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

dc.contributor.authorLagumersindez-Denis, Nielsen
dc.contributor.authorWrzos, Claudia
dc.contributor.authorMack, Matthias
dc.contributor.authorWinkler, Anne
dc.contributor.authorvan der Meer, Franziska
dc.contributor.authorReinert, Marie C.
dc.contributor.authorHollasch, Heiko
dc.contributor.authorFlach, Anne
dc.contributor.authorBrühl, Hilke
dc.contributor.authorCullen, Eilish
dc.contributor.authorSchlumbohm, Christina
dc.contributor.authorFuchs, Eberhard
dc.contributor.authorLinington, Christopher
dc.contributor.authorBarrantes-Freer, Alonso
dc.contributor.authorMetz, Imke
dc.contributor.authorWegner, Christiane
dc.contributor.authorLiebetanz, David
dc.contributor.authorPrinz, Marco
dc.contributor.authorBrück, Wolfgang
dc.contributor.authorStadelmann, Christine
dc.contributor.authorNessler, Stefan
dc.description.abstractCortical 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.
dc.subjectCortical demyelination; Experimental autoimmune encephalomyelitis; Inflammatory monocytes; Progressive multiple sclerosis
dc.titleDifferential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis
dc.bibliographicCitation.journalActa Neuropathologica

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