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.

Native/citrullinated LL37-specific T-cells help autoantibody production in systemic lupus erythematosus / Lande, R; Palazzo, R; Gestermann, N; Jandus, C; Falchi, M; Spadaro, F; Riccieri, V; James, E A; Butera, A; Boirivant, M; Feldmeyer, L; Surbeck, I; Di Lucca, J; Stuber, F; Spinelli, F R; Botti, E; Marinari, B; Bianchi, L; Pica, R; Cerbelli, B; Giannakakis, K; Auteri, S E; Daniels, I; Durrant, L G; Horstman, S; Costanzo, A; Romero, P; Alessandri, C; Conti, F; Valesini, G; Gilliet, M; Chizzolini, C; Frasca, L. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 10:1(2020). [10.1038/s41598-020-62480-3]

Native/citrullinated LL37-specific T-cells help autoantibody production in systemic lupus erythematosus

Riccieri, V;Spinelli, F R;Cerbelli, B;Giannakakis, K;Auteri, S E;Costanzo, A;Alessandri, C;Conti, F;Valesini, G;
2020

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.
2020
anti-citrullinated protein antibodies; antibodies, antinuclear; antibody formation; antimicrobial cationic peptides; autoantibodies; DNA; dendritic cells; female; humans; lupus erythematosus, systemic; male; psoriasis; T-Lymphocytes; TH17 Cells
01 Pubblicazione su rivista::01a Articolo in rivista
Native/citrullinated LL37-specific T-cells help autoantibody production in systemic lupus erythematosus / Lande, R; Palazzo, R; Gestermann, N; Jandus, C; Falchi, M; Spadaro, F; Riccieri, V; James, E A; Butera, A; Boirivant, M; Feldmeyer, L; Surbeck, I; Di Lucca, J; Stuber, F; Spinelli, F R; Botti, E; Marinari, B; Bianchi, L; Pica, R; Cerbelli, B; Giannakakis, K; Auteri, S E; Daniels, I; Durrant, L G; Horstman, S; Costanzo, A; Romero, P; Alessandri, C; Conti, F; Valesini, G; Gilliet, M; Chizzolini, C; Frasca, L. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 10:1(2020). [10.1038/s41598-020-62480-3]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1544034
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