Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
Roberto Lande, Raffaella Palazzo, Nicolas Gestermann, Camilla Jandus, Mario Falchi, Francesca Spadaro, Valeria Riccieri, Eddie A. James, Alessia Butera, Monica Boirivant, Laurence Feldmeyer, Isabelle Surbeck, Julie Di Lucca, Frank Stüber, Francesca Romana Spinelli, E. Botti, Barbara Marinari, Luca Bianchi, Roberta Pica, Bruna Cerbelli, K. Giannakakis, Simone E. Auteri, Ian Daniels, Lindy G. Durrant, Sheryl Horstman, Antonio Costanzo, Pedro Romero, Cristiano Alessandri, Fabrizio Conti, Guido Valesini, Michel Gilliet, Carlo Chizzolini, Loredana Frasca
Abstract
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-(T FH )-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.