scholarly journals Circulating and Synovial Pentraxin-3 (PTX3) Expression Levels Correlate With Rheumatoid Arthritis Severity and Tissue Infiltration Independently of Conventional Treatments Response

2021 ◽  
Vol 12 ◽  
Author(s):  
Marie-Astrid Boutet ◽  
Alessandra Nerviani ◽  
Gloria Lliso-Ribera ◽  
Roberto Leone ◽  
Marina Sironi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Sequencing Analysis ◽  
Baseline Serum ◽  
Healthy Donors ◽  
Gene And Protein Expression ◽  
Lymphoid Structures

AimsTo determine the relationship between PTX3 systemic and synovial levels and the clinical features of rheumatoid arthritis (RA) in a cohort of early, treatment naïve patients and to explore the relevance of PTX3 expression in predicting response to conventional-synthetic (cs) Disease-Modifying-Anti-Rheumatic-Drugs (DMARDs) treatment.MethodsPTX3 expression was analyzed in 119 baseline serum samples from early naïve RA patients, 95 paired samples obtained 6-months following the initiation of cs-DMARDs treatment and 43 healthy donors. RNA-sequencing analysis and immunohistochemistry for PTX3 were performed on a subpopulation of 79 and 58 synovial samples, respectively, to assess PTX3 gene and protein expression. Immunofluorescence staining was performed to characterize PTX3 expressing cells within the synovium.ResultsCirculating levels of PTX3 were significantly higher in early RA compared to healthy donors and correlated with disease activity at baseline and with the degree of structural damages at 12-months. Six-months after commencing cs-DMARDs, a high level of PTX3, proportional to the baseline value, was still detectable in the serum of patients, regardless of their response status. RNA-seq analysis confirmed that synovial transcript levels of PTX3 correlated with disease activity and the presence of mediators of inflammation, tissue remodeling and bone destruction at baseline. PTX3 expression in the synovium was strongly linked to the degree of immune cell infiltration, the presence of ectopic lymphoid structures and seropositivity for autoantibodies. Accordingly, PTX3 was found to be expressed by numerous synovial cell types such as plasma cells, fibroblasts, vascular and lymphatic endothelial cells, macrophages, and neutrophils. The percentage of PTX3-positive synovial cells, although significantly reduced at 6-months post-treatment as a result of global decreased cellularity, was similar in cs-DMARDs responders and non-responders.ConclusionThis study demonstrates that, early in the disease and prior to treatment modification, the level of circulating PTX3 is a reliable marker of RA activity and predicts a high degree of structural damages at 12-months. In the joint, PTX3 associates with immune cell infiltration and the presence of ectopic lymphoid structures. High synovial and peripheral blood levels of PTX3 are associated with chronic inflammation characteristic of RA. Additional studies to determine the mechanistic link are required.

584 Therapeutic vascular normalization to promote tumor-associated tertiary lymphoid structures

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A619-A619
Author(s):  
Jessica Filderman ◽  
Manoj Chelvanambi ◽  
Walter Storkus
Keyword(s):  
Immune Cell ◽  
Tumor Vasculature ◽  
Cell Infiltration ◽  
Global Changes ◽  
Antiangiogenic Agents ◽  
Immune Cell Infiltration ◽  
Low Doses ◽  
Vascular Normalization ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

