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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1706-x) contains supplementary material, which is available to authorized users.

The role of chemokines and chemokine receptors in multiple sclerosis

“…They developed a kind of novel mouse anti-human CCR2 monoclonal antibody aiming to deplete CCR2 + monocytes. Compared to isotype-treated controls, monocytedepleted animals revealed less perivascular type 2 cortical demyelination and less subpial type 3 cortical demyelination significantly, which is in line with the ameliorated clinical disease course [61].…”

“…According to Nielsen et.al., assessment of the demyelinating effect of CCR2 + monocytes on cortical shows: Th/ + CCR2 −/− mice developed EAE later than Th/ + CCR2 +/+ mice, but their severity is comparable. More importantly, both perivascular cortical and subpial demyelination(MOG induced in C57BL/6J mice) of Th/ + CCR2 −/− mice were significantly reduced compared with Th/ + CCR2 +/+ mice [61]. The CCR2 + 190 G/A(rs1799864) polymorphism might elevate susceptibility to multiple sclerosis, but the effect appears to be limited to the individuals with no primary risk allele HLA-DRB1 * 15:01 [48].…”

Animal models of multiple sclerosis: Focus on experimental autoimmune encephalomyelitis

“…Previously, it was reported that C57BL/6 mice immunized with MOG 35–55 develops cortical and callosal lesions (Mangiardi et al, ). However, in MOG 35–55 ‐ or rMOG 1–125 ‐immunized C57BL/6 mice, cortical demyelination lesions are not a regular feature of EAE (Lagumersindez‐Denis et al, ). In general, EAE induction in C57BL/6 mice displays heterogeneity in disease induction and progression.…”

Localized calcium accumulations prime synapses for phagocyte removal in cortical neuroinflammation

“…Gray matter pathology in progressive MS is characterized by inflammation dominated by innate immune cells, extensive loss of cortical myelin and some neuronal cell death (Lagumersindez-Denis et al, 2017;Mahad et al, 2015;Peterson et al, 2001). Of note, synapse 20 loss might be a key neuronal pathology in such gray matter lesions (Dutta et al, 2011) as it occurs widespread throughout both the demyelinated, as well as the non-demyelinated, i.e.…”

“…In vivo imaging of the mouse cortex allows assessing local circuit function (Busche et al, 2019;Rose et al, 2016), the corresponding structural correlates (Xu et al, 2009) as well as the cellular mechanisms of neurodegeneration (Kuchibhotla et al, 2008;Merlini et al, 2019). With the recent development 5 of rodent models of cortical neuroinflammation by others and us (Gardner et al, 2013;Lagumersindez-Denis et al, 2017;Lodygin et al, 2019;Merkler et al, 2006;Silva et al, 2018), imaging of MS-related pathology in cortical circuits has become possible. Here we interrogated the structural and functional neuronal consequences of such inflammatory changes using a range of in vivo imaging modalities.…”