MicroRNA Signature of Central Nervous System-Infiltrating Dendritic Cells in an Animal Model of Multiple Sclerosis
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ABSTRACT:
PROVIDER: PRJNA436357 | ENA |
REPOSITORIES: ENA
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Project description:Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen presenting cells which function as critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia have been shown to upregulate CD11c during inflammation, making it challenging to distinguish hematopoietically-derived DCs from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells within the CNS during neuro-inflammation and is proposed as a mechanism for the regulation of innate cell function. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non-biased murine array. Several miRNAs, including miR-31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR-31 expression was specific to bone marrow-derived DCs (BMDCs). Interestingly, miR-31 binding sites were enriched in mRNAs downregulated BMDCs that migrated into the CNS. Finally, miR-31 was enriched in DCs that migrated through an in vitro blood-brain barrier. Our findings suggest that miRNAs, including miR-31, may participate in the regulation of DCs entry into the CNS during EAE and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS.
2019-01-31 | GSE111256 | GEO
Project description:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Four histopathological patterns of MS have been described. Pattern II is characterized by antibody and complement deposition. MS is considered a prototypic T cell-mediated disease, but until now the study of pathogenic T cells has encountered major challenges, most importantly the limited access of brain-infiltrating T cells. Here, we used next generation sequencing to identify clonally expanded T cells in demyelinating pattern II brain autopsy lesions and subsequently isolated these as T cell clones from autologous cerebrospinal fluid. The functional characterization shows that T cells releasing Th2 cytokines and able to provide B cell help dominate the T cell infiltrate in pattern II brain lesions. Our data provide the first functional evidence for a role of Th2/Tc2 cells in pattern II MS. Two stimulated CD4+ Th2 brain infiltrating T cell clones compared with stimulated circulaiting memory CD4+ T cells and two stimulated CD8+ T cell clones (one Tc1 and one Tc2) compared with each other.
2016-07-03 | E-GEOD-60914 | biostudies-arrayexpress
Project description:Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Four histopathological patterns of MS have been described. Pattern II is characterized by infiltrating macrophages and T-cells and by antibody and complement deposition. Transcriptome analysis of three patern II demyelinating brain lesions from a multiple sclerosis patient using RNA sequencing demonstrated the presence of mRNA transcripts for genes specific of activated macrophages, T and B cells as well as genes coding for immunoglobulins, complement proteins and some pattern II associated proteins, providing additional evidence supporting pattern II demyelination. Examination of 3 different demyelinating lesions identified by Immunohistopathology.
2016-07-03 | E-GEOD-60942 | biostudies-arrayexpress
Project description:RATIONALE: Radiolabeled monoclonal antibodies, such as iodine I 131 monoclonal antibody 3F8, can find tumor cells and carry tumor-killing substances to them without harming normal cells. This may be an effective treatment for central nervous system cancer or leptomeningeal metastases.
PURPOSE: This phase II trial is studying the side effects and how well iodine I 131 monoclonal antibody 3F8 works in treating patients with central nervous system cancer or leptomeningeal cancer.
| 2037925 | ecrin-mdr-crc
Project description:Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with marked heterogeneity in several aspects including pathological processes. Four histopathological patterns of MS have been described. Pattern II is characterized by antibody and complement deposition. MS is considered a prototypic T cell-mediated disease, but until now the study of pathogenic T cells has encountered major challenges, most importantly the limited access of brain-infiltrating T cells. Here, we used next generation sequencing to identify clonally expanded T cells in demyelinating pattern II brain autopsy lesions and subsequently isolated these as T cell clones from autologous cerebrospinal fluid. The functional characterization shows that T cells releasing Th2 cytokines and able to provide B cell help dominate the T cell infiltrate in pattern II brain lesions. Our data provide the first functional evidence for a role of Th2/Tc2 cells in pattern II MS.
2016-01-01 | GSE60914 | GEO
Project description:Three mouse models of human central nervous system pathologies were selected for analyzing gene expression changes compared to wild type normal brain. The selected models are: TgAPP23 for Alzheimerï¾s disease (see Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.H., Mistl, C., Rothacher, S., Ledermann, B., B?rki, K., Frey, P., Paganetti, P.A., Waridel, C., Calhoun, M.E., Jucker, M., Probst, A., Staufenbiel, M. and Sommer, B. (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. PNAS 94, 13287-13292), Tg6074 for multiple sclerosis (see Akassoglou K, Bauer J, Kassiotis G, Pasparakis M, Lassmann H, Kollias G and Probert L. (1998). Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. Am J Pathol. 153, 801-813) and permanent mid-cerebral artery occlusion for stroke (see Welsh, F.A., Sakamoto, T., McKee, A.E. and Sims, R.E. (1987) Effect of lactacidosis on pyridine nucleotide stability during ischemia in mouse brain. J Neurochem. 49, 846-851). Trangenic mice were grown to appropriate age, so that they would manifest the symptoms of disease or disease was induced by a surgical procedure to adult mice. Mice were sacrificed and half brains were removed at selected time points after disease onset for RNA extraction and subsequent array hybridization.
2008-07-12 | E-MTAB-1 | biostudies-arrayexpress
Project description:Peripheral peptidolgycan (PGN) is present within antigen-presenting cells in the central nervous system (CNS) of multiple sclerosis (MS) patients, possibly playing a role in neuroinflammation. Accordingly, PGN is linked with disease progression in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), but the role of specific PGN-sensing proteins is unknown. Here we report that the progression of EAE was dependent on the intracellular PGN sensors NOD1 and NOD2 and their common downstream adaptor molecule, receptor interacting protein 2 (RIP2; also known as RIPK2 and RICK). We found that RIP2, but not toll-like receptor 2 (TLR2), played a critical role in the activation of CNS-infiltrating dendritic cells. Our results suggest that PGN in the CNS is involved in the pathogenesis of EAE through the activation of infiltrating dendritic cells via NOD1-, NOD2-, and RIP2-mediated pathways.
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Project description:Traumatic injuries to the central nervous system (CNS) affect millions of people worldwide yet lack an effective treatment. These injuries contain infiltrating immune cells that can promote tissue repair and could be exploited for therapeutic benefit. Here, using single-cell RNA-sequencing of T cells infiltrating the injured CNS we demonstrate their clonal expansion and antigen specificity towards CNS derived self-peptides. We confirm the beneficial effect of these injury-associated autoimmune CD4+ T cells in murine models of optic nerve and spinal cord injury. Subsequently, using mRNA-based transient T cell receptor (TCR) reconstitution, we demonstrate a therapeutic T cell strategy to alleviate CNS injury. Treatment of CNS-injured mice with this therapy improved locomotion and alleviated histological signs of damage, through regulation of myeloid cells, without detrimental autoimmune side effects. This strategy provides a means of developing custom-designed T cell therapies for CNS injury, and possibly for other neurodegenerative disorders.
2024-07-23 | GSE216388 | GEO
Project description:Efavirenz Central Nervous System Side Effects
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Project description:We have induced experimental autoimmune encephalomyelitis (EAE) in mice to mimic B cell aggregate formation as seen in progressive multiple sclerosis patients. Aggregates and regular central nervous system infiltrates were dissected using laser capture microdissection. RNA was collected using commercially available kits and subjected to RNA sequencing. Samples were compared to draining lymph nodes and to another EAE model, which had no involvement of B cells.
2019-06-10 | GSE125144 | GEO