Search

Byline: Jiaying. Qiu, Jiajia. Gu, Shiyi. Chang, Zhenyu. Zhang, Haibo. Zhang, Tianqing. Liu, Jing. Jie, Jinhuan. Wei Background: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelinating lesions [...]

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal degeneration. Abnormal expression of microRNAs (miRNAs) plays an important role in MS pathology. In this cohort study, differential expression of the four miRNAs (hsa-miR-155-5p, hsa-miR-9-5p, hsa-miR-181a-5p, and hsa-miR-125b-5p) was investigated in 69 individuals, including 39 MS patients (relapsing-remitting MS (RRMS), n = 27; secondary progressive MS (SPMS), n = 12) and 30 healthy controls. In silico analyses revealed possible genes and pathways specific to miRNAs. Peripheral blood miRNA expressions were detected by quantitative real-time PCR (qPCR). hsa-miR-181a-5p was downregulated and associated with increased MS risk (P = 0.012). The other three miRNAs were upregulated and not associated with MS (P < 0.05). The area under the curve (AUC) is 0.779. In silico analyses showed that hsa-miR-181a-5p may participate in MS pathology by targeting MAP2K1, CREB1, ATXN1, and ATXN3 genes in inflammation and neurodegeneration pathways. The circulatory hsa-miR-181a-5p can regulate target genes, reversing the mechanisms involved in MS pathologies such as protein uptake and processing, cell proliferation and survival, inflammation, and neurodegeneration. Thus, this miRNA could be used as an epigenomic-guided diagnostic tool and for therapeutic purpose. Key words: multiple sclerosis, miRNA biomarkers, peripheral blood molecular diagnostics La sclérose en plaques (SP) est une maladie inflammatoire chronique du système nerveux central (SNC) caractérisée par une démyélinisation et une dégénérescence axonale. L'expression anormale des microARN (miARN) joue un rôle important dans cette pathologie. Dans cette étude de cohorte, l'expression différentielle de quatre miRNA (hsa-miR-155-5p, hsa-miR-9-5p, hsa-miR-181a-5p et hsa-miR-125b-5p) a été examinée chez 69 individus dont 39 patients SP (forme récurrente-rémittente, SPRR ; n =27 ; ou forme progressive secondaire, SPPS ; n =12) et 30 témoins en santé. Des analyses in silico ont révélé de possibles gènes ou sentiers spécifiques aux miARN. L'expression des miARN dans le sang périphérique a été mesurée par PCR quantitatif en temps réel (qPCR). Le hsa-miR-181a-5p était moins fortement exprimé et il était associé à un risque accru de SP (P = 0,012). Les trois autres miARN étaient plus fortement exprimés chez les patients SP et n'étaient pas associés à la SP (P < 0,05). L'aire sous la courbe (AUC) était de 0,779. Des analyses in silico ont également montré que le hsa-miR-181a-5p pourrait participer à la pathologie de la SP en ciblant les gènes MAP2K1, CREB1, ATXN1 et ATXN3 des sentiers de l'inflammation et de la neurodégénérescence. Les hsa-miR-181a-5p en circulation peuvent réguler les gènes ciblés, renversant les mécanismes impliqués dans les pathologies liées à la SP telles que l'absorption et la transformation des protéines, la prolifération cellulaire et la survie, l'inflammation et la neurodégénérescence. Ainsi, ce miARN pourrait servir d'outil diagnostique épigénomique et thérapeutique. [Traduit par la Rédaction] Mots-clés : sclérose en plaques, miARN biomarqueurs, diagnostic moléculaire du sang périphérique, Introduction Multiple sclerosis (MS) is a demyelination disease mediated by the immune system and is characterized by pathological mechanisms originating from the autoimmune destruction of myelin and neurons in the [...]

BACKGROUND. Cytotoxic T lymphocyte antigen 4 (CTLA4) is essential for immune homeostasis. Genetic mutations causing haploinsufficiency (CTLA4h) lead to a phenotypically heterogenous, immune-mediated disease that can include neuroinflammation. The neurological manifestations of CTLA4h are poorly characterized. METHODS. We performed an observational natural history study of 50 patients with CTLA4h who were followed at the NIH. We analyzed clinical, radiological, immunological, and histopathological data. RESULTS. Evidence for neuroinflammation was observed in 32% (n = 16 of 50) of patients in this cohort by magnetic resonance imaging (MRI) and/or by cerebrospinal fluid analysis. Clinical symptoms were commonly absent or mild in severity, with headaches as the leading complaint (n = 13 of 16). The most striking findings were relapsing, large, contrast-enhancing focal lesions in the brain and spinal cord observed on MRI. We detected inflammation in the cerebrospinal fluid and leptomeninges before the parenchyma. Brain biopsies of inflammatory lesions from 10 patients showed perivascular and intraparenchymal mixed cellular infiltrates with little accompanying demyelination or neuronal injury. CONCLUSIONS. Neuroinflammation due to CTLA4h is mediated primarily by an infiltrative process with a distinct and striking dissociation between clinical symptoms and radiological findings in the majority of patients. FUNDING. NIAID, NIH, Division of Intramural Research, NINDS, NIH, Division of Intramural Research, and the National Multiple Sclerosis Society-American Brain Foundation. TRIAL REGISTRATION. ClinicalTrials.gov NCT00001355., Introduction Cytotoxic T lymphocyte antigen 4 (CTLA4) is an essential protein in immune homeostasis that is constitutively expressed on regulatory T cells (Tregs) and upregulated on effector T cells upon [...]

Multiple sclerosis is a chronic inflammatory disease of the CNS.sup.1. Astrocytes contribute to the pathogenesis of multiple sclerosis.sup.2, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2[alpha] to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2[alpha] and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis. Single-cell RNA sequencing of cells from humans with multiple sclerosis and mice with a model of the disease identifies a population of disease-promoting astrocytes in which anti-oxidant and anti-inflammatory proteins are suppressed., Author(s): Michael A. Wheeler [sup.1] [sup.2] , Iain C. Clark [sup.1] , Emily C. Tjon [sup.1] , Zhaorong Li [sup.1] , Stephanie E. J. Zandee [sup.3] [sup.4] , Charles P. [...]