title: Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis.
abstract: Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2+monocytes are required for both. Depleting CCR2+monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2+monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS.
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.|Klinik und Poliklinik für Neurologie and Center for Stroke Research Berlin, Charité Universitätsmedizin Berlin, 10117, Berlin, Germany.
authors.forename: Nielsen
authors.initials: N
authors.lastname: Lagumersindez-Denis
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wrzos
authors.affiliation: Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Winkler
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: van der Meer
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, 37075, Göttingen, Germany.|Department of Paediatrics and Paediatric Neurology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Reinert
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.|Department of Neurology, Albert Ludwigs University, Freiburg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Hollasch
authors.affiliation: Department of Neuroimmunology, Institute for Multiple-Sclerosis-Research, University of Göttingen and Hertie Foundation, 37073, Göttingen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Flach
authors.affiliation: Department of Internal Medicine, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Hilke
authors.initials: H
authors.lastname: Brühl
authors.affiliation: Medical Research Council Technology, Lynton House, 7-12 Tavistock Square, London, WC1H 9LT, UK.
authors.forename: Eilish
authors.initials: E
authors.lastname: Cullen
authors.affiliation: Neu Encepharm GmbH, Göttingen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schlumbohm
authors.affiliation: German Primate Center, Göttingen, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Fuchs
authors.affiliation: Institute for Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow, G12 8TA, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Linington
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Alonso
authors.initials: A
authors.lastname: Barrantes-Freer
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wegner
authors.affiliation: Department of Clinical Neurophysiology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Liebetanz
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.|BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany. cstadelmann@med.uni-goettingen.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany. stefan.nessler@googlemail.com.
authors.forename: Stefan
authors.initials: S
authors.lastname: Nessler
mesh_terms: D000328:Adult; D000818:Animals; D002144:Callithrix; D002540:Cerebral Cortex / Q000276:immunology* / Q000473:pathology; D015331:Cohort Studies; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D008297:Male; D008578:Meninges / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D011897:Random Allocation; D054390:Receptors, CCR2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: C515334:CCR2 protein, human; D054390:Receptors, CCR2
keywords: Cortical demyelination; Experimental autoimmune encephalomyelitis; Inflammatory monocytes; Progressive multiple sclerosis