Search for specific biomarkers of IFNß 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 IFNß bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFNß bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFNß. Here, we aimed to identify specific biomarkers of IFNß 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 IFNß 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 IFNß but not IFNγ, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFNß concentrations and more selective than the MX1 as biomarkers of IFNß 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 IFNß bioactivity, and to further explore their implication in MS pathogenesis.