TY - JOUR AU - Adriani, Marsilio AU - Nytrova, Petra AU - Mbogning, Cyprien AU - Hässler, Signe AU - Medek, Karel AU - Jensen, Poul Erik H. AU - Creeke, Paul AU - Warnke, Clemens AU - Ingenhoven, Kathleen AU - Hemmer, Bernhard AU - Sievers, Claudia AU - Lindberg Gasser, Raija L.P. AU - Fissolo, Nicolas AU - Deisenhammer, Florian AU - Bocskei, Zsolt AU - Mikol, Vincent AU - Fogdell-Hahn, Anna AU - Kubala Havrdova, Eva AU - Broët, Philippe AU - Dönnes, Pierre AU - Mauri, Claudia AU - Jury, Elizabeth C. AU - , T1 - Monocyte NOTCH2 expression predicts IFN-β immunogenicity in multiple sclerosis patients PY - 2018/06/07/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.99274 VL - 3 IS - 11 UR - https://doi.org/10.1172/jci.insight.99274 PB - The American Society for Clinical Investigation ER -