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.
Highlights
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a prevalence of about 20–50 cases per 100,000 in Northern Europe and USA1, characterized by immune-complex formation and deposition, which result in inflammation and tissue damage
Since peptidyl arginine deaminase (PAD) enzymes can become activated during inflammation[21,22,23] and perform citrullination of arginine-rich proteins, we searched for the presence of cit-LL37 in systemic lupus erythematosus (SLE)/cutaneous lupus (CLE) tissues
Since complement deposition in the form of membrane-attack-complexes (MAC) can be responsible for hypercitrullination of multiple substrates in other settings[25,26], we assessed the simultaneous presence of cit-LL37 and complement C9 deposition, which could co-localize in SLE kidney (Fig. S2)
Summary
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a prevalence of about 20–50 cases per 100,000 in Northern Europe and USA1, characterized by immune-complex formation and deposition, which result in inflammation and tissue damage. We hypothesized that LL37 is highly immunogenic for T-cells because its sequence contains multiple binding motifs for several HLA-class I/II alleles It is presently unclear whether: (a) anti-LL37 antibodies correlate with disease activity; (2) LL37-DNA complexes and/ or NET/NET-like structures are present in lupus-target tissues; (3) T-cells responding to LL37 exist and correlate with, and/or participate to, SLE pathogenesis. The latter aspect is important in that T-cells with T-helper follicular (TFH) functions are necessary for isotype immunoglobulin (Ig)-switch and somatic hypermutation, the processes that generate high affinity autoantibodies[17,18,19,20]. The intrinsic properties of this antigen, efficacious in both settings, lead to different outcomes, dictated by the disease-specific milieu
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