Search for Specific Biomarkers of IFNβ Bioactivity in Patients with Multiple Sclerosis

Myxovirus A (MxA), a protein encoded by the MX1 gene with antiviral activity, has proven to be a sensitive measure of IFN beta bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFN beta bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFN beta. Here, we aimed to identify specific biomarkers of IFN beta 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 IFN beta 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 IFN beta but not IFN gamma, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFN beta concentrations and more selective than the MX1 as biomarkers of IFN beta 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 IFN beta bioactivity, and to further explore their implication in MS pathogenesis.