Loss of synovial tissue macrophage homeostasis precedes Rheumatoid Arthritis clinical onset
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE246421 | GEO | 2024/09/10
REPOSITORIES: GEO
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Project description:This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of Rheumatoid Arthritis (RA) patients, ‘individuals-at-risk’ of RA and healthy controls (HC). Flow-cytometric analysis demonstrated for the first time, the presence of a CD40-expressing CD206+CD163+ macrophage population dominating the inflamed RA synovium, associated with disease-activity and treatment response. RNAseq/metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory, and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses. scRNAseq profiling of 67908 RA and HC synovial-tissue cells identified nine transcriptionally distinct macrophage-clusters. IL- 1B+CCL20+ and SPP1+MT2A+ are the principal macrophage clusters in RA synovium, displaying heightened CD40 gene expression, capable of shaping stromal cell responses, and importantly are enriched pre-disease onset. Combined these findings identify the presence of an early pathogenic myeloid signature that shapes the RA joint microenvironment and represents a unique opportunity for early diagnosis and therapeutic intervention.
2024-09-25 | GSE246416 | GEO
Project description:Synovial biopsies were obtained from rheumatoid arthritis (RA) synovium and from subjects without a joint disease to find gene upregulated during RA. The promoters of genes upregulated during RA compared to HC can be used to obtain disease-regulated gene therapy.
2016-01-27 | GSE77298 | GEO
Project description:Objective: To study epigenetic patterns in T lymphocytes that accumulate in rheumatoid arthritis (RA) synovium, we characterized DNA methylation of CD3+ T cells in peripheral blood and synovial tissue in RA and osteoarthritis (OA) patients. Methods: Genomic DNA of CD3+ T cells was isolated from RA (n = 8) and OA (n = 5) patients from blood or synovium at the time of arthroplasty using antibodies and magnetic beads. Methylation was measured using Illumina Infinium MethylationEPIC Kit. Differentially methylated loci (DMLs) and genes (DMGs) were identified using Welch’s t-test. Principal component analysis (PCA), hierarchical clustering and pathway analysis were used to determine relationships among groups. Results: Comparing DNA methylation of CD3+ T cells between peripheral blood and synovial tissue within each disease, 4615 and 164 DMLs were identified in RA and OA samples respectively, resulting in 832 and 36 DMGs. PCA showed that methylation differences in T cells were greater based on location (blood vs. synovium) than based on disease (RA vs. OA). Differentially modified pathways were significantly enriched between RA blood and synovial T cells, especially in genes related to complement, integrin cell surface interactions and P53 pathway. The limited number of DMGs identified between OA blood and synovial T cells did not conform to biologic pathways. Conclusion: The patterns of DNA methylation in RA show location-specific differences related to immune pathways, while methylation differences in OA are limited. The RA joint-specific signatures could be due to selective accumulation of T cell populations or expansion of differentially marked adaptive immune cells. Understanding epigenetic patterns could provide clues to the types of T cells that accumulate in the RA joint and identify potential therapeutic targets.
2021-02-01 | GSE164468 | GEO
Project description:Treatment refractory Rheumatoid Arthritis (RA) is a major clinical challenge. Drug-free remission is uncommon but provides proof-of-concept that articular immune-homeostasis can be reinstated. In this project, we used single-cell RNA- to study the role of synovial tissue macrophages in maintaining disease remission. We have sequenced synovial tissue macrophages from individuals with healthy synovium (as evaluated by MRI), patients with undifferentiated arthritis (UPA), RA patients naïve to treatment, RA patients resistant to treatment and RA patients in disease remission
2020-04-18 | E-MTAB-8322 | biostudies-arrayexpress
Project description:Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic destructive arthritis. Although helper T cells are involved in the pathogenesis of RA, the characteristics of synovium-infiltrating CD4+ T cells are still largely unknown. In this study, we investigated synovium-infiltrating helper T cells of rheumatoid arthritis patients
2023-05-18 | GSE216245 | GEO
Project description:Synovial fibroblasts (SF) are the main mesenchymal cell type constitutive in human synovial tissue. SF contribute to the homeostasis of normal joints by synthesizing extracellular matrix components and secreting the specific components of synovial fluid. SF are essential players in RA pathophysiology, they are the primary source of IL6 in the RA synovium contributing to perpetuate the inflammation in the joint. We used microarrays analysis to characterize the effector pro-inflammatory response of SF to TNFα and IL6/sIL6R signaling.
