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

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. Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a prevalence of about 20-50 cases per 100,000 in Northern Europe and USA 1 , characterized by immune-complex formation and deposition, which result in inflammation and tissue damage. In SLE, altered clearance of dying cells determines persistent exposure of autoantigens and activation of antigen-presenting cells (APCs), mainly via Toll-like receptors (TLR), thus favoring adaptive immune response licensing 1-3. SLE autoantibodies are preferentially directed against

Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature

“…Disposing of PBMCs from the SSc patients of the replication cohort, we could test the proliferative response of SSc T-helper cells to CXCL4 by bromodeoxyuridine (BrdU) incorporation, as previously done with other autoantigens [ 24 , 25 ]. As shown in Figure 5 a, six out of 16 (38%) SSc patients had T-cells that proliferated to CXCL4 (the gating strategy for proliferation assays is reported in Figure S2 ).…”

Psoriasis and Connective Tissue Diseases

“…LL37, an endogenous antimicrobial peptide, has recently been suggested to be involved in SLE, as well as psoriasis. LL37 triggers IFN-α production in pDCs, and SLE patients had circulating T-cells responding to LL37, which correlated with anti-LL37 antibodies and disease activity [21]. As compared with psoriasis, LL37-specific T-cells in SLE displayed a T-follicular helper-like phenotype, implicating a pathogenic role in SLE [21].…”

RB137 and RB138 antibodies recognize human cathelicidin LL37 by ELISA

“…2). RB137 has since been shown to recognize native LL37 in human tissue by immunofluorescence and immunohistochemistry (Lande et al, 2020).…”