BackgroundTertiary lymphoid structures (TLS) are non-encapsulated immune cell aggregates that form at sites of chronic inflammation, including in and around tumors. Recent studies have shown that the presence of TLS in human tumors is an indicator of positive clinical outcome. However, due to dysregulated angiogenesis, many tumors have a poorly-organized and leaky vasculature that impedes entry of immune effector cells into tumors and consequently, TLS formation. It has been shown in pre-clinical studies that low doses of antiangiogenic agents normalize the tumor vasculature, leading us to hypothesize that treating tumors with low-doses (well below drug MTD) of vascular normalizing (VN) therapies will improve immune cell infiltration and TLS formation within the tumor microenvironment (TME).MethodsTo test this hypothesis, melanoma-bearing mice were treated intratumorally with VN agents. Five days post-treatment, tumors were digested into single cell suspensions and RNA was isolated and used for RT-PCR. Transcript levels of TLS-promoting factors (CCL19, CCL21, CXCL13) and markers of vascular normalization (HIF1A, GLUT1) and inflammation/immune cell infiltration (CXCL10, VCAM1, CD8A) were measured and compared to PBS treated controls. Changes in tumor vasculature were evaluated using immunofluorescence microscopy (IFM) of tumor sections stained with CD31, PNAd, and PDGFRβ. Fluorescently-labeled lectin was injected into the mice to observe tumor perfusion. TLS formation was evaluated in tumor sections using IFM, with TLS being defined as PNAd+ vessels surrounded by clusters of CD45+ cells.ResultsWe observed that the VN agents dasatinib, STING agonist, bevacizumab, and agonist anti-TNFR1 antibody each induced global changes in the TME that are consistent with enhanced immune cell infiltration and TLS formation. These changes include increases in expression of CCL19, CCL21, and VCAM1. Dasatinib and STING agonists were shown to promote VN, as demonstrated by improved lectin perfusion into the tumor and increased pericyte coverage of blood vessels on-treatment.ConclusionsVN agents induce global changes in immune cell infiltration and TLS-promoting factors in the TME. In vivo, these agents induce VN in the TME and promote TLS formation. This knowledge can be used to develop optimal combination immunotherapy designs in the cancer setting.

scholarly journals Identification of Disease-Specific Hub Biomarkers and Immune Infiltration in Osteoarthritis and Rheumatoid Arthritis Synovial Tissues by Bioinformatics Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Fei Sun ◽  
Jian lin Zhou ◽  
Pu ji Peng ◽  
Chen Qiu ◽  
Jia rui Cao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Cells ◽  
Bioinformatics Analysis ◽  
Immune Cell ◽  
Relative Proportion ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Hub Genes ◽  
Synovial Tissues ◽  
Disease Specific

Background. Osteoarthritis (OA) and rheumatoid arthritis (RA) are well-known cause of joint disability. Although they have shown the analogous clinical features involving chronic synovitis that progresses to cartilage and bone destruction, the pathogenesis that initiates and perpetuates synovial lesions between RA and OA remains elusive. Objective. This study is aimed at identifying disease-specific hub genes, exploring immune cell infiltration, and elucidating the underlying mechanisms associated with RA and OA synovial lesion. Methods. Gene expression profiles (GSE55235, GSE55457, GSE55584, and GSE12021) were selected from Gene Expression Omnibus for analysis. Differentially expressed genes (DEGs) were identified by the “LIMMA” package in Bioconductor. The DEGs were identified by Gene Ontology (GO) and KEGG pathway analysis. A protein-protein interaction network was constructed to identify candidate hub genes by using STRING and Cytoscape. Hub genes were identified by validating from GSE12021. Furthermore, we employed the CIBERSORT website to assess immune cell infiltration between OA and RA. Finally, we explored the correlation between the levels of hub genes and relative proportion of immune cells in OA and RA. Results. We identified 68 DEGs which were mainly enriched in immune response and chemokine signaling pathway. Six hub genes with a cutoff of AUC > 0.80 by ROC analysis and relative expression of P < 0.05 were identified successfully. Compared with OA, the RA synovial tissues consisted of a higher proportion of 7 immune cells, whereas 4 immune cells were found in relatively lower proportion ( P < 0.05 ). In addition, the levels of 6 hub genes were closely associated with relative proportion of 11 immune cells in OA and RA. Conclusions. We used bioinformatics analysis to identify hub genes and explored immune cell infiltration of immune microenvironment in synovial tissues. Our results should offer insights into the underlying molecular mechanisms of synovial lesion and provide potential target for immune-based therapies of OA and RA.

scholarly journals Identification of Diagnostic Signatures and Immune Cell Infiltration Characteristics in Rheumatoid Arthritis by Integrating Bioinformatic Analysis and Machine-Learning Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Rongguo Yu ◽  
Jiayu Zhang ◽  
Youguang Zhuo ◽  
Xu Hong ◽  
Jie Ye ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Machine Learning ◽  
Nk Cells ◽  
Learning Strategies ◽  
Immune Cells ◽  
Immune Cell ◽  
Bioinformatic Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Qrt Pcr

