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Arthritis & Rheumatology (Hoboken, N.J.) Dec 2023Recent advances in single-cell RNA sequencing technology have improved our understanding of the immunological landscape of rheumatoid arthritis (RA). We aimed to...
OBJECTIVE
Recent advances in single-cell RNA sequencing technology have improved our understanding of the immunological landscape of rheumatoid arthritis (RA). We aimed to stratify the synovium from East Asian patients with RA by immune cell compositions and gain insight into the inflammatory drivers of each synovial phenotype.
METHODS
Synovial tissues were obtained from East Asian patients in Japan with RA (n = 41) undergoing articular surgery. The cellular composition was quantified by a deconvolution approach using a public single-cell-based reference. Inflammatory pathway activity was calculated by gene set variation analysis, and chromatin accessibility was evaluated using assay of transposase accessible chromatin-sequencing.
RESULTS
We stratified RA synovium into three distinct subtypes based on the hierarchical clustering of cellular composition data. One subtype was characterized by abundant HLA-DRA synovial fibroblasts, autoimmune-associated B cells, GZMK GZMB CD8 T cells, interleukin (IL)1-β monocytes, and plasmablasts. In addition, tumor necrosis factor (TNF)-α, interferons (IFNs), and IL-6 signaling were highly activated in this subtype, and the expression of various chemokines was significantly enhanced. Moreover, we found an open chromatin region overlapping with RA risk locus rs9405192 near the IRF4 gene, suggesting the genetic background influences the development of this inflammatory synovial state. The other two subtypes were characterized by increased IFNs and IL-6 signaling, and expression of molecules associated with degeneration, respectively.
CONCLUSION
This study adds insights into the synovial heterogeneity in East Asian patients and shows a promising link with predominant inflammatory signals. Evaluating the site of inflammation has the potential to lead to appropriate drug selection that matches the individual pathology.
Topics: Humans; Interleukin-6; CD8-Positive T-Lymphocytes; East Asian People; Synovial Membrane; Arthritis, Rheumatoid; Tumor Necrosis Factor-alpha; Interferons; Chromatin
PubMed: 37390361
DOI: 10.1002/art.42642 -
Osteoarthritis and Cartilage Oct 2023We have previously identified a granulocyte macrophage-colony stimulating factor (GM-CSF)/C-C motif ligand 17 (CCL17) pathway in monocytes/macrophages, in which GM-CSF...
OBJECTIVES
We have previously identified a granulocyte macrophage-colony stimulating factor (GM-CSF)/C-C motif ligand 17 (CCL17) pathway in monocytes/macrophages, in which GM-CSF regulates the formation of CCL17, and it is important for an experimental osteoarthritis (OA) model. We explore here additional OA models, including in the presence of obesity, such as a requirement for this pathway.
DESIGN
The roles of GM-CSF, CCL17, CCR4, and CCL22 in various experimental OA models, including those incorporating obesity (eight-week high-fat diet), were investigated using gene-deficient male mice. Pain-like behavior and arthritis were assessed by relative static weight distribution and histology, respectively. Cell populations (flow cytometry) and cytokine messenger RNA (mRNA) expression (qPCR) in knee infrapatellar fat pad were analyzed. Human OA sera were collected for circulating CCL17 levels (ELISA) and OA knee synovial tissue for gene expression (qPCR).
RESULTS
We present evidence that: i) GM-CSF, CCL17, and CCR4, but not CCL22, are required for the development of pain-like behavior and optimal disease in three experimental OA models, as well as for exacerbated OA development due to obesity, ii) obesity alone leads to spontaneous knee joint damage in a GM-CSF- and CCL17-dependent manner, and iii) in knee OA patients, early indications are that BMI correlates with a lower Oxford Knee Score (r = -0.458 and p = 0.0096), with elevated circulating CCL17 levels (r = 0.2108 and p = 0.0153) and with elevated GM-CSF and CCL17 gene expression in OA synovial tissue.
CONCLUSIONS
The above findings indicate that GM-CSF, CCL17, and CCR4 are involved in obesity-associated OA development, broadening their potential as targets for possible treatments for OA.
Topics: Humans; Male; Animals; Mice; Granulocyte-Macrophage Colony-Stimulating Factor; Cytokines; Pain; Osteoarthritis, Knee; Synovial Membrane; Chemokine CCL17
PubMed: 37225052
DOI: 10.1016/j.joca.2023.05.008 -
Clinical Immunology (Orlando, Fla.) Dec 2023Synovial fluid (SF) extracellular vesicles (EVs) play a pathogenic role in osteoarthritis (OA). However, the surface markers, cell and tissue origins, and effectors of...
Synovial fluid (SF) extracellular vesicles (EVs) play a pathogenic role in osteoarthritis (OA). However, the surface markers, cell and tissue origins, and effectors of these EVs are largely unknown. We found that SF EVs contained 692 peptides that were positively associated with knee radiographic OA severity; 57.4% of these pathogenic peptides were from 46 proteins of the immune system, predominantly the innate immune system. CSPG4, BGN, NRP1, and CD109 are the major surface markers of pathogenic SF EVs. Genes encoding surface marker CSPG4 and CD109 were highly expressed by chondrocytes from damaged cartilage, while VISG4, MARCO, CD163 and NRP1 were enriched in the synovial immune cells. The frequency of CSPG4 and VSIG4 EV subpopulations in OA SF was high. We conclude that pathogenic SF EVs carry knee OA severity-associated proteins and specific surface markers, which could be developed as a new source of diagnostic biomarkers or therapeutic targets in OA.
