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Search for specific biomarkers of IFN-beta bioactivity in patients with MS

ABSTRACT: We aimed to identify specific biomarkers of IFN-beta bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFN-beta. Nine genes followed patterns in gene expression over time similar to the MX1 and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments revealed specific induction of selected biomarkers by IFN-beta but not IFN-gamma, and several markers, in particular USP18 and HERC5, were significantly induced at lower IFN-beta concentrations and more selective than the MX1 as biomarkers of IFN-beta bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p=0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFN-beta bioactivity, and to further explore their implication in MS pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26104 | GEO | 2010/12/18

SECONDARY ACCESSION(S): PRJNA135181

REPOSITORIES: GEO

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Search for specific biomarkers of IFN-beta bioactivity in patients with MS

Project description:We aimed to identify specific biomarkers of IFN-beta bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFN-beta. Nine genes followed patterns in gene expression over time similar to the MX1 and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments revealed specific induction of selected biomarkers by IFN-beta but not IFN-gamma, and several markers, in particular USP18 and HERC5, were significantly induced at lower IFN-beta concentrations and more selective than the MX1 as biomarkers of IFN-beta bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p=0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFN-beta bioactivity, and to further explore their implication in MS pathogenesis. Number of samples: 32. We analyzed PBMC from 8 patients at baseline and after 3, 12 and 24 months of IFN-beta treatment

2010-12-18 | E-GEOD-26104 | biostudies-arrayexpress

Homo sapiens

Project description:Search for specific biomarkers of IFN-beta bioactivity in patients with MS

| PRJNA135181 | ENA

Microarray analysis to evaluate the role of USP18 in primary microglia and the microglia cell line BV-2

Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Primary microglia (WT, USP18ko and USP18_C61A mice) and BV-2 cells (treated with control siRNA or siRNA against USP18) were incubated with 500 U/ml IFN-b. At different timepoints (0h, 6h, and 24h) RNA samples were taken and analyzed via Microarray

2015-04-20 | E-GEOD-61500 | biostudies-arrayexpress

Microarray analysis to evaluate the function of USP18 in the mouse CNS

Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‚Äòmicrogliopathies‚Äô. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Brain lysate of adult WT, USP18ko, IFNAR1ko and USP18ko:IFNARko mice were analyzed

2015-04-20 | E-GEOD-61499 | biostudies-arrayexpress

USP18-dependent muscle proteome

Project description:USP18 is an interferon type 1 (IFN-1) induced gene that negatively regulates the IFN-1 signalling pathway, which plays a role in many immune related pathologies. Dermatomyositis (DM) is characterised by excessive IFN-1 immune response and muscle degeneration. We found USP18 to be expressed in DM myofibers suggesting a role in muscle cell biology. USP18 depletion induced muscle cell differentiation under nutrient-rich conditions independent of IFN-1 signalling. Downregulation of cell cycle gene network and sarcomeric protein networks, and dysregulation of myogenic (co-)transcription regulators were found in USP18-depleted differentiated cells. Sarcomeric integrity of USP18-depleted cells deteriorated during muscle cell maturation. Our results revealed USP18 as a critical regulator at the intersection between proliferation and differentiation as well as during the maturation of muscle cells. We suggest that a USP18 IFN-1-independent pathway may contribute to muscle regeneration in muscle pathologies.

2023-05-10 | PXD032406 | Pride

Microarray analysis to evaluate the role of USP18 in primary microglia and the microglia cell line BV-2

2015-04-20 | GSE61500 | GEO

Microarray analysis to evaluate the function of USP18 in the mouse CNS

2015-04-20 | GSE61499 | GEO

USP18 is an essential regulator of muscle cell differentiation and maturation

2022-03-23 | GSE198794 | GEO

Gene expression data: Plasmacytoid dendritic cells (pDCs) of healthy donors and MS patientes before and after IFN beta treatment

Project description:Multiple Sclerosis (MS) is an immune-mediated chronic inflammatory disease affecting the central nervous system. The cause of MS is not known and the mechanism of IFN-beta, a disease-modifying treatment (DMT) approved for MS, is not well-understood. Oligonucleotide microarrays were used to study gene expression in plasmacytoid denditic cells (pDCs) which are antigen-presenting cells implicated in MS pathogenesis. We analyzed gene expression in pDCs of healthy controls, untreated and IFN-beta treated MS patients. We were able to identify 60 genes which were abnormally expressed in untreated MS patients and were corrected after treatment with IFN-beta. PDCs were separated from healthy donors and MS patients at two time points: before and 3 months after initiation of treatment with IFN-beta for RNA extraction and hybridization on Affymetrix microarrays. Gene expression data analysis of was done by GeneSpring software (Agilent Technologies). An unpaired t-test was applied to select genes with significant difference in expression between healthy donors and untreated MS patients. A paired t-test was applied to select genes with significant difference in expression in MS patients before and after IFN-beta treatment. To select differentially expressed/regulated genes, the cut-off criteria consisted of a P value < 0.05 and fold change >1.5.

2015-05-02 | E-GEOD-37750 | biostudies-arrayexpress

The transcriptomic analysis for Usp18 heterozygous depletion in established AML1/ETO 9a leukemia mouse model [AE9a_RNA-seq II]

Project description:Usp18 is a potent negative reguator of type I IFN signaling. However, it is not well characterized how Usp18 affects IFN stimulated genes (ISGs) induction in AML in mouse model. Here, we analyzed the transcriptomic data when combined with heterozygous depletion of USP18, which phenotypicaly reduce AE9a leukemia progression.

2022-11-09 | GSE196581 | GEO

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