TY - JOUR
T1 - Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus
AU - Lande, R
AU - Palazzo, R
AU - Gestermann, N
AU - Jandus, C
AU - Falchi, M
AU - Spadaro, F
AU - Riccieri, V
AU - James, E A
AU - Butera, A
AU - Boirivant, M
AU - Feldmeyer, L
AU - Surbeck, I
AU - Di Lucca, J
AU - Stuber, F
AU - Spinelli, F R
AU - Botti, E
AU - Marinari, B
AU - Bianchi, L
AU - Pica, R
AU - Cerbelli, B
AU - Giannakakis, K
AU - Auteri, S E
AU - Daniels, I
AU - Durrant, L G
AU - Horstman, S
AU - Costanzo, A
AU - Romero, P
AU - Alessandri, C
AU - Conti, F
AU - Valesini, G
AU - Gilliet, M
AU - Chizzolini, C
AU - Frasca, L
PY - 2020/4/3
Y1 - 2020/4/3
N2 - 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.
AB - 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.
KW - Anti-Citrullinated Protein Antibodies/immunology
KW - Antibodies, Antinuclear/immunology
KW - Antibody Formation/immunology
KW - Antimicrobial Cationic Peptides/immunology
KW - Autoantibodies/immunology
KW - DNA/immunology
KW - Dendritic Cells/immunology
KW - Female
KW - Humans
KW - Lupus Erythematosus, Systemic/etiology
KW - Male
KW - Psoriasis/etiology
KW - T-Lymphocytes/immunology
KW - Th17 Cells/immunology
U2 - 10.1038/s41598-020-62480-3
DO - 10.1038/s41598-020-62480-3
M3 - Article
C2 - 32245990
VL - 10
SP - 5851
JO - Sci. Rep.
JF - Sci. Rep.
SN - 2045-2322
IS - 1
ER -