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Salivary gland epithelial cells from patients with Sjögren’s syndrome induce B-lymphocyte survival and activation
  1. Elodie Rivière1,2,3,
  2. Juliette Pascaud1,
  3. Nicolas Tchitchek1,
  4. Saida Boudaoud1,
  5. Audrey Paoletti1,
  6. Bineta Ly1,
  7. Anastasia Dupré1,
  8. Hua Chen4,
  9. Alice Thai5,
  10. Norm Allaire5,
  11. Bernd Jagla6,
  12. Michael Mingueneau5,
  13. Gaetane Nocturne1,3,
  14. Xavier Mariette1,3
  1. 1Immunology of viral Infections and Autoimmune Diseases, IDMIT, CEA, Paris-Saclay University, Paris-Sud University, INSERM U1184, Le Kremlin-Bicêtre, France
  2. 2Fondation Arthritis, Arthritis R&D, Paris, France
  3. 3Rheumatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux universitaires Paris-Sud, Hôpital Bicêtre, Le Kremlin Bicêtre, France
  4. 4Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
  5. 5Immunology Research, Biogen, Cambridge, Massachusetts, USA
  6. 6Biomarker Discovery Platform UTechS CB, Hub de Bioinformatique et biostatistique C3IB, Institut Pasteur, Paris, France
  1. Correspondence to Dr Gaetane Nocturne, Department of Rheumatology, Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, INSERM U1184, 78 rue du Général Leclerc, phone: +33 1 45 21 37 58, fax : +33 1 45 21 37 57, 94275, Le Kremlin Bicêtre, France; gaetane.nocturne{at}aphp.fr

Abstract

Objective Primary Sjögren's syndrome (pSS) is characterised by chronic hyperactivation of B lymphocytes. Salivary gland epithelial cells (SGECs) could play a role in promoting B-lymphocyte activation within the target tissue. We aimed to study the interactions between SGECs from patients with pSS or controls and B lymphocytes.

Methods Patients had pSS according to 2016 European League Against Rheumatism/American College of Rheumatology criteria. Gene expression analysis of SGECs and B lymphocytes from pSS and controls isolated from salivary gland biopsies and blood was performed by RNA-seq. SGECs from pSS and controls were cocultured with B-lymphocytes sorted from healthy donor blood and were stimulated. Transwell and inhibition experiments were performed.

Results Gene expression analysis of SGECs identified an upregulation of interferon signalling pathway and genes involved in immune responses (HLA-DRA, IL-7 and B-cell activating factor receptor) in pSS. Activation genes CD40 and CD48 were upregulated in salivary gland sorted B lymphocytes from patients with pSS. SGECs induced an increase in B-lymphocyte survival, which was higher for SGECs from patients with pSS than controls. Moreover, when stimulated with poly(I:C), SGECs from patients with pSS induced higher activation of B-lymphocytes than those from controls. This effect depended on soluble factors. Inhibition with anti-B-cell activating factor, anti-A proliferation-inducing ligand, anti-interleukin-6-R antibodies, JAK1/3 inhibitor or hydroxychloroquine had no effect, conversely to leflunomide, Bruton's tyrosine kinase (BTK) or phosphatidyl-inositol 3-kinase (PI3K) inhibitors.

Conclusions SGECs from patients with pSS had better ability than those from controls to induce survival and activation of B lymphocytes. Targeting a single cytokine did not inhibit this effect, whereas leflunomide, BTK or PI3K inhibitors partially decreased B-lymphocyte viability in this model. This gives indications for future therapeutic options in pSS.

  • Sjøgren's syndrome
  • B cells
  • autoimmune diseases
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Footnotes

  • GN and XM are joint senior authors.

  • Handling editor Josef S Smolen

  • GN and XM contributed equally.

  • Contributors ER participated in designing the research studies, conducting experiments, acquiring data, analysing data and writing the manuscript. JP participated in designing the research studies, conducting experiments, acquiring data and analysing data. NT participated in the analysis of the data and in writing the manuscript. SB participated in designing the research studies, conducting experiments and acquiring data. AP, BL and AD participated in designing the research studies, conducting experiments and acquiring data. HC, AT and NA participated in conducting experiments and acquiring data. BJ participated in acquiring data, analysing data and writing the manuscript. MM participated in designing the research studies, acquiring data, analysing data and writing the manuscript. GN and XM participated in designing the research studies, analysing data and writing the manuscript.

  • Funding Support was obtained from the Labex in Research on Medication and Therapeutic Innovation (ANR10), the Fondation pour la Recherche Médicale DEQ20150934719, an unrestricted grant from Biogen to Université Paris-Sud (UPSud/SAIC N 97731) and the Innovative Medicines Initiative 2 Joint Undertaking (JU) (NECESSITY grant agreement number 806975). This JU received support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. ER is the recipient of a PhD fellowship from Arthritis Fondation Courtin, Arthritis R&D (CIFRE 2016/1406).

  • Competing interests AT, NA and MM are employed by Biogen. XM received an honorarium for consultancy advice on Sjögren’s syndrome from BMS, GSK, Novartis and Servier and a research grant from Servier. The rest of the authors declare that they have no relevant conflicts of interest.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval This study received approval from the local ethics committee, and informed consent was obtained from all participants.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplementary information. Additional data are available on reasonable request.

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