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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01863

Molecular Characterization of Human Lymph Node Stromal Cells During the Earliest Phases of Rheumatoid Arthritis

 Emmanuel Karouzakis1, Janine Hähnlein2, Cristoforo Grasso2, Johanna F. Semmelink2, Paul P. Tak2, 3, 4, 5, Danielle M. Gerlag2, 6,  Steffen Gay1, 2, 7,  Caroline Ospelt1, 7* and  Lisa G. Van Baarsen2
  • 1Center for Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Switzerland
  • 2Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology and Rheumatology, University of Amsterdam, Netherlands
  • 3Independent researcher, United States
  • 4Ghent University, Belgium
  • 5University of Cambridge, United Kingdom
  • 6GlaxoSmithKline (United Kingdom), United Kingdom
  • 7Center for Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Switzerland

Rheumatoid arthritis (RA) is a progressive, destructive autoimmune arthritis. Break of tolerance and formation of autoantibodies occur years before arthritis. Adaptive immunity is initiated in lymphoid tissue where lymph node stromal cells (LNSCs) play a crucial role in shaping the immune response and maintaining peripheral tolerance. Here we performed the first epigenomic characterization of LNSCs during health and early RA, by analyzing their transcriptome and DNA methylome in LNSCs isolated from lymph node needle biopsies obtained from healthy controls (HC), autoantibody positive RA-risk individuals and patients with established RA. Of interest, LNSCs from RA-risk individuals and RA patients revealed a common significantly differential expressed gene signature compared with HC LNSCs. Pathway analysis of this common signature showed, among others, significant enrichment of pathways affecting the extracellular matrix (ECM), cholesterol biosynthesis and immune system. In a gel contraction assay LNSCs from RA-risk individuals and RA patients showed impaired collagen contraction compared to healthy LNSCs. In RA LNSCs a significant enrichment was observed for genes involved in cytokine signaling, hemostasis and packaging of telomere ends. In contrast, in RA-risk LNSCs pathways in cancer (cell cycle related genes) were differentially expressed compared with HC, which could be validated in vitro using a proliferation assay, which indicated a slower proliferation rate. DNA methylation analyses revealed common and specific differentially methylated CpG sites (DMS) in LNSC from RA patients and RA-risk individuals compared with HC. Intriguingly, shared DMS were all associated with antigen processing and presentation.
This data point towards alterations in cytoskeleton and antigen-processing and presentation in LNSC from RA-risk individuals and RA patients. Further studies are required to investigate the consequence of this LNSC abnormality on LNSC-mediated immunomodulation.

Keywords: Lymph Node, Stroma, fibroblast, Rheumatoid arthritis, Sequencing, DNA Methylation

Received: 11 Apr 2019; Accepted: 23 Jul 2019.

Edited by:

Claudio Lunardi, University of Verona, Italy

Reviewed by:

Dimitrios Vassilopoulos, Department of Medicine, School of Health Sciences, National and Kapodistrian University of Athens, Greece
Erika H. Noss, University of Washington, United States  

Copyright: © 2019 Karouzakis, Hähnlein, Grasso, Semmelink, Tak, Gerlag, Gay, Ospelt and Van Baarsen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Caroline Ospelt, Center for Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zürich, Switzerland,