Systemic levels of anti-PAD4 autoantibodies correlate with airway obstruction in cystic fibrosis

Published:January 10, 2019DOI:https://doi.org/10.1016/j.jcf.2018.12.010

      Highlights

      • CF serum contains elevated levels of anti-PAD4 antibodies
      • Anti-PAD4 antibody levels in CF serum correlate with lung disease
      • Anti-PAD4 antibody levels in CF are associated with Pseudomonas aeruginosa lung infection
      • Levels of NETs, cell-free DNA, anti-nucleosome antibodies or ACPAs are not elevated in CF
      • Pattern of autoantibodies in CF is different from that of RA or SLE, two diseases with autoantibody-linked pathogeneses

      Abstract

      Cystic fibrosis (CF) airway disease is characterized by the long-term presence of neutrophil granulocytes. Formation of neutrophil extracellular traps (NETs) and/or autoantibodies directed against extracellular components of NETs are possible contributors to neutrophil-mediated lung damage in CF. The goal of this study was to measure their levels in CF adults compared to healthy controls and subjects with rheumatologic diseases known to develop NET-related autoantibodies and pathologies, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Sera were analyzed from the following number of subjects: 37 CF, 23 healthy controls (HC), 20 RA, and 21 SLE. CF had elevated serum myeloperoxidase (MPO) concentrations (347.5±56.1 ng/ml, mean+/-S.E.M., p = .0132) compared to HC (144.5±14.6 ng/ml) but not of neutrophil elastase (NE) complexed with alpha-1-antitrypsin, cell-free DNA or NE-DNA complexes. The peptidylarginine deiminase 4 (PAD4) enzyme is required for NET formation and associated DNA release in neutrophils. Serum levels of anti-PAD4 antibodies (Ab) were elevated in CF ( p = .0147) compared to HC and showed an inverse correlation with a measure of lung function, FEV1% predicted ( r = −0.5020, p = .015), as did MPO levels ( r = −0.4801, p = .0026). Anti-PAD4 Ab levels in CF sera associated with lung infection by P. aeruginosa, but not that by S. aureus, age, sex, CF-related diabetes or the presence of musculoskeletal pain. Serum levels of anti-citrullinated protein Abs (ACPAs) and anti-nucleosome Abs were not elevated in CF compared to HC ( p = .7498, p = .0678). In summary, adult CF subjects develop an autoimmune response against NET components that correlates with worsening lung disease.

      Keywords

      Abbreviations:

      CF ( cystic fibrosis), PAD4 ( peptidylarginine deiminase 4), ACPA ( anti-citrullinated protein antibody), SLE ( systemic lupus erythematosus), RA ( rheumatoid arthritis), NET ( neutrophil extracellular traps), NE ( neutrophil elastase)
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