scholarly journals Long Non-Coding RNAs Target Pathogenetically Relevant Genes and Pathways in Rheumatoid Arthritis

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 816 ◽  
Author(s):  
Dolcino ◽  
Tinazzi ◽  
Puccetti ◽  
Lunardi
Keyword(s):  
Rheumatoid Arthritis ◽  
Mononuclear Cells ◽  
Differentially Expressed ◽  
Signalling Pathways ◽  
Epigenetic Factors ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Non Coding Rnas ◽  
Inflammatory Autoimmune Disease ◽  
Chronic Inflammatory Autoimmune Disease

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease driven by genetic, environmental and epigenetic factors. Long non-coding RNAs (LncRNAs) are a key component of the epigenetic mechanisms and are known to be involved in the development of autoimmune diseases. In this work we aimed to identify significantly differentially expressed LncRNAs (DE-LncRNAs) that are functionally connected to modulated genes strictly associated with RA. In total, 542,500 transcripts have been profiled in peripheral blood mononuclear cells (PBMCs) from four patients with early onset RA prior any treatment and four healthy donors using Clariom D arrays. Results were confirmed by real-time PCR in 20 patients and 20 controls. Six DE-LncRNAs target experimentally validated miRNAs able to regulate differentially expressed genes (DEGs) in RA; among them, only FTX, HNRNPU-AS1 and RP11-498C9.15 targeted a large number of DEGs. Most importantly, RP11-498C9.15 targeted the largest number of signalling pathways that were found to be enriched by the global amount of RA-DEGs and that have already been associated with RA and RA–synoviocytes. Moreover, RP11-498C9.15 targeted the most highly connected genes in the RA interactome, thus suggesting its involvement in crucial gene regulation. These results indicate that, by modulating both microRNAs and gene expression, RP11-498C9.15 may play a pivotal role in RA pathogenesis.

scholarly journals The molecular and cellular basis of corticosteroid resistance

2003 ◽  
Vol 179 (3) ◽  
pp. 301-310 ◽  
Author(s):  
IC Chikanza ◽  
D Kozaci ◽  
Y Chernajovsky
Keyword(s):  
Rheumatoid Arthritis ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Intracellular Signalling ◽  
Signalling Pathways ◽  
Peripheral Blood Mononuclear ◽  
Intracellular Signalling Pathways ◽  
Nf Kappab

Corticosteroids (CS) can modulate gene expression and are often used to treat a range of immunological and inflammatory diseases such as asthma, inflammatory bowel disease and rheumatoid arthritis. However, a proportion of patients fail to show an adequate response. On this basis patients have been subdivided into CS-sensitive (SS) and -resistant (SR) subgroups. The ability of CS to inhibit peripheral blood T cell proliferation in vitro has also been used similarly. In rheumatoid arthritis (RA), the in vitro-defined SS and SR subgroups correlate with the clinical responses to CS therapy. The mechanisms responsible for this observation are unknown but they appear to involve a number of known molecular events related to the described mechanisms of action of CS. These include alterations in the functional status of CS receptor-alpha, perturbations of the cytokine and hormonal milieu and intracellular signalling pathways. Peripheral blood mononuclear cells (MNCs) from SR significantly overexpress activated NF-kappaB. In vitro, CS fail to significantly inhibit concanavalin A (conA)-induced NF-kappaB activation in MNCs from SR RA patients. The alterations in the intracellular signalling pathways may explain in part our observations seen in SR RA subjects, CS fail to significantly inhibit conA-induced interleukin (IL)-2 and IL-4 secretion and lipopolysaccharide-induced IL-8 and IL-1beta secretion in vitro. CS therapy fails to reduce the circulating levels of IL-8 and IL-1beta in RA patients. In asthma, CS fail to induce L10 in SR asthma patients. Other molecular mechanisms such as enhanced AP-1 expression and alterations in the MAP kinase pathway are most likely to be involved too and we are currently investigating such possibilities. A full understanding of the molecular basis of SR will lead to the development of more rational therapeutic strategies.