Topics: Humans; Osteoarthritis, Knee; Synovial Fluid; Biomarkers; Peptides; Extracellular Vesicles
PubMed: 37866785
DOI: 10.1016/j.clim.2023.109812 -
Diagnostics (Basel, Switzerland) Nov 2023Adhesive capsulitis is an idiopathic and disabling disorder characterized by intense shoulder pain and progressive limitation of active and passive glenohumeral joint... (Review)
Review
Adhesive capsulitis is an idiopathic and disabling disorder characterized by intense shoulder pain and progressive limitation of active and passive glenohumeral joint range of motion. Although adhesive capsulitis has been traditionally considered a diagnosis of exclusion that can be established based on a suggestive medical history and the detection of supporting findings at the physical exam, imaging studies are commonly requested to confirm the diagnostic suspicion and to exclude other causes of shoulder pain. Indeed, clinical findings may be rather unspecific, and may overlap with diseases like calcific tendinitis, rotator cuff pathology, acromioclavicular or glenohumeral arthropathy, autoimmune disorders, and subacromial/subdeltoid bursitis. Magnetic resonance imaging, magnetic resonance arthrography, and high-resolution ultrasound have shown high sensitivity and accuracy in diagnosing adhesive capsulitis through the demonstration of specific pathological findings, including thickening of the joint capsule and of the coracohumeral ligament, fibrosis of the subcoracoid fat triangle, and extravasation of gadolinium outside the joint recesses. This narrative review provides an updated analysis of the current concepts on the role of imaging modalities in patients with adhesive capsulitis, with the final aim of proposing an evidence-based imaging protocol for the radiological evaluation of this condition.
PubMed: 37998547
DOI: 10.3390/diagnostics13223410 -
Clinical and Experimental Rheumatology Mar 2024Mast cells (MC) are tissue duelling cells playing an active role in both innate and adaptive immune system. They act as first players in different microbial infections... (Review)
Review
Mast cells (MC) are tissue duelling cells playing an active role in both innate and adaptive immune system. They act as first players in different microbial infections and exert a crucial role in allergy, chronic inflammation, fibrosis, and rheumatic diseases (RD), including rheumatoid arthritis (RA). MC are normally present in human synovia and they increase in the joints of RA patients, contributing to inflammatory and remodelling processes. Due to their great plasticity and multifunctionality, MC exert a wide range of roles in different stages of the disease. To date, the results obtained by in-vitro and in-vivo studies have contributed to better clarify the dynamic role of MC in local arthritis of RA and have improved our knowledge on different aspect of the disease. Although different mice models have been extensively used to investigate the contribution of MC in different stages of RA, those models often fail to reproduce the complexity and the heterogeneity of the human disease. Here, we provide an overview on different roles of MC in RA pathogenesis and how these cells might influence some clinical features of the disease.
Topics: Humans; Mice; Animals; Mast Cells; Arthritis, Rheumatoid; Inflammation; Synovial Fluid
PubMed: 37706304
DOI: 10.55563/clinexprheumatol/eontou -
Immunology Letters Nov 2023Synovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid...
BACKGROUND
Synovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid arthritis. However, little is known about the interactions among different cell subtypes and the specific sets of signaling pathways and activities that they trigger.
METHODS
Using social network analysis, pattern recognition, and manifold learning approaches, we identified patterns of single-cell communication in OA (osteoarthritis) and RA (rheumatoid arthritis).
RESULTS
Our results suggest that OA and RA have distinct cellular communication patterns and signaling pathways. The LAMININ (Laminin) and COLLAGEN (Collagen) pathways predominate in osteoarthritis, while the EGF (Epidermal growth factor), NT (Neurotrophin) and CDH5 (Cadherin 5) pathways predominate in rheumatoid arthritis, with a central role for THY1 (Thy-1 cell surface antigen) CDH11 (Cadherin 11) cells. The OA opens the PDGF (Platelet-derived growth factors) pathway (driver of bone angiogenesis), the RA opens the EGF pathway (bone formation) and the SEMA3 (Semaphorin 3A) pathway (involved in immune regulation). Interestingly, we found that OA no longer has cell types involved in the MHC complex (Major histocompatibility complex) and their activity, whereas the MHC complex functions primarily in RA in the presentation of inflammatory antigens, and that the complement system in OA has the potential to displace the function of the MHC complex. The specific signaling patterns of THY1CDH11 cells and their secreted ligand receptors are more conducive to cell migration and lay the foundation for promoting osteoclastogenesis. This subpopulation may also be involved in the accumulation of lymphocytes, affecting the recruitment of immune cells. Members of the collagen family (COL1A1 (Collagen Type I Alpha 1 Chain), COL6A2 (Collagen Type VI Alpha 2 Chain) and COL6A1 (Collagen Type VI Alpha 1 Chain)) and transforming growth factor (TGFB3) maintain the extracellular matrix in osteoarthritis and mediate cell migration and adhesion in rheumatoid arthritis, including the PTN (Pleiotrophin) / THBS1 (Thrombospondin 1) interaction.