BackgroundRheumatoid arthritis (RA) refers to an autoimmune rheumatic disease that imposes a huge burden on patients and society. Early RA diagnosis is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively. In the present study, the aim was at examining RA’s diagnostic signatures and the effect of immune cell infiltration in this pathology.MethodsGene Expression Omnibus (GEO) database provided three datasets of gene expressions. Firstly, this study adopted R software for identifying differentially expressed genes (DEGs) and conducting functional correlation analyses. Subsequently, we integrated bioinformatic analysis and machine-learning strategies for screening and determining RA’s diagnostic signatures and further verify by qRT-PCR. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. Moreover, this study employed cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) website for assessing the inflammatory state of RA, and an investigation was conducted on the relationship of diagnostic signatures and infiltrating immune cells.ResultsOn the whole, 54 robust DEGs received the recognition. Lymphocyte-specific protein 1 (LSP1), Granulysin (GNLY), and Mesenchymal homobox 2 (MEOX2) (AUC = 0.955) were regarded as RA’s diagnostic markers and showed their statistically significant difference by qRT-PCR. As indicated from the immune cell infiltration analysis, resting NK cells, neutrophils, activated NK cells, T cells CD8, memory B cells, and M0 macrophages may be involved in the development of RA. Additionally, all diagnostic signatures might be different degrees of correlation with immune cells.ConclusionsIn conclusion, LSP1, GNLY, and MEOX2 are likely to be available in terms of diagnosing and treating RA, and the infiltration of immune cells mentioned above may critically impact RA development and occurrence.

scholarly journals OP0011 INTEGRATION OF FLOW AND DIGITAL CYTOMETRY IN EARLY TREATMENT-NAÏVE RHEUMATOID ARTHRITIS IDENTIFIES DISTINCT IMMUNOPHENOTYPES IN PERIPHERAL BLOOD AND DISEASE TISSUE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 7.2-7
Author(s):  
F. Rivellese ◽  
E. Pontarini ◽  
L. Fossati-Jimack ◽  
R. A. Moura ◽  
V. C Romão ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Activity ◽  
Clinical Outcomes ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Blood Samples ◽  
Value Decomposition ◽  
Relationship Of

Background:The study of synovial tissue in patients with Rheumatoid Arthritis (RA) has led to the identification of synovial patterns of immune cell infiltration and specific cellular subsets associated that have been disease activity and clinical outcomes(1–3). However, the relationship of circulating and synovial immune cell sub-sets with histopathological features and clinical outcomes remains to be defined.Objectives:To assess the relationship of peripheral blood and synovial immune cells with RA histopathology and clinical outcomes, by performing flow and digital cytometry in matched peripheral blood and synovial samples from patients with early RA.Methods:70 patients with early (<12 months) untreated RA (2010 criteria) recruited in the pathobiology of early Arthritis Cohort (PEAC) at the Barts Health NHS Trust were included(1). Peripheral blood mononuclear cells (n=70) were analysed by flow cytometry. Matched synovial tissues (n=70) obtained by minimally invasive ultrasound-guided synovial biopsy underwent semi-quantitative scoring (0-4) of immune cell infiltration and classification into lympho-myeloid (LM), diffuse-myeloid (DM) and pauci-immune (PI) pathotypes, as previously described(1). 49 synovial and 36 matched peripheral blood samples underwent RNA-sequencing and were analysed by digital cytometry (Xcell) (4) and Singular Value Decomposition (SVD).Results:Circulating B cells and their subsets showed significant inverse correlations with inflammatory markers (ESR, CRP), disease activity (swollen joints, four components and two components(5) DAS28) and ultrasound scores (Fig 1A). Among T cell subsets, CXCR5-PD1hiICOS+CD4+ T cells (T peripheral helper cells, Tph) had strong positive correlations with inflammatory markers (ESR and CRP), disease activity (DAS28) and ultrasound scores (Fig 1B). Tph in the peripheral blood also correlated with immune cell infiltration in synovia (Fig 1C) and were significantly higher in patients with a LM pathotype (Fig 1D). Accordingly, circulating Tph were associated with synovial LM pathotype independently of clinical features such as DAS28, ACPA positivity, Body Mass Index (BMI) and age (AUC 0.821). By applying digital cytometry in matched synovial and peripheral blood samples, synovial B and T cells were significantly higher in patients with a LM pathotype, in line with the histological definition of the LM pathotype – rich in B and T cells. On the contrary, circulating B cells and total CD4 and CD8 T cells were significantly lower in patients with a synovial LM pathotype (Fig 1E). The Tph signature in synovia derived by Singular Value Decomposition (SVD) correlated with baseline ESR (R 0.38, p<0.0001) and DAS28 (R 0.35, p <0.0001) and with delta-DAS28 after 6 months of treatment with conventional synthetic DMARDs (R 0.27, p 0.026). Finally, the baseline synovial Tph signature was significantly higher in patients who progressed to the use of biologics and was predictive of future biologic DMARDs use, independently of baseline DAS28, ACPA positivity, BMI and age (AUC 0.703).Conclusion:By combining conventional flow cytometry in the peripheral blood and digital cytometry on matched synovial and peripheral blood samples, we highlight diverging associations of circulating immune cell subsets with synovial inflammation and pathotypes. Tph cells, in particular, emerge as predictors of lympho-myeloid synovial inflammation and disease progression.References:[1]F. Humby et al., Ann. Rheum. Dis. 78, 761–772 (2019), doi:10.1136/annrheumdis-2018-214539. [2]M. J. Lewis et al., Cell Rep. 28, 2455-2470.e5 (2019), doi:10.1016/j.celrep.2019.07.091.[3]D. a Rao et al., Nat. Publ. Gr. 542, 110–114 (2017), doi:10.1038/nature20810.[4]D. Aran et al., Genome Biol. 18, 220 (2017), doi:10.1186/s13059-017-1349-1.[5]E. M. A. Hensor et al., Rheumatology. 58, 1400–1409 (2019), doi:10.1093/rheumatology/kez049.Figure 1.Acknowledgements:The Pathobiology of Early Arthritis Cohort (PEAC) was supported by the MRC (grant 36661). Versus Arthritis provided funding infrastructure support (grant 20022). F. Rivellese is funded by an NIHR Transitional Research Fellowship (TRF-2018-11-ST2-002). We would like to thank the patients and the clinical and laboratory team (core team) at Queen Mary University of London.Disclosure of Interests:None declared