scholarly journals AB0044 ESTABLISHED RHEUMATOID ARTHRITIS PATIENTS HAVE INCREASED FREQUENCIES OF FOLLICULAR REGULATORY T CELLS IN PERIPHERAL BLOOD

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1325.3-1325
Author(s):  
C. Tomé ◽  
S. C. Barreira ◽  
P. Martins ◽  
A. Valido ◽  
R. Barros ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
T Cell Subsets ◽  
Peripheral Blood Mononuclear ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Healthy Donors ◽  
Cd69 Expression

Background:Several studies have demonstrated that an immune dysregulation affecting both B and T cells occurs in rheumatoid arthritis (RA). Follicular helper T (Tfh) cells are crucial for B cell maturation, activation and class-switching as well as for germinal center (GC) formation, whereas follicular regulatory T (Tfr) cells can modulate the GC reaction by suppressing Tfh and B cells.Objectives:The main goal of this study was to analyze the phenotype and frequency of circulating follicular T cell subsets in established RA patients.Methods:Blood samples were collected from established RA patients with active disease, treated with methotrexate (n=32) and from a group of age and sex-matched healthy donors (n=11). Peripheral blood mononuclear cells (PBMC) were isolated and Tfh (CD4+CXCR5+CD45RO+) and Tfr (CD4+ CXCR5+CD25+FoxP3+) cells, as well as their three major subsets [CXCR3+CCR6- (Th1-like), CXCR3-CCR6- (Th2-like) and CXCR3-CCR6+ (Th17-like)] were evaluated by flow cytometry.Results:The frequency of circulating Tfh cells was similar between established RA patients and controls. Nonetheless, RA patients had a decreased frequency of Th1-like Tfh cells, and an increased frequency of Th2-like Tfh cells when compared to controls. No significant differences were observed in the frequencies of Th17-like Tfh cells between both groups. The frequency of circulating Tfr cells was significantly increased in RA patients in comparison to controls. Furthermore, Tfr cells from RA patients had significantly increased CD69 median fluorescence intensity (MFI) values when compared to controls. No significant differences were found in the percentages and MFI values of PD-1, ICOS, CD28, CTLA-4, CD40-L and HLA-DR expressed by Tfh and Tfr cells in RA patients when compared to controls.Conclusion:Established RA patients have increased circulating frequencies of Tfr cells, with higher CD69 expression levels, when compared to healthy controls. These results suggest a pre-activation state of Tfr cells in RA and a potential role in the disease physiopathology.*RA Moura, JE Fonseca and L Graca are joint senior authors.Disclosure of Interests:None declared

scholarly journals Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 42 (5) ◽  
pp. 749-759 ◽  
Author(s):  
Abby Jones Weldon ◽  
Ioana Moldovan ◽  
Marven G. Cabling ◽  
Elvin A. Hernandez ◽  
Sheri Hsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Flow Cytometry ◽  
Disease Activity ◽  
Mononuclear Cells ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Monocyte Subsets ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Highly Correlated

Objective.To assess surface APRIL (a proliferation-inducing ligand; CD256) expression by circulating myeloid cells in rheumatoid arthritis (RA) and to determine its relationship to disease activity.Methods.Peripheral blood mononuclear cells (PBMC) and plasma were obtained from patients with RA and healthy donors. PBMC were stained for flow cytometry to detect surface APRIL and blood cell markers to identify circulating myeloid cell subsets. Based on CD14 and CD16 phenotypes, monocyte subsets described as classical (CD14+CD16−), intermediate (CD14+CD16+), and nonclassical (CD14loCD16+) were identified. Levels of surface APRIL expression were measured by flow cytometry and median fluorescence intensity was used for comparisons. Levels of soluble APRIL in the plasma were determined by ELISA. Disease activity was measured by the Disease Activity Score in 28 joints.Results.In patients with RA, total myeloid cells showed expression of surface APRIL that correlated with disease activity and with plasma APRIL levels observed in these patients. In healthy donors, classical monocytes were composed of > 80% of circulating monocytes. However, in patients with RA, the intermediate and nonclassical subsets were elevated and made up the majority of circulating monocytes. In contrast to healthy donors, where high levels of surface APRIL were only observed in nonclassical monocytes, patients with RA showed high levels of surface APRIL expression by all circulating monocyte subsets.Conclusion.Surface APRIL is elevated in circulating myeloid cells in patients with RA where it is highly correlated with disease activity. Patients with RA also showed skewing of monocytes toward subsets associated with secretion of tumor necrosis factor-α and/or interleukin 1β.

