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Publication Detail
Monocyte NOTCH2 expression predicts interferon-beta immunogenicity in multiple sclerosis patients
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Jury EC
  • Publisher:
    American Society for Clinical Investigation
  • Publication date:
    07/06/2018
  • Journal:
    JCI Insight
  • Volume:
    3
  • Issue:
    11
  • Article number:
    e99274.
  • Status:
    Published
  • Print ISSN:
    0021-9738
  • Language:
    english
  • Keywords:
    Multiple Sclerosis, Monocytes, Immunogenicity
Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-β is an established treatment for MS, however, up to 30 percent of IFN-β-treated MS patients develop neutralizing anti-drug antibodies (nADA) leading to reduced drug bioactivity and efficacy. Mechanisms driving anti-drug immunogenicity remain uncertain and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry NOTCH2 expression on CD14+ monocytes and increased frequency of pro-inflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-β. The association of this monocyte profile with nADA development was validated in two independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-β administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes towards a non-classical phenotype and increased pro-inflammatory IL-6 production. NOTCH2 activation was T-cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus nADA development was driven by a pro-inflammatory environment that triggered activation of the NOTCH2-signalling pathway prior to first IFN-β administration
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