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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.

SUBMITTER: Lagumersindez-Denis N

PROVIDER: S-EPMC5486638 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Lagumersindez-Denis Nielsen N Wrzos Claudia C Mack Matthias M Winkler Anne A van der Meer Franziska F Reinert Marie C MC Hollasch Heiko H Flach Anne A Brühl Hilke H Cullen Eilish E Schlumbohm Christina C Fuchs Eberhard E Linington Christopher C Barrantes-Freer Alonso A Metz Imke I Wegner Christiane C Liebetanz David D Prinz Marco M Brück Wolfgang W Stadelmann Christine C Nessler Stefan S

Acta neuropathologica 20170406 1

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-myeli ...[more]

PMID: 28386765

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Project description:Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).

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

Publications

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

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