Universität zu Köln

Adriani, Marsilio, Nytrova, Petra, Mbogning, Cyprien ORCID: 0000-0002-6619-3883, Hassler, Signe, Medek, Karel ORCID: 0000-0003-4350-8659, Jensen, Poul Erik H., Creeke, Paul, Warnke, Clemens, Ingenhoven, Kathleen, Hemmer, Bernhard, Sievers, Claudia, Gasser, Raija L. P. Lindberg, Fissolo, Nicolas ORCID: 0000-0002-7701-9346, Deisenhammer, Florian, Bocskei, Zsolt, Mikol, Vincent, Fogdell-Hahn, Anna ORCID: 0000-0002-0311-9184, Havrdova, Eva Kubala, Broet, Philippe, Donnes, Pierre ORCID: 0000-0002-4613-2952, Mauri, Claudia ORCID: 0000-0001-9761-2625 and Jury, Elizabeth C. (2018). Monocyte NOTCH2 expression predicts IFN-beta immunogenicity in multiple sclerosis patients. JCI Insight, 3 (11). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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Abstract

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-beta is an established treatment for MS; however, up to 30% of IFN-beta-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-beta. 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-beta 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-beta administration.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Adriani, Marsilio UNSPECIFIED UNSPECIFIED UNSPECIFIED Nytrova, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Mbogning, Cyprien UNSPECIFIED orcid.org/0000-0002-6619-3883 UNSPECIFIED Hassler, Signe UNSPECIFIED UNSPECIFIED UNSPECIFIED Medek, Karel UNSPECIFIED orcid.org/0000-0003-4350-8659 UNSPECIFIED Jensen, Poul Erik H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Creeke, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Warnke, Clemens UNSPECIFIED UNSPECIFIED UNSPECIFIED Ingenhoven, Kathleen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hemmer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Sievers, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Gasser, Raija L. P. Lindberg UNSPECIFIED UNSPECIFIED UNSPECIFIED Fissolo, Nicolas UNSPECIFIED orcid.org/0000-0002-7701-9346 UNSPECIFIED Deisenhammer, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Bocskei, Zsolt UNSPECIFIED UNSPECIFIED UNSPECIFIED Mikol, Vincent UNSPECIFIED UNSPECIFIED UNSPECIFIED Fogdell-Hahn, Anna UNSPECIFIED orcid.org/0000-0002-0311-9184 UNSPECIFIED Havrdova, Eva Kubala UNSPECIFIED UNSPECIFIED UNSPECIFIED Broet, Philippe UNSPECIFIED UNSPECIFIED UNSPECIFIED Donnes, Pierre UNSPECIFIED orcid.org/0000-0002-4613-2952 UNSPECIFIED Mauri, Claudia UNSPECIFIED orcid.org/0000-0001-9761-2625 UNSPECIFIED Jury, Elizabeth C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-182963
DOI:	10.1172/jci.insight.99274
Journal or Publication Title:	JCI Insight
Volume:	3
Number:	11
Date:	2018
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	2379-3708
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CENTRAL-NERVOUS-SYSTEM; INTERFERON-BETA; DENDRITIC CELLS; I-INTERFERON; BRAIN ATROPHY; B-CELLS; BLOOD; ACTIVATION; PATHWAYS; DISEASE Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18296