IgA autoantibodies directed against self DNA are elevated in cystic fibrosis and associated with more severe lung dysfunction

Autoimmunity. 2020 Dec;53(8):476-484. doi: 10.1080/08916934.2020.1839890.

Abstract

Although extracellular host DNA (ecDNA) levels in CF airways were linked to airflow obstruction and recombinant DNAse therapy is beneficial for CF patients, it remains incompletely understood whether ecDNA also leads to an autoimmune response. Here we hypothesized that chronic presence of DNA in CF airways triggers the production of autoantibodies targeting host human DNA. We measured the levels of IgA autoantibodies recognising host double-stranded (ds) DNA in the blood and sputum samples of CF patients and only sera of controls subjects and patients suffering from rheumatoid arthritis and systemic lupus erythematosus (SLE) that served as non-CF, autoimmune disease cohorts. We found that concentrations of anti-dsDNA IgA, but not IgG, autoantibodies in the circulation were significantly elevated in adult CF patients compared to age-matched, control subjects. Systemic levels of anti-dsDNA IgA antibodies negatively correlated with FEV1% predicted, a measure of lung function, in CF patients. Anti-dsDNA IgA autoantibodies were also detected in CF sputa but sputum levels did not correlate with the degree of airway obstruction or sputum levels of DNA. We also found elevated autoantibody levels in CF children as 76.5% of CF patients younger than 10 years and 87.5% of CF patients 10-21 years had higher blood anti-dsDNA IgA levels than the highest value found in healthy control adults. Overall, our results detect elevated systemic anti-dsDNA IgA autoantibody levels in CF adults, teenagers and young children. We speculate that the appearance of an autoimmune response against host DNA in CF is an early event potentially contributing to disease pathogenesis. Highlights CF serum contains elevated levels of anti-dsDNA IgA, but not anti-dsDNA IgG, autoantibodies Anti-dsDNA IgA autoantibody levels in serum correlate with airflow obstruction in CF Anti-dsDNA IgA autoantibodies are detected in CF sputum but do not correlate with airflow obstruction Anti-dsDNA IgA autoantibodies are also elevated in the blood of the majority of CF toddlers and youth.

Keywords: Cystic fibrosis; DNA; IgA; autoantibody; autoimmunity.

MeSH terms

  • Adult
  • Aged
  • Antibodies, Antinuclear / immunology*
  • Arthritis, Rheumatoid / immunology
  • Autoantibodies / immunology*
  • Case-Control Studies
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / immunology*
  • Cystic Fibrosis / physiopathology
  • DNA / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Traps / immunology
  • Female
  • Humans
  • Immunoglobulin A / immunology*
  • Immunoglobulin G / immunology
  • Male
  • Middle Aged
  • Respiratory Function Tests
  • Severity of Illness Index
  • Sputum / immunology
  • Young Adult

Substances

  • Antibodies, Antinuclear
  • Autoantibodies
  • Immunoglobulin A
  • Immunoglobulin G
  • DNA