Autoantibodies targeting components of neutrophil extracellular traps are elevated in cystic fibrosis

Abstract

Abstract Cystic fibrosis (CF) lung disease is characterized by the presence of neutrophils and released neutrophil extracellular traps (NETs). NETs are composed of a genomic DNA scaffold decorated with histones and neutrophil granule proteins. The long-term presence of NETs could lead to an autoimmune response in CF. This is supported by our published results showing elevated levels of anti-PAD4 autoantibodies in a U.S. CF cohort. To confirm and expand this observation, here we hypothesized that anti-PAD4 autoantibodies are also elevated in another CF cohort from Hungary, and additional, NET-targeting autoantibodies can be identified in CF. Fifty-seven CF patients (class I–III CFTR mutations, stable lung function, 26±−5.4 years of age (mean±SD), 54% female) and forty healthy subjects (26.2±3.6 years of age, 57% female) were recruited into this study in Hungary. Anti-PAD4 and anti-dsDNA autoantibodies were measured by ELISA while additional autoantibodies were determined by autoantigen microarray. Increased levels of anti-PAD4 autoantibodies were confirmed in this CF cohort. Serum levels of anti-dsDNA IgA autoantibodies were significantly higher in CF patients compared to control subjects. The autoantigen microarray analysis revealed significantly elevated levels of several, novel, NET-targeting autoantibodies in CF: anti-chromatin IgA, anti-core Histone IgA and IgE, anti-Histone H1 IgA, anti-Histone H2A IgA and IgM. No significant correlations of these autoantibodies with lung function (FEV1%pred), age or inflammatory markers (human epididymis protein 4, C-reactive protein) were found. Overall, these results indicate that chronic presence of NETs leads to a systemic autoimmune response in CF.