Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis
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ABSTRACT:
PROVIDER: PRJNA604770 | ENA |
REPOSITORIES: ENA
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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
Project description:BackgroundMultiple 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 (BBB).MethodsWe 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).FindingsWe identify a specific pathogenic CD161+/lymphotoxin beta (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.ConclusionsAs a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression.FundingThis 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.
| S-EPMC7966680 | biostudies-literature
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
Project description:Gut-microbiota specific IgA B cells traffic to the CNS in multiple sclerosis
| PRJEB32763 | ENA
Project description:Tuberous sclerosis complex-associated CNS abnormalities depend on hyperactivation of mTORC1 and Akt
| PRJNA430419 | ENA
Project description:In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevent the activation of neuroinflammatory reactive astrocytes while promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin regenerative and supportive agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.
2024-10-29 | GSE280579 | GEO
Project description:In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 stimulated scavenger pathways, phagocytosis, and secretion of factors that prevent the activation of neuroinflammatory reactive astrocytes while promoting neuroaxonal health and oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and possibly a wider class of PKC modulators as myelin regenerative and supportive agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.
2024-10-29 | GSE280578 | GEO
Project description:Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis
| PRJEB40803 | ENA
Project description:Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis
| PRJNA844329 | ENA
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