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RNA-sequencing of CD4+ T cells in Relapsing-Remitting Multiple Sclerosis patients at relapse; deciphering the involvement of novel genes and pathways

ABSTRACT: Objective: CD4+ T cells known as a noteworthy potential modulator of inflammation in multiple sclerosis (MS). In the current study, we proposed a systems biology approach to investigate the transcriptome profile of CD4+ T cells in patients at relapse phase. Materials and Methods: We performed RNA sequencing of CD4+ T cells isolated from four relapsing-remitting MS (RRMS) patients at relapse phase and four age- and sex-matched healthy controls. The edgeR statistical method was employed to determine differential expression genes (DEGs). The gene set enrichment analysis was subsequently performed. Applying physical interaction network, genes with higher degrees were selected as hub genes. Results: A total of 1278 genes and 1034 gens were defined at significantly higher or lower levels, respectively, in CD4+ T cells of RRMS patients as compared with healthy controls. The top up- and down-regulated gene were JAML and KDM3A. The detected DEGs were remarkably on chromosomes 1 and 2, respectively. The DEGs were mainly enriched in pathways such as ‘regulation of transcription, DNA-templated’, ‘regulation of B cell receptor signaling pathway’, ‘protein phosphorylation’, ‘epidermal growth factor receptor signaling pathway’, and ‘positive regulation of neurogenesis’. Moreover, 16 KEGG pathways mostly associated with the immune system and viral infections were enriched. In the constructed physical interaction networks, UBA52 and TP53 were illustrated as the most highly ranked hub genes among up- and down-regulated genes, correspondingly. Conclusions: By applying global transcriptome profiling of CD4+ T cells, we deciphers the involvement of several novel genes and pathways in MS pathogenesis. The present results need to be affirmed by in vivo and in vitro studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172009 | GEO | 2021/07/27

REPOSITORIES: GEO

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Project description:IFNb has been used as a first line therapy for relapsing remitting multiple sclerosis (RRMS). Since only a few studies have addressed the role of endogenous IFNb in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In-vitro studies have demonstrated that IFNb inhibited IL-17A, IL-17F, IL-21, IL-22 and IFN-b secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion (SOCS)1 and 3. We found that patients with RRMS have increased serum and cerebrospinal fluid (CSF) Th17 (IL-17A and IL-17F) cytokine levels in comparison to the control subjects, suggesting that deficient endogenous IFNbeta secretion and/or signaling may contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFNb from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison to healthy controls (HCs). In addition, in-vitro studies have revealed a deficient endogenous and exogenous IFNb signaling in CD4+ cells derived from MS patients. Interestingly, upon inhibition of the endogenous IFNb signaling by silencing interferon regulatory factor (IRF)7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22 and IL-9, suggesting that endogenous IFNb suppresses the secretion of these pathogenic cytokines. In-vivo recombinant IFNb-1a treatment induced IFNAR1 and its downstream signaling moleculesM-bM-^@M-^Y gene expression, suggesting that treatment may reconstitute a deficient endogenous IFNbeta regulation of the CD4+ T-cellsM-bM-^@M-^Y pathogenic cytokine production in MS patients. Gene expression changes induced by IFNM-NM-2M-bM-^HM-^R1a were tested using Affymetrix Human Genome U133 (HG-U133) arrays (Affymetrix) that contain 45,000 probe sets representing 39,000 transcripts derived from approximately 33,000 human genes. 107 PBMCs per condition derived from 15 CIS patients were stimulated with plate-immobilized M-NM-1CD3 (1 M-NM-<g/ml) and M-NM-1CD28 (5 M-NM-<g/ml) mAb (BD Biosciences) in the absence or presence of IFNM-NM-2-1a (1000 U/ml) (EMD Serono Inc) for 24 h in serum-free medium (Gibco). Cells were harvested and the total RNA was isolated using a Rneasy kit (Quiagen). Arrays were hybridized for 16 hours at 45oC in the GeneChipM-BM-. Hybridization Oven 640 (Affymetrix). The arrays were washed and stained with R-phycoerythrin streptavidin in the GeneChipM-BM-. Fluidics Station 400 (Affymetrix). The arrays were scanned with a Hewlett Packard GeneArray Scanner. Affymetrix GeneChipM-BM-. Microarray Suite 5.0 software was used for washing, scanning and basic analysis.

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RNA-sequencing of CD4+ T cells in Relapsing-Remitting Multiple Sclerosis patients at relapse; deciphering the involvement of novel genes and pathways

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