Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis

Lars Börnsen; Jeppe Romme Christensen; Rikke Ratzer; Chris Juul Hedegaard; Helle B Søndergaard; Martin Krakauer; Dan Hesse; Claus H Nielsen; Per S Sorensen; Finn Sellebjerg

doi:10.1371/journal.pone.0118830

Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis

Lars Börnsen, Jeppe Romme Christensen, Rikke Ratzer, Chris Juul Hedegaard, Helle B Søndergaard, Martin Krakauer, Dan Hesse, Claus H Nielsen, Per S Sorensen, Finn Sellebjerg

15 Citationer (Scopus)

Abstract

Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-β-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-β. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-β-inducible genes in peripheral blood mononuclear cells and interferon-β-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-β-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-β-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-β are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.

Originalsprog	Engelsk
Artikelnummer	e0118830
Tidsskrift	P L o S One
Vol/bind	10
Udgave nummer	3
Sider (fra-til)	1-20
Antal sider	20
ISSN	1932-6203
DOI	https://doi.org/10.1371/journal.pone.0118830
Status	Udgivet - 4 mar. 2015

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10.1371/journal.pone.0118830Licens: CC BY

Citationsformater

Börnsen, L., Christensen, J. R., Ratzer, R., Hedegaard, C. J., Søndergaard, H. B., Krakauer, M., Hesse, D., Nielsen, C. H., Sorensen, P. S., & Sellebjerg, F. (2015). Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis. P L o S One, 10(3), 1-20. [e0118830]. https://doi.org/10.1371/journal.pone.0118830

Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis. / Börnsen, Lars; Christensen, Jeppe Romme; Ratzer, Rikke et al.

I: P L o S One, Bind 10, Nr. 3, e0118830, 04.03.2015, s. 1-20.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Börnsen, L, Christensen, JR, Ratzer, R, Hedegaard, CJ, Søndergaard, HB, Krakauer, M, Hesse, D, Nielsen, CH, Sorensen, PS & Sellebjerg, F 2015, 'Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis', P L o S One, bind 10, nr. 3, e0118830, s. 1-20. https://doi.org/10.1371/journal.pone.0118830

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abstract = "Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-β-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-β. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-β-inducible genes in peripheral blood mononuclear cells and interferon-β-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-β-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-β-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-β are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.",

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AU - Börnsen, Lars

AU - Christensen, Jeppe Romme

AU - Ratzer, Rikke

AU - Hedegaard, Chris Juul

AU - Søndergaard, Helle B

AU - Krakauer, Martin

AU - Hesse, Dan

AU - Nielsen, Claus H

AU - Sorensen, Per S

AU - Sellebjerg, Finn

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AB - Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-β-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-β. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-β-inducible genes in peripheral blood mononuclear cells and interferon-β-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-β-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-β-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-β are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.

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KW - Gene Expression Regulation

KW - Humans

KW - Interferon Type I

KW - Interferon-beta

KW - Interleukin-10

KW - Intracellular Space

KW - Male

KW - Monocytes

KW - Multiple Sclerosis

KW - Myelin Basic Protein

KW - T-Lymphocyte Subsets

U2 - 10.1371/journal.pone.0118830

DO - 10.1371/journal.pone.0118830

M3 - Journal article

C2 - 25738751

SN - 1932-6203

VL - 10

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JF - PLoS Computational Biology

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ER -

Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis

Abstract

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