CONCLUSION
Increased understanding of the interaction networks between synovial fibroblast subtypes, particularly the shared and unique cellular communication features between osteoarthritis and rheumatoid arthritis and their hub cells, should help inform the design of therapeutic agents for inflammatory joint disease.
Topics: Humans; Synovial Membrane; Epidermal Growth Factor; Laminin; Collagen Type VI; Arthritis, Rheumatoid; Osteoarthritis; Cell Communication; Fibroblasts; Communication
PubMed: 37704178
DOI: 10.1016/j.imlet.2023.09.005 -
Annals of the Rheumatic Diseases Dec 2023Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven...
OBJECTIVES
Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups.
METHODS
RNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections.
RESULTS
PCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers.
CONCLUSION
In this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.
Topics: Humans; Transcriptome; Synovitis; Arthritis, Rheumatoid; Synovial Membrane; Inflammation
PubMed: 37507201
DOI: 10.1136/ard-2023-224068 -
Nature Communications Feb 2024Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are...
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKCD48 macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.
Topics: Humans; c-Mer Tyrosine Kinase; Bursitis; Inflammation; Synovial Membrane; Fibrosis
PubMed: 38374174
DOI: 10.1038/s41467-024-45341-9 -
Journal of Orthopaedic Research :... Jan 2024Periprosthetic joint infection (PJI) is a major complication of total joint arthroplasty. Even with current treatments, failure rates are unacceptably high with a 5-year... (Review)
Review
Periprosthetic joint infection (PJI) is a major complication of total joint arthroplasty. Even with current treatments, failure rates are unacceptably high with a 5-year mortality rate of 26%. Majority of the literature in the field has focused on development of better biomarkers for diagnostics and treatment strategies including innovate antibiotic delivery systems, antibiofilm agents, and bacteriophages. Nevertheless, the role of the immune system, our first line of defense during PJI, is not well understood. Evidence of infection in PJI patients is found within circulation, synovial fluid, and tissue and include numerous cytokines, metabolites, antimicrobial peptides, and soluble receptors that are part of the PJI diagnosis workup. Macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs) are initially recruited into the joint by chemokines and cytokines produced by immune cells and bacteria and are activated by pathogen-associated molecular patterns. While these cells are efficient killers of planktonic bacteria by phagocytosis, opsonization, degranulation, and recruitment of adaptive immune cells, biofilm-associated bacteria are troublesome. Biofilm is not only a physical barrier for the immune system but also elicits effector functions. Additionally, bacteria have developed mechanisms to evade the immune system by inactivating effector molecules, promoting killing or anti-inflammatory effector cell phenotypes, and intracellular persistence and dissemination. Understanding these shortcomings and the mechanisms by which bacteria can subvert the immune system may open new approaches to better prepare our own immune system to combat PJI. Furthermore, preoperative immune system assessment and screening for dysregulation may aid in developing preventative interventions to decrease PJI incidence.
Topics: Humans; Prosthesis-Related Infections; Anti-Bacterial Agents; Biofilms; Arthritis, Infectious; Biomarkers; Cytokines; Bacteria; Synovial Fluid
PubMed: 37874328
DOI: 10.1002/jor.25723 -
JSES International May 2024Because of the proximity of several ligaments, aponeuroses, and capsule in the limited area of the elbow joint, the precise anatomy is difficult to understand. In the... (Review)
Review
BACKGROUND
Because of the proximity of several ligaments, aponeuroses, and capsule in the limited area of the elbow joint, the precise anatomy is difficult to understand. In the current narrative review, we focused on two anatomical perspectives: the capsular attachment and structures consisting of ligaments.
METHODS
Based on the previously performed studies regarding the elbow anatomy, a narrative review was prepared in terms of the capsular attachment and structures consisting of ligaments.
RESULTS
At the tip of the coronoid process, the joint capsule attaches roughly 6 mm distal to its tip with 6-12 mm length. On the lateral epicondyle of the humerus, the capsular attachment at the anterior part of the extensor carpi radialis brevis origin is narrower than the one distal to it. A single interpretation of the lateral collateral ligament is the capsulo-aponeurotic membrane, which is composed of the joint capsule intermingling with the supinator aponeurosis. The anterior bundle of the ulnar collateral ligament could be interpreted as the grossly separated collagenous structure from the tendinous complex, which is composed of the tendinous septum between the flexor digitorum superficialis and pronator teres muscle, the medial part of the brachialis muscle, and deep aponeurosis of the flexor digitorum superficialis muscle.
DISCUSSION
Based on these perspectives, ligaments could function as a "static-dynamic" stabilizer rather than a simple static one.
PubMed: 38707559
DOI: 10.1016/j.jseint.2024.01.006