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

R Lande, R Palazzo, N Gestermann, C Jandus, M Falchi, F Spadaro, V Riccieri, E A James, A Butera, M Boirivant, L Feldmeyer, I Surbeck, J Di Lucca, F Stuber, F R Spinelli, E Botti, B Marinari, L Bianchi, R Pica, B CerbelliK Giannakakis, S E Auteri, I Daniels, L G Durrant, S Horstman, A Costanzo, P Romero, C Alessandri, F Conti, G Valesini, M Gilliet, C Chizzolini, L Frasca

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)5851
JournalSci. Rep.
Volume10
Issue number1
DOIs
Publication statusPublished - Apr 3 2020

Keywords

  • Anti-Citrullinated Protein Antibodies/immunology
  • Antibodies, Antinuclear/immunology
  • Antibody Formation/immunology
  • Antimicrobial Cationic Peptides/immunology
  • Autoantibodies/immunology
  • DNA/immunology
  • Dendritic Cells/immunology
  • Female
  • Humans
  • Lupus Erythematosus, Systemic/etiology
  • Male
  • Psoriasis/etiology
  • T-Lymphocytes/immunology
  • Th17 Cells/immunology

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