2021-06-01 | GSE132830 | GEO
Project description:Gene expression microarray was applied to discover novel rheumatoid arthritis (RA)-specific gene expressions by comparing the expression profiles of synovial membranes from patients with RA, osteoarthritis (OA) and ankylosing spondylitis (AS). We performed a gene expression microarray analysis of RA synovial membranes and simultaneously compared the expression profile with the profiles of AS and OA synovial membranes.
2012-10-22 | GSE39340 | GEO
Project description:Macrophages from RA synovial fluids were compared to primary human monocyte-derived macrophages.
2017-08-10 | GSE97779 | GEO
Project description:The variant rs26232, in the first intron of the C5orf30 locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation implying a central function in these organisms. Here we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro and gene-profiling following C5orf30 inhibition confirmed upregulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, since inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a novel negative regulator of tissue damage in RA and this may act by modulating the autoaggressive phenotype that is characteristic of RASFs. Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that affects synovial joints. A key characteristic of RA is hyperplasia of fibroblast-like synoviocytes (FLS) which develop a stable, auto-aggressive phenotype that augments tissue destruction. It is unknown how this phenotype is stably maintained; however, epigenetic changes have been implicated. Histone deacetylation is one proposed method; a process controlled by histone deacetylases (HDACs). However, there have recently been reports publishing conflicting data regarding the expression of HDACs in RA synovium and FLS. The objective of this thesis is to determine the role of HDACs in regulating the auto-aggressive phenotype of RA through studies in FLS and in mice. Real time-quantitative PCR was used to assess the levels of HDAC1-11 in RA compared to osteoarthritis (OA) FLS. Immunohistochemistry and western blotting were used to assess protein expression of HDAC1 in RA and OA synovial tissue and FLS. HDAC1 was found to be overexpressed in RA compared to OA. HDAC1 was knocked down in RA FLS, then cell proliferation, migration and invasion were assessed by using tritiated thymidine, a scratch assay and a Matrigel invasion assay respectively. All three functions were significantly reduced following HDAC1 knockdown. An Illumina BeadChip (47,000 transcripts) was used to analyse global gene expression changes after knockdown. This revealed significant gene changes in important functional clusters, such as proliferation and migration. HDAC1 knockout is embryonic lethal in mice, so the in vivo role of HDAC1 was investigated in a mouse model of collagen-induced arthritis (CIA) using in vivo siRNAs. Clinical scores of CIA were measured daily and HDAC1 knockdown mice showed a significantly reduced clinical score compared to controls, comparable to dexamethasone-treated mice. The bones were analysed using a microCT scanner and histology. Knocking down HDAC1 showed reduced bone erosion, joint inflammation and cartilage degradation compared to controls. Overall, this study shows that HDAC1 is dysregulated in RA and it has a significant role in the autoaggressive phenotype shown in RA FLS and collagen-induced arthritis. The novel data shown in this thesis demonstrates that inhibiting HDAC1 may provide a powerful new target for treating RA. Three independent patient RASF samples were analysed in this study for each siRNA gene knockdown. Also a non targerting control siRNA was also used for each of the patient RASFs
2015-08-22 | E-GEOD-72258 | biostudies-arrayexpress
Project description:Gene expression microarray was applied to discover novel rheumatoid arthritis (RA)-specific gene expressions by comparing the expression profiles of synovial membranes from patients with RA, osteoarthritis (OA) and ankylosing spondylitis (AS). We performed a gene expression microarray analysis of RA synovial membranes and simultaneously compared the expression profile with the profiles of AS and OA synovial membranes. This study was undertaken to investigate the global gene expression profiles in synovial tissues from RA (n=10), OA (n=7), and AS patients (n=5). The Illumina HumanHT-12 v4 Expression BeadChip were used for a complete genome-wide transcript profiling.
2012-10-22 | E-GEOD-39340 | biostudies-arrayexpress