Endogenous and Recombinant Type I Interferons and Disease Activity in Multiple Sclerosis

Finn Sellebjerg,Henrik Lund,Dan Hesse,Helle Bach Søndergaard,Martin Krakauer,Annika Langkilde,Signe Limborg,Per Soelberg Sørensen,Celia Oreja-Guevara

doi:10.1371/journal.pone.0035927

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+CD26high T cells (Th1 helper cells), and this effect was associated with less MRI disease activity. IFN-β therapy reduced CD49d expression on CD4+CD26high T cells, and the percentage of CD4+CD26high T cells that were CD49dhigh 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.

Highlights

The type I interferons (IFNs) IFN-a and IFN-b are produced in response to viral infections and induce changes in cellular function by binding to specific receptors on the cell surface, resulting in the induction or repression of numerous genes and a wide range of antiviral and immunological effects [1,2]
There was no difference in the absolute number of circulating leukocytes, lymphocytes, monocytes, dendritic cells, CD3+ T cells or CD4+ T cells in untreated multiple sclerosis (MS) patients and healthy controls, and the expression of all other molecules studied was comparable in untreated MS patients and healthy controls
The major findings in the present study are that: 1) endogenous type I IFN-like activity and treatment with IFN-b are both associated with reduced expression of CD49d on CD26high CD4+ T cells (Th1 helper cells) and this correlates with magnetic resonance imaging (MRI) disease activity in IFN-b-treated MS patients; 2) treatment with IFN-b induces activation of CD4+ T cells, as evidenced by the induction of CD71 and HLA-DR, and this is associated with an increased relapse risk

Summary

Introduction

The type I interferons (IFNs) IFN-a and IFN-b are produced in response to viral infections and induce changes in cellular function by binding to specific receptors on the cell surface, resulting in the induction or repression of numerous genes and a wide range of antiviral and immunological effects [1,2]. Other studies have suggested that the expression of IFN-stimulated genes in untreated MS patients is associated with a diminished capacity to induce IFN-stimulated genes and a higher risk of breakthrough disease upon subsequent treatment with exogenous IFN-b [11]. The reason for these differences, which indicate completely different roles of endogenous and exogenous IFN-b in the pathogenesis of MS, is unknown

Methods

Results

Conclusion