scholarly journals RNA-seq reveals the circular RNA and miRNA expression profile of peripheral blood mononuclear cells in patients with rheumatoid arthritis

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Jianting Wen ◽  
Jian Liu ◽  
Pingheng Zhang ◽  
Hui Jiang ◽  
Ling Xin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Differentially Expressed ◽  
Sequencing Analysis ◽  
Rna Seq ◽  
Peripheral Blood Mononuclear ◽  
Wide Range ◽  
Blood Mononuclear Cells

Abstract Objective: Circular RNAs (circRNAs) are a significant class of molecules involved in a wide range of diverse biological functions that are abnormally expressed in many types of diseases. The present study aimed to determine the circRNAs specifically expressed in peripheral blood mononuclear cells (PBMCs) from rheumatoid arthritis (RA) patients to identify their possible molecular mechanisms. Methods: To identify the circRNAs specifically expressed in RA, we started by sequencing the of PBMCs circRNA and microRNAs (miRNAs) from a RA group (n = 3) and a control group (n = 3). We constructed a network of differentially expressed circRNAs and miRNAs. Then, we selected differentially expressed circRNAs in PBMCs from 10 RA patients relative to 10 age- and sex-matched controls using real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Spearman’s correlation test was used to evaluate the correlation of circRNAs with biochemical measurements. Results: A total of 165 circRNAs and 63 miRNAs were differently expressed between RA patients and healthy people according to RNA-seq, including 109 circRNAs that were significantly up-regulated and 56 circRNAs that were down-regulated among the RA patients. RT-qPCR validation demonstrated that the expression levels of hsa_circ_0001200, hsa_circ_0001566, hsa_circ_0003972, and hsa_circ_0008360 were consistent with the results from the sequencing analysis. Then, we found that there were significant correlations between the circRNAs and disease severity. Conclusion: Generally, these results suggest that expression of hsa_circ_0001200, hsa_circ_0001566, hsa_circ_0003972, and hsa_circ_0008360 in PBMCs from RA patients may serve as potential biomarkers for the diagnosis of RA, and these circRNAs may influence the occurrence and development of RA.

Epigenetically regulated co-expression network of genes significant for rheumatoid arthritis

Epigenomics ◽  
2019 ◽  
Vol 11 (14) ◽  
pp. 1601-1612 ◽  
Author(s):  
Pei He ◽  
Xing-Bo Mo ◽  
Shu-Feng Lei ◽  
Fei-Yan Deng
Keyword(s):  
Rheumatoid Arthritis ◽  
Causal Inference ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Differentially Expressed ◽  
Peripheral Blood Mononuclear ◽  
Differentially Expressed Mirnas ◽  
Blood Mononuclear Cells ◽  
Inference Test

Aim: To identify epigenetically regulated network of genes in peripheral blood mononuclear cells significant for rheumatoid arthritis (RA). Methods: Differentially expressed genes (DEGs) and their associated differentially expressed miRNAs and differentially methylated positions (DMPs) were identified. Causal inference test (CIT) identified the causal regulation chains. The analyses, for example, weighted gene co-expression network (WGCNA), protein–protein interaction and functional enrichment, evaluated interaction patterns among the DEGs and the associated epigenetic factors. Results: A total of 181 DEGs were identified. The DEGs were significantly regulated by DMPs and/or differentially expressed miRNAs. Causal inference test analyses identified 18 causal chains of DMP-DEG-RA and 16 intermediate DEGs enriched in ‘protein kinase inhibitor activity’. BTN2A1 was co-expressed with other 9 intermediate genes and 11 known RA-associated genes and played a pivotal role in the co-expression network. Conclusion: Epigenetically regulated network of genes in peripheral blood mononuclear cells (PBMC) contributed to RA. The causal DMPs and key intermediate genes may serve as potential biomarkers for RA.

