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Endogenous and recombinant type I interferons and disease activity in multiple sclerosis.

Sellebjerg F, Krakauer M, Limborg S, Hesse D, Lund H, Langkilde A, Søndergaard HB, Sørensen PS - PLoS ONE (2012)

Bottom Line: Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells), and this effect was associated with less MRI disease activity.In conclusion, the effects of IFN-β treatment and endogenous type I IFN activity on VLA-4 expression are similar and associated with control of disease activity.However, immune-activating effects of treatment with IFN-β may counteract the beneficial effects of treatment and cause an insufficient response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. sellebjerg@dadlnet.dk

ABSTRACT
Although treatment of multiple sclerosis (MS) with the type I interferon (IFN) IFN-β lowers disease activity, the role of endogenous type I IFN in MS remains controversial. We studied CD4+ T cells and CD4+ T cell subsets, monocytes and dendritic cells by flow cytometry and analysed the relationship with endogenous type I IFN-like activity, the effect of IFN-β therapy, and clinical and magnetic resonance imaging (MRI) disease activity in MS patients. Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells), and this effect was associated with less MRI disease activity. IFN-β therapy reduced CD49d expression on CD4+CD26(high) T cells, and the percentage of CD4+CD26(high) T cells that were CD49d(high) correlated with clinical and MRI disease activity in patients treated with IFN-β. Treatment with IFN-β also increased the percentage of CD4+ T cells expressing CD71 and HLA-DR (activated T cells), and this was associated with an increased risk of clinical disease activity. In contrast, induction of CD71 and HLA-DR was not observed in untreated MS patients with evidence of endogenous type IFN I activity. In conclusion, the effects of IFN-β treatment and endogenous type I IFN activity on VLA-4 expression are similar and associated with control of disease activity. However, immune-activating effects of treatment with IFN-β may counteract the beneficial effects of treatment and cause an insufficient response to therapy.

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T cell activation, CXCL10 and MX1 expression.The relationship between the percentage of CD4+CD26high T cells expressing CD49d or CXCR3 and the expression of MX1 and CXCL10 mRNA in blood mononuclear cells from untreated patients with relapsing-remitting multiple sclerosis was analysed by Spearman rank correlation coefficients (SRCC).
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pone-0035927-g001: T cell activation, CXCL10 and MX1 expression.The relationship between the percentage of CD4+CD26high T cells expressing CD49d or CXCR3 and the expression of MX1 and CXCL10 mRNA in blood mononuclear cells from untreated patients with relapsing-remitting multiple sclerosis was analysed by Spearman rank correlation coefficients (SRCC).

Mentions: The expression of MX1 mRNA was associated with a type I IFN-induced gene expression signature in 36 of the untreated MS patients included in the present study [9]. The percentage of CD4+CD26high T cells that were CD49dhigh correlated negatively with expression of MX1 mRNA in blood cells (Figure 1). Expression of FOXP3 in blood cells also correlated negatively with the percentage of CD49dhigh CD4+ T cells (SRCC = −0.50, p = 0.002), whereas there was no correlation with IL10 expression (data not shown). There were no other significant relationships between MX1 gene expression and CD4+ T cell or APC activation, but the expression of MX1 correlated with expression of the chemokine CXCL10 (Figure 1) which, in turn, correlated negatively with the percentage of CD4+CD26high T cells that expressed the CXCL10 receptor CXCR3 (Figure 1).


Endogenous and recombinant type I interferons and disease activity in multiple sclerosis.

Sellebjerg F, Krakauer M, Limborg S, Hesse D, Lund H, Langkilde A, Søndergaard HB, Sørensen PS - PLoS ONE (2012)

T cell activation, CXCL10 and MX1 expression.The relationship between the percentage of CD4+CD26high T cells expressing CD49d or CXCR3 and the expression of MX1 and CXCL10 mRNA in blood mononuclear cells from untreated patients with relapsing-remitting multiple sclerosis was analysed by Spearman rank correlation coefficients (SRCC).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368920&req=5

pone-0035927-g001: T cell activation, CXCL10 and MX1 expression.The relationship between the percentage of CD4+CD26high T cells expressing CD49d or CXCR3 and the expression of MX1 and CXCL10 mRNA in blood mononuclear cells from untreated patients with relapsing-remitting multiple sclerosis was analysed by Spearman rank correlation coefficients (SRCC).
Mentions: The expression of MX1 mRNA was associated with a type I IFN-induced gene expression signature in 36 of the untreated MS patients included in the present study [9]. The percentage of CD4+CD26high T cells that were CD49dhigh correlated negatively with expression of MX1 mRNA in blood cells (Figure 1). Expression of FOXP3 in blood cells also correlated negatively with the percentage of CD49dhigh CD4+ T cells (SRCC = −0.50, p = 0.002), whereas there was no correlation with IL10 expression (data not shown). There were no other significant relationships between MX1 gene expression and CD4+ T cell or APC activation, but the expression of MX1 correlated with expression of the chemokine CXCL10 (Figure 1) which, in turn, correlated negatively with the percentage of CD4+CD26high T cells that expressed the CXCL10 receptor CXCR3 (Figure 1).

Bottom Line: Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells), and this effect was associated with less MRI disease activity.In conclusion, the effects of IFN-β treatment and endogenous type I IFN activity on VLA-4 expression are similar and associated with control of disease activity.However, immune-activating effects of treatment with IFN-β may counteract the beneficial effects of treatment and cause an insufficient response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. sellebjerg@dadlnet.dk

ABSTRACT
Although treatment of multiple sclerosis (MS) with the type I interferon (IFN) IFN-β lowers disease activity, the role of endogenous type I IFN in MS remains controversial. We studied CD4+ T cells and CD4+ T cell subsets, monocytes and dendritic cells by flow cytometry and analysed the relationship with endogenous type I IFN-like activity, the effect of IFN-β therapy, and clinical and magnetic resonance imaging (MRI) disease activity in MS patients. Endogenous type I IFN activity was associated with decreased expression of the integrin subunit CD49d (VLA-4) on CD4+CD26(high) T cells (Th1 helper cells), and this effect was associated with less MRI disease activity. IFN-β therapy reduced CD49d expression on CD4+CD26(high) T cells, and the percentage of CD4+CD26(high) T cells that were CD49d(high) correlated with clinical and MRI disease activity in patients treated with IFN-β. Treatment with IFN-β also increased the percentage of CD4+ T cells expressing CD71 and HLA-DR (activated T cells), and this was associated with an increased risk of clinical disease activity. In contrast, induction of CD71 and HLA-DR was not observed in untreated MS patients with evidence of endogenous type IFN I activity. In conclusion, the effects of IFN-β treatment and endogenous type I IFN activity on VLA-4 expression are similar and associated with control of disease activity. However, immune-activating effects of treatment with IFN-β may counteract the beneficial effects of treatment and cause an insufficient response to therapy.

Show MeSH
Related in: MedlinePlus