Abstract
Myxovirus A (MxA), a protein encoded by the MX1 gene with antiviral activity, has proven to be a sensitive measure of IFNβ bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFNβ bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFNβ. Here, we aimed to identify specific biomarkers of IFNβ bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFNβ at 12 and/or 24 months of treatment and patients who remained NAB negative. Nine genes followed patterns in gene expression over time similar to the MX1, which was considered the gold standard gene, and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments in PBMC from healthy controls revealed specific induction of selected biomarkers by IFNβ but not IFNγ, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFNβ concentrations and more selective than the MX1 as biomarkers of IFNβ bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p = 0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFNβ bioactivity, and to further explore their implication in MS pathogenesis.
Highlights
In 1993, IFNb became the first FDA-approved drug for the treatment of relapsing-remitting multiple sclerosis (MS) (RRMS), and since it has widely been used in clinical practice
In order to identify new markers of IFNb bioactivity, we stratified patients based on the presence and absence of neutralizing antibodies (NAB) at 12 and/or 24 months of IFNb treatment
USP18 expression is deficient in MS patients We aimed to evaluate the potential implication of selected biomarkers in MS pathogenesis
Summary
In 1993, IFNb became the first FDA-approved drug for the treatment of relapsing-remitting MS (RRMS), and since it has widely been used in clinical practice. IFNb has demonstrated beneficial effects on decreasing the number of clinical relapses and disease activity measured by magnetic resonance imaging [1,2,3]. IFNb is a type I IFN that binds a heterodimeric cell surface receptor composed of the IFN receptor 1 (IFNAR1) and 2 (IFNAR2) subunits and activates the JAK-STAT signaling pathway. Among the different type I IFN-responsive genes, myxovirus resistance protein A (MxA), a GTPase protein encoded by the MX1 gene with potent antiviral activity [5], has proven to be one of the most sensitive and specific biomarkers of IFNb bioactivity [6,7].
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