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

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

[1]  J. Clancy,et al.  Dissociation of systemic and mucosal autoimmunity in cystic fibrosis. , 2020, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[2]  S. L. Bridges,et al.  Systemic levels of anti-PAD4 autoantibodies correlate with airway obstruction in cystic fibrosis. , 2019, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[3]  K. Winthrop,et al.  Autoimmunity to bactericidal/permeability-increasing protein in bronchiectasis exhibits a requirement for Pseudomonas aeruginosa IgG response , 2019, European Respiratory Journal.

[4]  C. Goss,et al.  Changing Rates of Chronic Pseudomonas aeruginosa Infections in Cystic Fibrosis: A Population-Based Cohort Study , 2018, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[5]  Hongbo Hu,et al.  Self‐dsDNA in the pathogenesis of systemic lupus erythematosus , 2018, Clinical and experimental immunology.

[6]  M. Mamula,et al.  The role for neutrophil extracellular traps in cystic fibrosis autoimmunity. , 2016, JCI insight.

[7]  Jasmine N Stannard,et al.  Cutaneous lupus erythematosus: updates on pathogenesis and associations with systemic lupus , 2016, Current opinion in rheumatology.

[8]  Dae-Goon Yoo,et al.  High Throughput Measurement of Extracellular DNA Release and Quantitative NET Formation in Human Neutrophils In Vitro. , 2016, Journal of visualized experiments : JoVE.

[9]  D. Pisetsky.  Anti-DNA antibodies — quintessential biomarkers of SLE , 2016, Nature Reviews Rheumatology.

[10]  M. Segelmark,et al.  BPI-ANCA Provides Additional Clinical Information to Anti-Pseudomonas Serology: Results from a Cohort of 117 Swedish Cystic Fibrosis Patients , 2015, Journal of immunology research.

[11]  O. Eickelberg,et al.  Free DNA in Cystic Fibrosis Airway Fluids Correlates with Airflow Obstruction , 2015, Mediators of inflammation.

[12]  S. Moskowitz,et al.  NET formation induced by Pseudomonas aeruginosa cystic fibrosis isolates measured as release of myeloperoxidase-DNA and neutrophil elastase-DNA complexes. , 2014, Immunology letters.

[13]  S. Sagel,et al.  Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. , 2012, American journal of respiratory and critical care medicine.

[14]  Ferry Kienberger,et al.  Ultrastructural characterization of cystic fibrosis sputum using atomic force and scanning electron microscopy. , 2012, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[15]  Mariana J. Kaplan,et al.  Neutrophils in the pathogenesis and manifestations of SLE , 2011, Nature Reviews Rheumatology.

[16]  M. Segelmark,et al.  Pseudomonas aeruginosa in cystic fibrosis: pyocyanin negative strains are associated with BPI-ANCA and progressive lung disease. , 2011, Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.

[17]  J. Weiss,et al.  The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[18]  I. Megson,et al.  Clearance of dying cells and autoimmunity , 2007, Autoimmunity.

[19]  J. Cambier,et al.  Multiple paths to loss of anergy and gain of autoimmunity , 2007, Autoimmunity.

[20]  B. Rubin,et al.  Pulmonary function is negatively correlated with sputum inflammatory markers and cough clearability in subjects with cystic fibrosis but not those with chronic bronchitis. , 2006, Chest.

[21]  M. Rotschild,et al.  Autoantibodies against bactericidal/permeability–increasing protein (BPI–ANCA) in cystic fibrosis patients treated with azithromycin , 2005, Clinical and Experimental Medicine.

[22]  O. Cinek,et al.  Anti-GAD65 reactive peripheral blood mononuclear cells in the pathogenesis of cystic fibrosis related diabetes mellitus , 2005, Autoimmunity.

[23]  J. Wieslander,et al.  Pseudomonas-induced lung damage in cystic fibrosis correlates to bactericidal-permeability increasing protein (BPI)-autoantibodies. , 2003, Clinical and experimental rheumatology.

[24]  J. Mattick,et al.  Extracellular DNA required for bacterial biofilm formation. , 2002, Science.

[25]  L. Noël.  [Antineutrophil cytoplasm antibodies (ANCA): description and immunopathological role]. , 2000, Annales de medecine interne.

[26]  G. Glick,et al.  Anti-DNA autoantibodies and systemic lupus erythematosus. , 1999, Pharmacology & therapeutics.

[27]  M. Hochberg,et al.  Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. , 1997, Arthritis and rheumatism.

[28]  F. Accurso,et al.  Increased DNA levels in bronchoalveolar lavage fluid obtained from infants with cystic fibrosis. , 1996, American journal of respiratory and critical care medicine.

[29]  W. Regelmann,et al.  Sputum peroxidase activity correlates with the severity of lung disease in cystic fibrosis , 1995, Pediatric pulmonology.

[30]  S. Shak,et al.  Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Lethem,et al.  The origin of DNA associated with mucus glycoproteins in cystic fibrosis sputum. , 1990, The European respiratory journal.

[32]  L. Reid,et al.  Pus, deoxyribonucleic acid, and sputum viscosity. , 1978, Thorax.

[33]  J. L. Potter,et al.  STUDIES ON PULMONARY SECRETIONS. I. THE OVER-ALL CHEMICAL COMPOSITION OF PULMONARY SECRETIONS FROM PATIENTS WITH CYSTIC FIBROSIS, BRONCHIECTASIS, AND LARYNGECTOMY. , 1963, The American review of respiratory disease.

[34]  G. Barbero,et al.  Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. , 1959, Pediatrics.

[35]  F. Celada,et al.  A DNA-Reacting Factor in Serum of a Patient with Lupus Erythematosus Diffusus.∗ , 1957, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[36]  S. Turchini,et al.  [Anti-Pseudomonas aeruginosa antibodies, circulating immune complexes, and anticytoplasm antibodies of neutrophils in patients with cystic fibrosis with and without Pseudomonas aeruginosa colonization]. , 2001, La Pediatria medica e chirurgica : Medical and surgical pediatrics.

[37]  C. Feighery,et al.  Anti-phagocyte antibodies and infection. , 1998, Autoimmunity.

[38]  A. Daugherty,et al.  Distribution of DNA and alginate in purulent cystic fibrosis sputum: implications to pulmonary targeting strategies. , 1996, Journal of drug targeting.

[39]  J. Zahm,et al.  Physical and functional properties of airway secretions in cystic fibrosis--therapeutic approaches. , 1995, Respiration; international review of thoracic diseases.

[40]  T. Wilkin.  Autoimmunity: attack, or defence? (The case for a primary lesion theory). , 1989, Autoimmunity.