Interferon receptor expression in multiple sclerosis patients

https://doi.org/10.1016/j.jneuroim.2006.11.010Get rights and content

Abstract

To determine the gene expression of IFNAR1, IFNAR2 and MxA protein and the association with IFNβ treatment response in MS patients.

MS patients treated with IFNβ had a significant decrease in IFNAR1 and IFNAR2 expression, and a significant increase in MxA compared to non-treated patients and healthy controls. Also, those patients who had a good response to treatment had a significant decrease in IFNAR1 and IFNAR2 expression compared to non-responders, non-treated patients and healthy controls.

IFNβ influences the expression of its receptors, and is greater in patients who respond to IFNβ treatment. This down-regulation could be indicative of the response to IFNβ.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) (Polman and Uitdehaag, 2000). The disease is characterised by different patterns of lesions, involving the myelin sheath or oligodendrocyte destruction, but axonal lesion also occurs from onset, correlating with long-term irreversible disability (Polman and Uitdehaag, 2000, Trapp et al., 1999). Immune factors are involved in the pathogenesis of MS, suggesting that treatment should be directed at re-establishing the immune alterations. Interferon beta (IFNβ) is a cytokine that possesses immunomodulatory activity (Pestka et al., 1987). The biological activity of IFNβ takes place by interaction with high-affinity cell-surface receptors. All type I interferons (alpha, beta and omega) share the same surface receptor, composed of two subunits, IFNAR1 and IFNAR2, each formed by an extracellular transmembrane and intracytoplasmic domains (Oritani et al., 2001). These two subunits are not pre-associated on the cell surface, but interaction with the ligand of one subunit leads to binding of the other, which in turn activates the intracellular signalling cascade (Croze et al., 1996). The different type I interferons have different cellular effects upon interaction with the same receptor, as their binding sites differ (Platanias et al., 1996). All type I IFNs activate receptor-associated tyrosine kinases, Jak1 and Jak2, which in turn activate a series of latent, cytoplasmic transcriptional activator proteins known as Stat (Joe and Lau, 2002). These all result in the induction of several proteins responsible for the biological function of interferons, such as the myxovirus resistance protein A (MxA) (von Wussow et al., 1990).

Two forms of recombinant IFNβ (IFNβ-1a and IFNβ-1b) have been approved for the treatment of relapsing–remitting MS by the FDA. The main difference is that IFNβ-1b is a non-glycosylated recombinant product in which serine is substituted for cysteine at position 17 (Runkel et al., 1998). These differences have repercussions on the immunological response (Fernández et al., 2001), but not on their efficacy in MS patients (The IFN-β Multiple Sclerosis Study Group, 1993, PRIMS, 1998, PRISMS study group, 2001). However, a percentage of MS patients are considered suboptimal or non-responders to this treatment. One of the explanations for this lack of response could be the presence of neutralising antibodies against IFNβ (NABs), (Redlich et al., 1991) the clinical significance of which remains controversial. Some authors found an association between NABs and lack of clinical response (Pachner et al., 2003, Rudick et al., 1998, The IFN-β Multiple Sclerosis Study Group, 1996, Sorensen et al., 2003) after at least 18 months of therapy (Vartanian et al., 2004), whereas others found no definitive association (Fernández et al., 2001, Antonelli et al., 1998, Mayorga et al., 1999), most probably due to low sample sizes. Another reason might be a low IFN receptor expression in patients, which would hinder the biological activity of IFNβ, especially if we consider the low number of IFNAR on the cell surface compared to receptors for other substances (Novick et al., 1994).

The purpose of this study was to determine the relative gene expression of the two subunits of type I IFN receptor as well as the MxA protein in peripheral blood cells from MS patients, with and without IFNβ treatment, using Real Time-PCR, and to analyse the association between these expressions and the response to IFNβ treatment.

Section snippets

Patients

The study included Caucasian MS patients from Carlos Haya Hospital cohort, over a three-year period (2003–2005) treated with IFNβ-1a (Avonex, Biogen, Cambridge, MA and Rebif, Serono SA Laboratorios, Madrid, Spain) or IFNβ-1b (Betaferon, Schering AG, Berlin, Germany) and patients who had not yet started therapy. The clinical data were monitored throughout the treatment, and the annual relapse rate, expressed as the total number of relapses in a year per group with respect to the total number of

Results

The study included 250 MS patients, 84 men (mean age, 41.4 ± 9.14 years), and 166 women (mean age, 39.3 ± 11.2 years). One hundred and eighty-two patients (73.76%) had RRMS and 63 (26.24%) SPMS. The patients were classified into two groups according to treatment: 219 treated with IFNβ and 31 not treated. Significant differences were found in evolution time (P = 0.003) and sex (P = 0.028) comparing treated versus non-treated MS patients by chi-square analysis. Nevertheless, no significant differences in

Discussion

IFNβ treatment has important benefits in MS, decreasing the relapse rate and the lesions measured by MRI, and probably also slowing the accumulation of disability (Polman and Uitdehaag, 2000, Weinshenker et al., 1989). There is, however, a high degree of variability in the response, and about 30% of patients fail to respond, or respond suboptimally to IFNβ therapy. No consensus exists regarding the definition of response to IFNβ treatment and no surrogate clinical marker of response has yet

Acknowledgements

We thank Ian Johnstone for help with the final English language version of this manuscript. This study was partly supported by the Spanish Ministry of Health (FIS PI020698 and PI051878).

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