Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis

Lagumersindez-Denis, N. et al. (2017) Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis. Acta Neuropathologica, 134(1), pp. 15-34. (doi: 10.1007/s00401-017-1706-x) (PMID:28386765)

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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.

Item Type:Articles
Keywords:Cortical demyelination, experimental autoimmune encephalomyelitis, inflammatory monocytes, progressive multiple sclerosis.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Linington, Professor Christopher
Authors: Lagumersindez-Denis, N., Wrzos, C., Mack, M., Winkler, A., van der Meer, F., Reinert, M. C., Hollasch, H., Flach, A., Brühl, H., Cullen, E., Schlumbohm, C., Fuchs, E., Linington, C., Barrantes-Freer, A., Metz, I., Wegner, C., Liebetanz, D., Prinz, M., Brück, W., Stadelmann, C., and Nessler, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Acta Neuropathologica
Publisher:Springer
ISSN:0001-6322
ISSN (Online):1432-0533
Published Online:06 April 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Acta Neuropathologica 134(1):15-34
Publisher Policy:Reproduced under a Creative Commons License

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