Multiple Sclerosis: Mechanisms and Immunotherapy

Baecher-Allan, Clare; Kaskow, Belinda J.; Weiner, Howard L.

doi:10.1016/j.neuron.2018.01.021

Cited by 687 publications

(700 citation statements)

References 283 publications

(256 reference statements)

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“…These results are supported by previous studies indicating that both white matter lesions and overall tissue destruction in the brain contribute to neurologic dysfunction in MS, and tend to provide complementary information on disease status and treatment efficacy . In RRMS, white matter lesions are thought to be largely the result of adaptive immunity responses such as lymphocyte entry into the CNS . In contrast, brain atrophy, and the risk for developing secondary progressive disease, reflects a wide variety of processes not limited to the effect of destructive white matter lesions in the brain, but also gray matter factors such as cortical lesions, innate immunity, meningeal pathology, and neurodegeneration …”

Section: Discussionsupporting

confidence: 82%

Brain MRI Predicts Worsening Multiple Sclerosis Disability over 5 Years in the SUMMIT Study

Bakshi

Healy

Dupuy

et al. 2020

Journal of Neuroimaging

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BACKGROUND AND PURPOSE Brain MRI‐derived lesions and atrophy are related to multiple sclerosis (MS) disability. In the Serially Unified Multicenter MS Investigation (SUMMIT), from Brigham and Women's Hospital (BWH) and University of California, San Francisco (UCSF), we assessed whether MRI methodologic heterogeneity may limit the ability to pool multisite data sets to assess 5‐year clinical‐MRI associations. METHODS Patients with relapsing‐remitting (RR) MS (n = 100 from each site) underwent baseline brain MRI and baseline and 5‐year clinical evaluations. Patients were matched on sex (74 women each), age, disease duration, and Expanded Disability Status Scale (EDSS) score. MRI was performed with differences between sites in both acquisition (field strength, voxel size, pulse sequences), and postprocessing pipeline to assess brain parenchymal fraction (BPF) and T2 lesion volume (T2LV). RESULTS The UCSF cohort showed higher correlation than the BWH cohort between T2LV and disease duration. UCSF showed a higher inverse correlation between BPF and age than BWH. UCSF showed a higher inverse correlation than BWH between BPF and 5‐year EDSS score. Both cohorts showed inverse correlations between BPF and T2LV, with no between‐site difference. The pooled but not individual cohort data showed a link between a lower baseline BPF and the subsequent 5‐year worsening in disability in addition to other stronger relationships in the data. CONCLUSIONS MRI acquisition and processing differences may result in some degree of heterogeneity in assessing brain lesion and atrophy measures in patients with MS. Pooling of data across sites is beneficial to correct for potential biases in individual data sets.

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Section: Discussionsupporting

confidence: 82%

Brain MRI Predicts Worsening Multiple Sclerosis Disability over 5 Years in the SUMMIT Study

Bakshi

Healy

Dupuy

et al. 2020

Journal of Neuroimaging

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“…Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) representing the primary cause of neurological disability in young adults in the Western world [1,2]. The initiation of the pathogenesis is characterized by the infiltration of auto-reactive immune cells into the CNS leading to inflammatory lesions consequently inducing extensive demyelination and neurodegeneration [1].…”

Section: Introductionmentioning

confidence: 99%

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Hundehege¹,

Fernández‐Orth²,

Römer³

et al. 2018

Neurosignals

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Background/Aims: Multiple sclerosis (MS) is a prototypical autoimmune central nervous system (CNS) disease. Particularly progressive forms of MS (PMS) show significant neuroaxonal damage as consequence of demyelination and neuronal hyperexcitation. Immuno-modulatory treatment strategies are beneficial in relapsing MS (RMS), but mostly fail in PMS. Pregabalin (Lyrica®) is prescribed to MS patients to treat neuropathic pain. Mechanistically, it targets voltage-dependent Ca²⁺ channels and reduces harmful neuronal hyperexcitation in mouse epilepsy models. Studies suggest that GABA analogues like pregabalin exert neuroprotective effects in animal models of ischemia and trauma. Methods: We tested the impact of pregabalin in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and performed histological and immunological evaluations as well as intravital two-photon-microscopy of brainstem EAE lesions. Results: Both prophylactic and therapeutic treatments ameliorated the clinical symptoms of EAE and reduced immune cell infiltration into the CNS. On neuronal level, pregabalin reduced long-term potentiation in hippocampal brain slices indicating an impact on mechanisms of learning and memory. In contrast, T cells, microglia and brain endothelial cells were unaffected by pregabalin. However, we found a direct impact of pregabalin on neurons during CNS inflammation as it reversed the pathological elevation of neuronal intracellular Ca²⁺ levels in EAE lesions. Conclusion: The presented data suggest that pregabalin primarily acts on neuronal Ca²⁺ channel trafficking thereby reducing Ca²⁺-mediated cytotoxicity and neuronal damage in an animal model of MS. Future clinical trials need to assess the benefit for neuronal survival by expanding the indication for pregabalin administration to MS patients in further disease phases.

