Peripheral blood cellular dynamics of Rheumatoid arthritis treatment informs about efficacy of response to disease modifying drugs.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229449 | GEO | 2023/06/28
REPOSITORIES: GEO
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Project description:This microarray study was conducted along with SATORI study, the clinical trial evaluated 125 patients with active RA with an inadequate response to low dose of MTX. Patients were allocated to receive either Tocilizumab(TCZ) 8 mg/kg every 4 weeks (TCZ group) or MTX 8 mg/week (MTX/control group) for 24 weeks. Gene expression profiles (GEP) of 112 patients - 54 patients from TCZ group and 58 patients from MTX group - were obtained in this study.
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Project description:Rheumatoid arthritis (RA) is an autoimmune disease characterized by systemic inflammation and is mediated by multiple immune cell types. In this work, we aimed to determine the relevance of changes in cell proportions in peripheral blood mononuclear cells (PBMCs) during the development of disease and following treatment. Samples from healthy blood donors, newly diagnosed RA patients, and established RA patients that had an inadequate response to MTX and were about to start tumor necrosis factor inhibitors (TNFi) treatment were collected before and after 3 months of treatment. We used in parallel a computational deconvolution approach based on RNA expression and flow cytometry to determine the relative cell-type frequencies. Cell-type frequencies from deconvolution of gene expression indicate that monocytes (both classical and non-classical) and CD4+ cells (Th1 and Th2) were increased in RA patients compared to controls, while NK cells and B cells (naïve and mature) were significantly decreased in RA patients. Treatment with MTX caused a decrease in B cells (memory and plasma cell), and a decrease in CD4 Th cells (Th1 and Th17), while treatment with TNFi resulted in a significant increase in the population of B cells. Characterization of the RNA expression patterns found that most of the differentially expressed genes in RA subjects after treatment can be explained by changes in cell frequencies (98% and 74% respectively for MTX and TNFi).
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Project description:This microarray study was conducted along with SATORI study, the clinical trial evaluated 125 patients with active RA with an inadequate response to low dose of MTX. Patients were allocated to receive either Tocilizumab(TCZ) 8 mg/kg every 4 weeks (TCZ group) or MTX 8 mg/week (MTX/control group) for 24 weeks. Gene expression profiles (GEP) of 112 patients - 54 patients from TCZ group and 58 patients from MTX group - were obtained in this study. PB samples were collected directly into PAXGene tubes before and after the treatments. Total RNA was extracted using PAXGene Blood RNA Kit with the optimal on-column DNase digestion. Two-color microarray was used to directly compare the samples before versus after the treatment. Total RNA was amplified and amino allyl aRNA of the sample before/after treatments was further labeled with Cy3/Cy5. The labeled aRNAs (mixture of Cy3 and Cy5) was hybridized onto microarray slide. Dye swapping was done with each investigation to account for dye bias in microarray experiments.
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Project description:Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4+ T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4+ T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4+ T cell populations (CD4+ memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients (N=11), methotrexate (MTX) treated RA patients (N=18), and healthy controls (N=9) matched for age, gender and smoking status. Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4+ memory than in CD4+ naïve T cells (904 vs 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (+/- 500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbour both the lead RA risk SNP and two DMPs in CD4+ memory T cells. Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment.
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Project description:This research aims at assessing the m6A methylome in the RA peripheral blood mononuclear cells (PBMCs) and perform potential drug targets prediction analysis. Five RA samples and ten control samples were obtained from China-Japan Friendship Hospital. The various expression of m6A methylation and genes in RA and control group were compared with methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). Bioinformatics explorations were also made to explore the enriched biological roles and paths of the differentially expressed m6A methylation and genes. Potential drug targets prediction and validation were also constructed to provide potential therapeutic targets for RA. In total, 583 dysregulated m6A peaks, of which 295 were greatly upregulated and 288 were greatly downregulated, were identified. Similarly, 1570 differentially genes were acquired by RNA-seq, including 539 upregulated and 1031 downregulated. According to deeper joint exploration, the m6A methylation and mRNA expression degrees of 35 genes varied greatly, of which including 13 hyper-methylated as well as upregulated genes (hyper-up), 12 hyper-methylated and downregulated genes (hyper-down), 5 hypo-methylated as well as upregulated genes (hypo-up), and 5 hypo-methylated and downregulated genes (hypo-down) GO and KEGG explorations showed the enrichment of these distinct genes in “protein transport” “protein binding” and “lysosome”. In addition, the mRNA levels of TUBB2A, IGF2BP3, DYNC1I1 and FOSL1 were increased and consistent with the trend of our sequencing results. While after the treatment of TP and MTX, their mRNA levels were decreased. This research set up the transcriptional map of m6A in RA PBMCs and displayed the hidden association between RNA methylation alternation and associated genes in RA. The outcomes highlight the importance of m6A modification as a gene regulatory system in RA. Furthermore, TUBB2A, IGF2BP3, DYNC1I1 and FOSL1 might be potential therapeutic targets of TP and MTX during RA treatment.
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Project description:Rheumatoid arthritis (RA) is a heterogeneous disease. We used cDNA microarray technology to subclassify RA patients and disclose disease pathways in rheumatoid synovium. Hierarchical clustering of gene expression data identified two main groups of tissues (RA-I and RA-II). A total of 121 genes were significantly higher expressed in the RA-I tissues, whereas 39 genes were overexpressed in the RA-II tissues. Among the 121 genes overexpressed in RA-I tissues, a relative majority of nine genes are located on chromosome 6p21.3. An interpretation of biological processes that take place revealed that the gene expression profile in RA-I tissues is indicative for an adaptive immune response. The RA-II group showed expression of genes suggestive for fibroblast dedifferentiation. Within the RA-I group, two subgroups could be distinguished; the RA-Ia group showed predominantly immune-related gene activity, while the RA-Ib group showed an additional higher activity of genes indicative for the classical pathway of complement activation. All tissues except the RA-Ia subgroup showed elevated expression of genes involved in tissue remodeling. These results confirm the heterogeneous nature of RA and suggest the existence of distinct pathogenic mechanisms that contribute to RA. The differences in expression profiles provide opportunities to stratify patients based on molecular criteria. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Keywords: all_pairs
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Project description:Rheumatoid arthritis (RA) is a heterogeneous disease. We used cDNA microarray technology to subclassify RA patients and disclose disease pathways in rheumatoid synovium. Hierarchical clustering of gene expression data identified two main groups of tissues (RA-I and RA-II). A total of 121 genes were significantly higher expressed in the RA-I tissues, whereas 39 genes were overexpressed in the RA-II tissues. Among the 121 genes overexpressed in RA-I tissues, a relative majority of nine genes are located on chromosome 6p21.3. An interpretation of biological processes that take place revealed that the gene expression profile in RA-I tissues is indicative for an adaptive immune response. The RA-II group showed expression of genes suggestive for fibroblast dedifferentiation. Within the RA-I group, two subgroups could be distinguished; the RA-Ia group showed predominantly immune-related gene activity, while the RA-Ib group showed an additional higher activity of genes indicative for the classical pathway of complement activation. All tissues except the RA-Ia subgroup showed elevated expression of genes involved in tissue remodeling. These results confirm the heterogeneous nature of RA and suggest the existence of distinct pathogenic mechanisms that contribute to RA. The differences in expression profiles provide opportunities to stratify patients based on molecular criteria. An all pairs experiment design type is where all labeled extracts are compared to every other labeled extract. Using regression correlation
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