scholarly journals AB0111 THE COMPARISON OF SYNDECAN-4 LEVEL IN SERA, SYNOVIAL FLUID AND SYNOVIUM OF RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1356.1-1356
Author(s):  
J. Zhao ◽  
X. Ye ◽  
Z. Zhang
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Synovial Fluid ◽  
Disease Activity ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Heparan Sulphate ◽  
Healthy Controls ◽  
Baseline Serum

Background:Syndecan-4, one of the members of heparan sulphate proteoglycans (HSPGs), has been shown to be involved in regulating inflammatory responses, angiogenesis, and cell migration. Its role has been proved in animal arthritis models, however not clearly elucidated in rheumatoid arthritis (RA) patientsObjectives:To investigate the role of Syndecan-4 in the pathogenesis of RA, by detecting Syndecan-4 expression in the serum, synovial fluid and synovium of RA patients and comparing with osteoarthritis (OA) patientsMethods:The concentrations of syndecan-4 in sera and synovial fluid of RA and osteoarthritis (OA) patients were detected by ELISA. The expression of syndecan-4 in synovium of RA and OA patients was detected by immunohistochemistry. In another cohort of 60 RA patients, the association analysis was performed. All the RA patients were with disease duration more than 6 months and with DAS28-CRP>3.2 although after csDMARDs (including MTX and/or leflunomide) treatment for more than 3 months. The RA patients were treated with tumour necrosis factor α (TNFα) inhibitor (TNFi) and MTX 10mg per week for 12 weeks. The correlations between sera Syndecan-4 and disease activity of RA as well as therapeutic response to TNFi were analyzed.Results:The serum Syndedcan-4 level of RA patients [637.1 (483.6-1069.6) pg/mL] was significantly higher than that of OA patients [345.0 (287.9-421.1) pg/mL] and healthy controls [195.6 (165.0-225.2) pg/mL](P<0.001, P<0.001, respectively). The serum concentration of Syndecan-4 is also higher in OA patients than that in healthy controls (P<0.001). It was also higher in RF-positive RA patients than in RF-negative ones [603.0 (100.0-8879.1) pg/mL vs 460.3 (178.7-2468.9) pg/mL, (p=0.026)]. The Syndedcan-4 level in synovial fluid and synovia were comparable between RA and OA patients. No correlation was found between serum Syndedcan-4 and disease activity of RA. TNFi treatment did not change the serum Syndecan-4 level significantly. The baseline serum Syndecan-4 did not show predictive value for TNFi response.Conclusion:Syndecan-4 can be expressed in the synovia of RA and OA patients. The serum Syndecan-4 is higher in RA patients than in OA patients and healthy controls, and significantly higher in sero-positive RA patients than in sero-negative ones. Syndecan-4 may participate in the pathogenesis of RA.References:[1]Leonova EI, Galzitskaya OV. Role of Syndecans in Lipid Metabolism and Human Diseases. Adv Exp Med Biol, 2015, 855: 241-58.[2]Xie J, Wang J, Li R, Dai Q, Yong Y, Zong B, et al. Syndecan-4 over-expression preserves cardiac function in a rat model of myocardial infarction. J Mol Cell Cardiol 2012; 53: 250-8.[3]Strand ME, Aronsen JM, Braathen B, Sjaastad I, Kvaløy H, Tønnessen T, et al. Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice. J Mol Cell Cardiol. 2015;88:133-44.[4]Endo T, Ito K, Morimoto J, Kanayama M, Ota D, Ikesue M, et al. Syndecan 4 Regulation of the Development of Autoimmune Arthritis in Mice by Modulating B Cell Migration and Germinal Center Formation. Arthritis Rheumatol. 2015; 67:2512-22.Disclosure of Interests:None declared

