title: Search for specific biomarkers of IFNβ bioactivity in patients with multiple sclerosis.
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.
authors: Centre d'Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors: Sunny
authors: S
authors: Malhotra
authors: Marta F
authors: MF
authors: Bustamante
authors: Francisco
authors: F
authors: Pérez-Miralles
authors: Jordi
authors: J
authors: Rio
authors: Mari Carmen
authors: MC
authors: Ruiz de Villa
authors: Esteban
authors: E
authors: Vegas
authors: Lara
authors: L
authors: Nonell
authors: Florian
authors: F
authors: Deisenhammer
authors: Nicolás
authors: N
authors: Fissolo
authors: Ramil N
authors: RN
authors: Nurtdinov
authors: Xavier
authors: X
authors: Montalban
authors: Manuel
authors: M
authors: Comabella
mesh_terms: D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D064547:Myxovirus Resistance Proteins; D020411:Oligonucleotide Array Sequence Analysis; D013997:Time Factors; D043222:Ubiquitin Thiolesterase
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D016899:Interferon-beta; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase; D019204:GTP-Binding Proteins