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Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

ABSTRACT: Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

PROVIDER: PRJNA604770 | ENA |

REPOSITORIES: ENA

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Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

Project description:Background: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood brain barrier. Methods: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA-sequencing we localize these cells in post-mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). Findings: We identify a specific pathogenic CD161+/LTB+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. Conclusions: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression. Funding: This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK and Wellcome.

2021-02-16 | GSE144744 | GEO

Bioinformatics Analyses Determined the Distinct CNS and Peripheral Surrogate Biomarker Candidates between Two Mouse Models for Progressive Multiple Sclerosis

Project description:Previously, we have established two distinct progressive multiple sclerosis (MS) models by induction of experimental autoimmune encephalomyelitis (EAE) with myelin oligodendrocyte glycoprotein (MOG) in two mouse strains. A.SW mice develop ataxia with antibody deposition, but no T cell infiltration, in the central nervous system (CNS), while SJL/J mice develop paralysis with CNS T cell infiltration. In this study, we determined biomarkers contributing to the heterogeneities of the two models. Using the CNS and spleen microarray transcriptome and cytokine data, we conducted computational supervised analyses (volcano plot, heat map, and pathway analysis) and unsupervised principal component analysis (PCA) with pattern matching analysis (PMA).

2019-04-09 | GSE99300 | GEO

Gut-microbiota specific IgA B cells traffic to the CNS in multiple sclerosis

Project description:Gut-microbiota specific IgA B cells traffic to the CNS in multiple sclerosis

| PRJEB32763 | ENA

Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt

Project description:Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt

| PRJNA430419 | ENA

Identification of early neurodegenerative pathways in progressive multiple sclerosis

Project description:Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand–receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.

2022-06-05 | PXD026529 | Pride

Mononuclear phagocyte phenotypes in a multiple sclerosis model

Project description:Mononuclear phagocytes are key regulators of both tissue damage and repair in neuroinflammatory conditions such as multiple sclerosis (MS). To examine divergent phagocyte phenotypes in the inflamed central nervous system (CNS) we introduce an in vivo imaging approach combined with RNAseq and proteomics that allows us to temporally and spatially resolve the evolution of phagocyte polarization in a murine MS model. We show that the initial pro-inflammatory polarization of phagocytes is established after spinal cord entry and critically depends on the compartment they enter. Guided by signals from the CNS environment individual phagocytes then switch their phenotype as lesions move from expansion to resolution. Our study thus provides a first real-time analysis of the temporo-spatial determinants and regulatory principles of phagocyte specification in the inflamed CNS.

2019-07-10 | PXD010245 | Pride

Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis

Project description:Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis

| PRJNA844329 | ENA

Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis

Project description:Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis

| PRJEB40803 | ENA

Regional CNS immune fingerprint in chronic peripheral inflammation

Project description:Rheumatoid arthritis (RA) is linked to depression and dementia in later life by inflammatory involvement of the central nervous system (CNS). Regional heterogeneity of brain immunophenotypes was described under homeostasis, but a topographical resolution of CNS immune responses in chronic peripheral inflammatory diseases like RA is missing. We demonstrate regional heterogeneity of CNS susceptibility to chronic peripheral inflammation in the human tumor necrosis factor α transgenic (TNFtg) mouse model of RA. TNFtg mice showed myeloid cell infiltration, microglial activation, and a mutual transcriptomic fingerprint of neuroinflammation in the cortex, striatum, and thalamus. Immune responses were minimal in the hippocampus and cerebellum. We demonstrate regional CNS immune responses to chronic peripheral inflammation, sparing the hippocampus and cerebellum and reversible by peripheral anti-inflammatory treatment. Targeting microenvironmental susceptibility or resilience of brain regions will help to prevent and treat RA-related neuropsychiatric comorbidity. RNA-sequencing was performed from five brain regions (cortex, striatum, thalamus, hippocampus, and cerebellum) from C57Bl6/J wild type mice and TNFtg mice (strain Tg197; kindly provided by George Kollias (Fleming Institute, Vari, Greece).

2018-10-22 | E-MTAB-7279 | biostudies-arrayexpress

Human brain tissues from healthy controls and multiple sclerosis patients

Project description:Multiple sclerosis (MS) is characterized by cell proliferation, migration and damage in various cell types in different CNS regions and causes disabilities related to distinct neurological pathways, such as walking, vision and cognition. Here, region-specific transcriptomic approach was used to determine changes in gene expression in five different CNS regions (hippocampus, frontal cortex, internal capsule, corpus callosum, and parietal cortex) in MS.

2019-04-29 | GSE123496 | GEO

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