Metabolites as drivers and targets in Rheumatoid Arthritis

2021 ◽  
Author(s):  
Megan M Hanlon ◽  
Mary Canavan ◽  
Brianne E Barker ◽  
Ursula Fearon
Keyword(s):  
Rheumatoid Arthritis ◽  
Energy Demand ◽  
Functional Disability ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Synovial Cells ◽  
Inflammatory Phenotype ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

Abstract Rheumatoid Arthritis is a chronic autoimmune disease characterised by neovascularisation, immune cell infiltration and synovial hyperplasia, which leads to degradation of articular cartilage and bone, and subsequent functional disability. Dysregulated angiogenesis, synovial hypoxia and immune cell infiltration results in a ‘bioenergetic crisis’ in the inflamed joint which further exacerbates synovial invasiveness. Several studies have examined this vicious cycle between metabolism, immunity and inflammation and the role metabolites play in these interactions. To add to this complexity the inflamed synovium is a multicellular tissue with many cellular subsets having different metabolic requirements. Metabolites can shape the inflammatory phenotype of immune cell subsets during disease and act as central signaling hubs. In the RA joint the increased energy demand of stromal and immune cells leads to the accumulation of metabolites such as lactate, citrate, and succinate as well as adipocytokines which can regulate downstream signalling pathways. Transcription factors such as HIF1ɑ and mTOR can act as metabolic sensors to activate synovial cells and drive pro-inflammatory effector function, thus perpetuating chronic inflammation further. These metabolic intermediates may be potential therapeutic targets and so understanding the complex interplay between metabolites and synovial cells in RA may allow for identification of novel therapeutic strategies but also may provide significant insight into the underlying mechanisms of disease pathogenesis.

scholarly journals Immune Cell Infiltration and Tertiary Lymphoid Structures as Determinants of Antitumor Immunity

2018 ◽  
Vol 200 (2) ◽  
pp. 432-442 ◽  
Author(s):  
Victor H. Engelhard ◽  
Anthony B. Rodriguez ◽  
Ileana S. Mauldin ◽  
Amber N. Woods ◽  
J. David Peske ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Tertiary Lymphoid Structures ◽  
Lymphoid Structures

scholarly journals Local Injection of Submicron Particle Docetaxel is Associated with Tumor Eradication, Reduced Systemic Toxicity and an Immunologic Response in Uro-Oncologic Xenografts

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 577 ◽  
Author(s):  
Holly A. Maulhardt ◽  
Lauren Hylle ◽  
Michael V. Frost ◽  
Ashley Tornio ◽  
Sara Dafoe ◽  
...  
Keyword(s):  
Tumor Volume ◽  
Immune Cell ◽  
Transitional Cell ◽  
Clinical Signs ◽  
Tumor Burden ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Submicron Particle ◽  
Cell Renal Carcinoma ◽  
Lymphoid Structures

