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Monocyte NOTCH2 expression predicts IFN-β immunogenicity in multiple sclerosis patients

M. Adriani, P. Nytrova, C. Mbogning, S. Hässler, K. Medek, PEH. Jensen, P. Creeke, C. Warnke, K. Ingenhoven, B. Hemmer, C. Sievers, RL. Lindberg Gasser, N. Fissolo, F. Deisenhammer, Z. Bocskei, V. Mikol, A. Fogdell-Hahn, E. Kubala Havrdova, P....

. 2018 ; 3 (11) : . [pub] 20180607

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc19045423

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.

Centre d'Esclerosi Múltiple de Catalunya Hospital Universitari Vall d'Hebron Barcelona Spain

CESP Fac De Médecine Univ Paris Sud Fac De Médecine UVSQ INSERM Université Paris Saclay Villejuif France

CESP Fac De Médecine Univ Paris Sud Fac De Médecine UVSQ INSERM Université Paris Saclay Villejuif France Assistance Publique Hôpitaux de Paris Hôpital Paul Brousse Villejuif France

Clinical Department of Neurology Innsbruck Medical University Innsbruck Austria

Department of Neurology and Center for Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Neurology Medical Faculty Research Group for Clinical and Experimental Neuroimmunology Heinrich Heine University Düsseldorf Germany

Department of Neurology Medical Faculty Research Group for Clinical and Experimental Neuroimmunology Heinrich Heine University Düsseldorf Germany University Hospital Koeln Deptartment of Neurology Koeln Germany

Department of Rheumatology University College Hospital London United Kingdom

Karolinska Institutet Department of Clinical Neuroscience Center for Molecular Medicine Karolinska University Hospital Sweden

Klinikum rechts der Isar Department of Neurology School of Medicine Technical University of Munich Munich Germany

Laboratory of Clinical Neuroimmunology Departments of Biomedicine and Clinical Research University Hospital Basel and University of Basel Basel Switzerland

Neuroimmunology Laboratory DMSC Department of Neurology Rigshospitalet Region H Copenhagen Denmark

Neuroimmunology Unit Centre for Neuroscience and Trauma Blizard Institute Queen Mary University of London London United Kingdom

Scicross AB Skövde Sweden

Translational Sciences Unit Sanofi R and D 91385 Chilly Mazarin Paris France

Citace poskytuje Crossref.org

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