Anti-LL37 antibodies are present in psoriatic arthritis (PsA) patients: New biomarkers in PsA

L. Frasca, R. Palazzo, M.S. Chimenti, S. Alivernini, B. Tolusso, L. Bui, E. Botti, A. Giunta, L. Bianchi, L. Petricca, S.E. Auteri, F. Spadaro, G.L. Fonti, M. Falchi, A. Evangelista, B. Marinari, I. Pietraforte, F.R. Spinelli, T. Colasanti, C. AlessandriF. Conti, E. Gremese, A. Costanzo, G. Valesini, R. Perricone, R. Lande

Research output: Contribution to journalArticlepeer-review

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. A third of psoriatic patients develop PsA via unknown mechanisms. No reliable diagnostic markers are available for PsA, or prognostic biomarkers for PsA development in psoriasis. We previously uncovered a pro-inflammatory role for cathelicidin LL37 in lesional psoriasis skin. LL37 binds nucleic acids and stimulates plasmacytoid/myeloid dendritic cells (pDC, mDCs) to secrete type I interferon (IFN-I) and pro-inflammatory factors. LL37 becomes an autoantigen for psoriatic Th1-Th17/CD8 T cells. Anti-LL37 antibodies were detected in systemic lupus erythematosus, an autoimmune disease characterized by neutrophil-extracellular-traps release (NETosis) in target organs. LL37 can be substrate of irreversible post-translational modifications, citrullination or carbamylation, linked to neutrophil activity. Here we analyzed inflammatory factors, included LL37, in PsA and psoriasis plasma and PsA synovial fluids (SF)/biopsies. We show that LL37 (as a product of infiltrating neutrophils) and autoantibodies to LL37 are elevated in PsA, but not OA SF. Anti-LL37 antibodies correlate with clinical inflammatory markers. Anti-carbamylated/citrullinated-LL37 antibodies are present in PsA SF/plasma and, at lower extent, in psoriasis plasma, but not in controls. Plasma anti-carbamylated-LL37 antibodies correlate with PsA (DAS44) but not psoriasis (PASI) disease activity. Ectopic lymphoid structures, and deposition of immunoglobulin-(Ig)G-complexes (IC) co-localizing with infiltrating neutrophils, are observed in PsA and not OA synovial tissues (ST). Activated complement (C5a, C9), GM-CSF and IFN-I are up-regulated in PsA and not OA synovia and in PsA and psoriasis plasma but not in HD. C9 and GM-CSF levels in PsA SF correlate with clinical inflammatory markers and DAS44 (C9) and with anti-carbamylated/citrullinated-LL37 antibodies (GM-CSF and IFN-I). Thus, we uncover a role for LL37 as a novel PsA autoantibody target and correlation studies suggest participation of anti-LL37 antibodies to PsA pathogenesis. Notably, plasma antibodies to carbamylated-LL37, which correlate with DAS44, suggest their use as new disease activity markers. GM-CSF and complement C5a and C9 elevation may be responsible for autoantigens release by neutrophils and their modification, fueling inflammation and autoreactivity establishment. Finally, targeting GM-CSF, C5a, C9 can be beneficial in PsA. © 2018 Frasca, Palazzo, Chimenti, Alivernini, Tolusso, Bui, Botti, Giunta, Bianchi, Petricca, Auteri, Spadaro, Fonti, Falchi, Evangelista, Marinari, Pietraforte, Spinelli, Colasanti, Alessandri, Conti, Gremese, Costanzo, Valesini, Perricone and Lande.
Original languageEnglish
JournalFrontiers in Immunology
Volume9
Issue numberSEP
DOIs
Publication statusPublished - 2018

Keywords

  • alpha1 interferon
  • autoantibody
  • autoantigen
  • C reactive protein
  • cathelicidin antimicrobial peptide LL 37
  • CD23 antigen
  • CD8 antigen
  • complement component C3d receptor
  • complement component C5a
  • granulocyte macrophage colony stimulating factor
  • immunoglobulin G
  • interferon
  • Ki 67 antigen
  • myeloperoxidase
  • nucleic acid
  • protein bcl 6, adult
  • antigen antibody complex
  • Article
  • carbamoylation
  • cell activation
  • cell proliferation
  • citrullination
  • confocal laser scanning microscopy
  • disease activity
  • disease activity score
  • enzyme linked immunosorbent assay
  • erythrocyte sedimentation rate
  • female
  • follicular dendritic cell
  • gene expression
  • human
  • human tissue
  • immunofluorescence test
  • immunohistochemistry
  • inflammation
  • joint biopsy
  • major clinical study
  • male
  • middle aged
  • myeloid dendritic cell
  • osteoarthritis
  • plasmacytoid dendritic cell
  • protein expression
  • psoriasis vulgaris
  • psoriatic arthritis
  • staining
  • synovium
  • systemic lupus erythematosus
  • T lymphocyte
  • visual analog scale

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