Intratumoral (IT) administration of submicron particle docetaxel (NanoDoce®, NanOlogy LLC, Fort Worth, TX, USA) and its efficacy against genitourinary-oncologic xenografts in rats and mice, xenograft-site docetaxel concentrations and immune-cell infiltration were studied. IT-NanoDoce®, IV-docetaxel and IT-vehicle were administered to clear cell renal carcinoma (786-O: rats), transitional cell bladder carcinoma (UM-UC-3: mice) and prostate carcinoma (PC-3: mice). Treatments were given every 7 days with 1, 2, or 3 doses administered. Animals were followed for tumor growth and clinical signs. At necropsy, 786-O and UM-UC-3 tumor-site tissues were evaluated by H&E and IHC and analyzed by LC-MS/MS for docetaxel concentration. Two and 3 cycles of IT-NanoDoce® significantly reduced UM-UC-3 tumor volume (p < 0.01) and eliminated most UM-UC-3 and 786-O tumors. In both models, NanoDoce® treatment was associated with (peri)tumor-infiltrating immune cells. Lymphoid structures were observed in IT-NanoDoce®-treated UM-UC-3 animals adjacent to tumor sites. IT-vehicle and IV-docetaxel exhibited limited immune-cell infiltration. In both studies, high levels of docetaxel were detected in NanoDoce®-treated animals up to 50 days post-treatment. In the PC-3 study, IT-NanoDoce® and IV-docetaxel resulted in similar tumor reduction. NanoDoce® significantly reduced tumor volume compared to IT-vehicle in all xenografts (p < 0.0001). We hypothesize that local, persistent, therapeutic levels of docetaxel from IT-NanoDoce® reduces tumor burden while increasing immune-cell infiltration. IT NanoDoce® treatment of prostate, renal and bladder cancer may result in enhanced tumoricidal effects.

scholarly journals Identifying Immune Cell Infiltration and Effective Diagnostic Biomarkers in Rheumatoid Arthritis by Bioinformatics Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Sheng Zhou ◽  
Hongcheng Lu ◽  
Min Xiong
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Immune Cells ◽  
Cd4 T Cells ◽  
Bioinformatics Analysis ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
M1 Macrophages ◽  
Tfh Cells

BackgroundRheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by inflammatory cell infiltration, leading to persistent synovitis and joint destruction. The pathogenesis of RA remains unclear. This study aims to explore the immune molecular mechanism of RA through bioinformatics analysis.MethodsFive microarray datasets and a high throughput sequencing dataset were downloaded. CIBERSORT algorithm was performed to evaluate immune cell infiltration in synovial tissues between RA and healthy control (HC). Wilcoxon test and Least Absolute Shrinkage and Selection Operator (LASSO) regression were conducted to identify the significantly different infiltrates of immune cells. Differentially expressed genes (DEGs) were screened by “Batch correction” and “RobustRankAggreg” methods. Functional correlation of DEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Candidate biomarkers were identified by cytoHubba of Cytoscape, and their diagnostic effectiveness was predicted by Receiver Operator Characteristic Curve (ROC) analysis. The association of the identified biomarkers with infiltrating immune cells was explored using Spearman’s rank correlation analysis in R software.ResultsTen significantly different types of immune cells between RA and HC were identified. A total of 202 DEGs were obtained by intersection of DEGs screened by two methods. The function of DEGs were significantly associated with immune cells. Five hub genes (CXCR4, CCL5, CD8A, CD247, and GZMA) were screened by R package “UpSet”. CCL5+CXCR4 and GZMA+CD8A were verified to have the capability to diagnose RA and early RA with the most excellent specificity and sensitivity, respectively. The correlation between immune cells and biomarkers showed that CCL5 was positively correlated with M1 macrophages, CXCR4 was positively correlated with memory activated CD4+ T cells and follicular helper T (Tfh) cells, and GZMA was positively correlated with Tfh cells.ConclusionsCCL5, CXCR4, GZMA, and CD8A can be used as diagnostic biomarker for RA. GZMA-Tfh cells, CCL5-M1 macrophages, and CXCR4- memory activated CD4+ T cells/Tfh cells may participate in the occurrence and development of RA, especially GZMA-Tfh cells for the early pathogenesis of RA.

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