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Bulk and single cell transcriptomic data indicate that a dichotomy between inflammatory pathways in peripheral blood and arthritic joints complicates biomarker discovery
Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Yonsei Univ, South Korea.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Biomedical and Clinical Sciences, Division of Children's and Women's Health. Linköping University, Faculty of Medicine and Health Sciences.
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2020 (English)In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 127, article id 154960Article in journal (Refereed) Published
Abstract [en]

Background: Unbiased studies using different genome-wide methods have identified several novel biomarkers for diagnosis and treatment response in Rheumatoid Arthritis (RA). However, clinical translation has proven difficult. Here, we hypothesized that one reason could be that inflammatory responses in peripheral blood are different from those in the arthritic joint. Methods: We performed meta-analysis of gene expression microarray data from synovium, whole blood cells (WBC), peripheral blood mononuclear cells (PBMC), and CD4+ T cells from patients with RA and healthy controls in order to identify overlapping pathways, upstream regulators and potential biomarkers. We also analyzed single cell RNA-sequencing (scRNA-seq) data from peripheral blood and whole joints from a mouse model of antigen-induced arthritis. Results: Analyses of two profiling data sets from synovium from RA patients and healthy controls all showed significant activation of pathways with known pathogenic relevance, such as the Th1 pathway, the role of NFAT in regulation of the immune response, dendritic cell maturation, iCOS-iCOSL signaling in T helper cells, Fc gamma receptor-mediated phagocytosis, interferon signaling, Cdc42 signaling, and cytotoxic T lymphocyte-mediated apoptosis. The most activated upstream regulators included TNF, an important drug target, as well as IFN-gamma and CD40LG, all of which are known to play important pathogenic roles in RA. The differentially expressed genes from synovium included several potential biomarkers, such as CCL5, CCL13, CCL18, CX3CL1, CXCL6, CXCL9, CXCL10, CXCL13, ILLS, IL32, IL1RN, SPP1, and TNFSF11. By contrast, microarray studies of WBC, PBMC and CD4+ T cells showed variable pathways and limited pathway overlap with synovium. Similarly, scRNA-seq data from a mouse model of arthritis did not support that inflammatory responses in peripheral blood reflect those in the arthritic joints. These data showed pathway overlap between mouse joint cells and synovium from patients with RA, but not with cells in peripheral blood. Conclusions: Our findings indicate a dichotomy between gene expression changes, pathways, upstream regulators and biomarkers in synovium and cell types in peripheral blood, which complicates identification of biomarkers in blood.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD , 2020. Vol. 127, article id 154960
Keywords [en]
Rheumatoid arthritis; Single cell RNA sequencing; Blood; Joint; Biomarker; Meta-analysis
National Category
Immunology
Identifiers
URN: urn:nbn:se:liu:diva-164371DOI: 10.1016/j.cyto.2019.154960ISI: 000515418400032PubMedID: 31881419OAI: oai:DiVA.org:liu-164371DiVA, id: diva2:1415876
Note

Funding Agencies|Swedish Cancer Foundation [17 0542, 15 0532]; European CommissionEuropean Commission Joint Research Centre [305033]; Swedish Research CouncilSwedish Research Council [2015-02575, 2015-03495, 2015-03807]; Clinical Cancer Research, Jonkoping Sweden, Torsten Soderberg Foundation

Available from: 2020-03-20 Created: 2020-03-20 Last updated: 2020-03-20

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Jung Lee, Eun JungLilja, SandraLi, XinxiuSchäfer, SamuelZhang, HuanBenson, Mikael
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Division of Children's and Women's healthFaculty of Medicine and Health SciencesDivision of Children's and Women's HealthH.K.H. Kronprinsessan Victorias barn- och ungdomssjukhus Linköping/Motala
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