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Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Authors
  • Lande, R.1, 2
  • Palazzo, R.1
  • Gestermann, N.2
  • Jandus, C.3
  • Falchi, M.4
  • Spadaro, F.5
  • Riccieri, V.6
  • James, E. A.7
  • Butera, A.1
  • Boirivant, M.1
  • Feldmeyer, L.2
  • Surbeck, I.2
  • Di Lucca, J.2
  • Stuber, F.2
  • Spinelli, F. R.6
  • Botti, E.8
  • Marinari, B.8
  • Bianchi, L.8
  • Pica, R.9
  • Cerbelli, B.10, 11
  • And 13 more
  • 1 Istituto Superiore di Sanità, National Centre for pre-clinical and clinical drug research and evaluation, Pharmacological research and experimental therapy Unit, Rome, 00166, Italy , Rome (Italy)
  • 2 University Hospital CHUV, Dept. of Dermatology, Lausanne, 1011, Switzerland , Lausanne (Switzerland)
  • 3 Translational tumor immunology group, Department of fundamental oncology, University of Lausanne, Epalinges, 1066, Switzerland , Epalinges (Switzerland)
  • 4 Istituto Superiore di Sanità, National AIDS Center, Rome, 00166, Italy , Rome (Italy)
  • 5 Istituto Superiore di Sanità, Confocal Microscopy Unit, Core Facilities, Rome, Italy , Rome (Italy)
  • 6 Division of Rheumatology, Internal medicine and medical specialties, University Sapienza, Rome, Italy , Rome (Italy)
  • 7 Department of Translational Research, Benaroya Research Institute, Seattle, WA, USA , Seattle (United States)
  • 8 Department of Systems Medicine University of Tor Vergata, Dermatology Unit, Rome, Italy , Rome (Italy)
  • 9 “Sandro Pertini” Hospital, IBD, GE Unit, Rome, Italy , Rome (Italy)
  • 10 Department of Radiological, oncological and anatomo-pathological sciences, Sapienza University, Rome, Italy , Rome (Italy)
  • 11 Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy , Latina (Italy)
  • 12 Department of Pathology, Sapienza University, Rome, Italy , Rome (Italy)
  • 13 Academic Department of Clinical Oncology, University of Nottingham, Nottingham, UK , Nottingham (United Kingdom)
  • 14 Skin pathology laboratory, Dermatology Unit, IRCCS Humanitas clinical and research center, Rozzano, Milan, Italy , Rozzano, Milan (Italy)
  • 15 Department of Immunology and Allergy, University Hospital and Medical School, Geneva, Switzerland , Geneva (Switzerland)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Apr 03, 2020
Volume
10
Issue
1
Identifiers
DOI: 10.1038/s41598-020-62480-3
Source
Springer Nature
License
Green

Abstract

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.

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