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

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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125190/
https://www.ncbi.nlm.nih.gov/pubmed/32245990
http://dx.doi.org/10.1038/s41598-020-62480-3
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author 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.
author_facet 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.
author_sort Lande, R.
collection PubMed
description 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.
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spelling pubmed-71251902020-04-08 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. Sci Rep Article 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. Nature Publishing Group UK 2020-04-03 /pmc/articles/PMC7125190/ /pubmed/32245990 http://dx.doi.org/10.1038/s41598-020-62480-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
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.
Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
title Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
title_full Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
title_fullStr Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
title_full_unstemmed Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
title_short Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
title_sort native/citrullinated ll37-specific t-cells help autoantibody production in systemic lupus erythematosus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125190/
https://www.ncbi.nlm.nih.gov/pubmed/32245990
http://dx.doi.org/10.1038/s41598-020-62480-3
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