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

Front. Immunol. | doi: 10.3389/fimmu.2019.02743

T cell dysregulation in non-silicotic silica exposed workers: a step towards immune tolerance breakdown

 Benoit BRILLAND1, 2,  Céline BEAUVILLAIN1, 3, Géry MAZURKIEWICZ4, Pierre RUCAY5, Yves ROQUELAURE5,  Julie TABIASCO1, Emeline VINATIER1, 3,  Jérémie RIOU6, Pascale JEANNIN1, 3, Gilles RENIER3, Jean-François SUBRA1, 2 and  Jean-François AUGUSTO1, 2*
  • 1INSERM U1232 Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), France
  • 2Service de Néphrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire d'Angers, France
  • 3Laboratoire d’Immunologie, Centre Hospitalier Universitaire d'Angers, France
  • 4Independent researcher, France
  • 5Centre Hospitalier Universitaire d'Angers, France
  • 6INSERM U1066 Micro et Nanomédecines Biomimétiques (MINT), France

Background. Chronic silica exposure can lead to silicosis, complicated or not by autoimmune diseases (AID). The pathophysiology of silica-induced AID remains not fully understood, especially immune mechanisms that may develop in patients without yet established silicosis. We conducted a prospective clinical study to analyze the impact of crystalline silica (CS) on T cell phenotype and regulatory T cells (Tregs) frequency, as well as on auto-antibodies development in non-silicotic workers exposed to CS.

Methods. Workers with moderate to high exposure level to CS and aged between 30 and 60 years-old were considered for inclusion. Peripheral blood mononuclear cells were analyzed by flow cytometry. Auto-antibodies were screened in serum by immunofluorescence. Blood from 42 and 45 healthy subjects (HC) was used as control for T cell phenotype and serum analyses, respectively.

Results. Among the 63 included workers exposed to CS, 55 had full data available and were analyzed. Ten were exposed to CS for less than 5 years, 18 for 5 to 10 years and 27 for more than 10 years. The frequency of Tregs (CD4+CD25+CD127–FoxP3+) was significantly lower in CS exposed workers as compared to HC. We found an increased expression of the activation marker HLA-DR on T cells (CD3+, CD4+ and CD8+) of CS exposed workers as compared to HC. Tregs to activated T cells ratio was also lower in exposed subjects. In the latter, HLA-DR expression level and Tregs frequency were significantly associated with CS exposure duration. Serum autoantibody detection was significantly higher in CS exposed workers as compared to HC. Especially, among workers exposed more than 10 years, antinuclear antibodies and ANCA were detected in 44% and 22% among them, as compared to 5% and 2.5% in HC, respectively.

Conclusion. This work shows that CS exposure is associated with a decrease of Tregs frequency, an increase of T cell activation status, and a tolerance breakdown against auto-antigens. These results show that alterations of the T cell compartment can be detected early over the course of CS exposure, preceding silicosis development or AID onset.

Keywords: Crystalline silica, Occupational Diseases, Auto-immune diseases, activated T cells, regulatory T cells, auto-antibodies Running title: Silica-induced lymphocytes dysregulation

Received: 23 Aug 2019; Accepted: 08 Nov 2019.

Copyright: © 2019 BRILLAND, BEAUVILLAIN, MAZURKIEWICZ, RUCAY, ROQUELAURE, TABIASCO, VINATIER, RIOU, JEANNIN, RENIER, SUBRA and AUGUSTO. 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: MD, PhD. Jean-François AUGUSTO, INSERM U1232 Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), Nantes, 44007, Pays de la Loire, France, jfaugusto@chu-angers.fr