@article{10.1172/jci.insight.99274, author = {Marsilio Adriani AND Petra Nytrova AND Cyprien Mbogning AND Signe Hässler AND Karel Medek AND Poul Erik H. Jensen AND Paul Creeke AND Clemens Warnke AND Kathleen Ingenhoven AND Bernhard Hemmer AND Claudia Sievers AND Raija L.P. Lindberg Gasser AND Nicolas Fissolo AND Florian Deisenhammer AND Zsolt Bocskei AND Vincent Mikol AND Anna Fogdell-Hahn AND Eva Kubala Havrdova AND Philippe Broët AND Pierre Dönnes AND Claudia Mauri AND Elizabeth C. Jury AND The ABIRISK Consortium}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Monocyte NOTCH2 expression predicts IFN-β immunogenicity in multiple sclerosis patients}, year = {2018}, month = {6}, volume = {3}, url = {https://insight.jci.org/articles/view/99274}, 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% of IFN-β–treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug 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 proinflammatory 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 2 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 toward a nonclassical phenotype, and increased proinflammatory 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 proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-β administration.}, number = {11}, doi = {10.1172/jci.insight.99274}, url = {https://doi.org/10.1172/jci.insight.99274}, }