scholarly journals Long non-coding RNAs (lncRNAs) NEAT1 and MALAT1 are differentially expressed in severe COVID-19 patients: An integrated single-cell analysis

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261242
Author(s):  
Kai Huang ◽  
Catherine Wang ◽  
Christen Vagts ◽  
Vanitha Raguveer ◽  
Patricia W. Finn ◽  
...  
Keyword(s):  
Single Cell ◽  
Mononuclear Cells ◽  
Single Cell Analysis ◽  
Cell Types ◽  
Differentially Expressed ◽  
Cellular Stress Response ◽  
Peripheral Blood Mononuclear ◽  
Diagnostic Measures ◽  
Multiple Cell ◽  
Non Coding Rnas

Hyperactive and damaging inflammation is a hallmark of severe rather than mild Coronavirus disease 2019 (COVID-19). To uncover key inflammatory differentiators between severe and mild COVID-19, we applied an unbiased single-cell transcriptomic analysis. We integrated two single-cell RNA-seq datasets with COVID-19 patient samples, one that sequenced bronchoalveolar lavage (BAL) cells and one that sequenced peripheral blood mononuclear cells (PBMCs). The combined cell population was then analyzed with a focus on genes associated with disease severity. The immunomodulatory long non-coding RNAs (lncRNAs) NEAT1 and MALAT1 were highly differentially expressed between mild and severe patients in multiple cell types. Within those same cell types, the concurrent detection of other severity-associated genes involved in cellular stress response and apoptosis regulation suggests that the pro-inflammatory functions of these lncRNAs may foster cell stress and damage. Thus, NEAT1 and MALAT1 are potential components of immune dysregulation in COVID-19 that may provide targets for severity related diagnostic measures or therapy.

scholarly journals Profiling of small non-coding RNAs across cellular and biofluid compartments: implications for multiple sclerosis immunopathology

2020 ◽  
Author(s):  
Galina Yurevna Zheleznyakova ◽  
Eliane Piket ◽  
Maria Needhamsen ◽  
Michael Hagemann-Jensen ◽  
Diana Ekman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mononuclear Cells ◽  
Mrna Translation ◽  
Rna Degradation ◽  
Chronic Inflammatory Disease ◽  
Differentially Expressed ◽  
Peripheral Blood Mononuclear ◽  
Csf Cells ◽  
The Central Nervous System ◽  
Non Coding Rnas

AbstractMultiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS), is associated with dysregulation of microRNAs (miRNA). We here analyzed all classes of small non-coding RNAs (sncRNAs) in matching peripheral blood mononuclear cells (PBMCs), plasma, cerebrospinal fluid (CSF) cells and cell-free CSF from relapsing-remitting (RRMS, n=12 in relapse, n=11 in remission), secondary progressive (SPMS, n=6) MS patients and non-inflammatory and inflammatory neurological disease controls (NINDC, n=11; INDC, n=5). We show widespread changes in small nuclear, nucleolar, transfer RNAs and miRNAs. In CSF cells, 133/133 and 115/117 differentially expressed sncRNAs are increased in RRMS relapse compared to remission and RRMS compared to NINDC, respectively. In contrast, 65/67 differentially expressed PBMC sncRNAs are decreased in RRMS compared to NINDC. The striking contrast between periphery and CNS suggests that sncRNA-mediated mechanisms, including alternative splicing, RNA degradation and mRNA translation, regulate the transcriptome of pathogenic cells primarily in the target organ.

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