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“…considerably increased the efficacy of MS treatments 47 , but research in this field has largely focused on different classes of T and B lymphocytes [48][49][50] . While recent data have highlighted the prominent heterogeneity of monocyte-derived cells at CNS borders [2][3][4] , the trafficking routes of circulating monocytes infiltrating the CNS during neuroinflammation remain to this date surprisingly unclear.…”

Section: Studying the Migration Of Immune Cells Through Distinct Cns mentioning

confidence: 99%

Monocyte recruitment to the inflamed central nervous system: migration pathways and distinct functional polarization

Ivan

Walthert

Locatelli

2020

Preprint

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The central nervous system (CNS) parenchyma is enclosed by anatomical interfaces including multilayered meninges, the blood-brain barrier (BBB), the choroid plexuses within ventricles and the glia limitans. These border areas hold distinct functional specializations which control the trafficking of monocyte-derived cells toward the CNS parenchyma, altogether maintaining CNS homeostasis. By crossing activated endothelial, epithelial and glial borders, circulating leukocytes gain however access to the CNS parenchyma in several inflammatory diseases including multiple sclerosis.Studies in animal models of neuroinflammation have helped describing the phenotypic specifications of these invading monocyte-derived cells, able to exert detrimental or beneficial functions depending on the local environment. In this context, in vivo visualization of iNOS + pro-inflammatory and arginase-1 + anti-inflammatory macrophages has recently revealed that these distinct cell phenotypes are highly compartmentalized by CNS borders. While arginase-1 + macrophages densely populate the leptomeninges, iNOS + macrophages rather accumulate in perivascular spaces and at the pia mater-CNS parenchymal interface.How and where these macrophages acquire their functional commitment, and whether differentially-activated monocyte-derived cells infiltrate the CNS through distinct gateways, remains however unclear.In this study, we have investigated the interaction of monocyte-derived macrophages with endothelial (BBB) and epithelial (choroid plexus) barriers of the CNS, both in vitro and in vivo. By using primary mouse brain microvascular endothelial cells as in vitro model of the BBB, we observed that, compared to unpolarized primary macrophages, adhesion of functionally-committed macrophages to endothelial cells was drastically reduced, literally abrogating their diapedesis across the BBB. Conversely, when interacting with an activated choroid plexus epithelium, both pro-and anti-inflammatory macrophages displayed substantial adhesive and migratory properties. Accordingly, in vivo analysis of choroid plexuses revealed increased macrophage trafficking and a scattered presence of polarized cells upon induction of anti-CNS inflammation.Altogether, we show that acquisition of distinct macrophage polarizations significantly alters the adhesive and migratory properties of these cells in a barrier-specific fashion. While monocytes trafficking at the level of the BBB seem to acquire their signature phenotype only following diapedesis, other anatomical interfaces can be the entry site for functionally activated monocyte-derived cells. Our study highlights the choroid plexus as a key access gateway for macrophages during neuroinflammation, and its stroma as a potential priming site for their functional polarization.3

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Multiple Sclerosis: Mechanisms and Immunotherapy

Cited by 687 publications

References 283 publications

Brain MRI Predicts Worsening Multiple Sclerosis Disability over 5 Years in the SUMMIT Study

Brain MRI Predicts Worsening Multiple Sclerosis Disability over 5 Years in the SUMMIT Study

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Monocyte recruitment to the inflamed central nervous system: migration pathways and distinct functional polarization

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