasan, S, Di Dario, M, Giacomini, E, Buscarinu, MC, Cruciani, M, Etna, MP, Sandini, S, Mechelli, R, Farina, A, Trivedi, P, Hertzog, PJ, Salvetti, M, Farina, C & Coccia, EM 2019, 'A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis', Journal of Autoimmunity, vol. 101, pp. 1-16. https://doi.org/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. / 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, Vol. 101, 01.07.2019, p. 1-16.

Research output: Contribution to journalArticleResearchpeer-review

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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.

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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.

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KW - Antiviral state

KW - Apoptosis

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KW - Interferome

KW - Monocyte

KW - Relapsing-remitting multiple sclerosis

KW - Transcriptome

KW - Type I interferon signaling

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