title: The role for neutrophil extracellular traps in cystic fibrosis autoimmunity.
abstract: While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection byPseudomonas aeruginosa, no single factor predicts the extent of lung damage in CF. To elucidate other causes, we studied the autoantibody profile in CF and rheumatoid arthritis (RA) patients, given the similar association of airway inflammation and autoimmunity in RA. Even though we observed that bactericidal permeability-increasing protein (BPI), carbamylated proteins, and citrullinated proteins all localized to the neutrophil extracellular traps (NETs), which are implicated in the development of autoimmunity, our study demonstrates striking autoantibody specificity in CF. Particularly, CF patients developed anti-BPI autoantibodies but hardly any anti-citrullinated protein autoantibodies (ACPA). In contrast, ACPA-positive RA patients exhibited no reactivity with BPI. Interestingly, anti-carbamylated protein autoantibodies (ACarPA) were found in both cohorts but did not cross-react with BPI. Contrary to ACPA and ACarPA, anti-BPI autoantibodies recognized the BPI C-terminus in the absence of posttranslational modifications. In fact, we discovered thatP.aeruginosa-mediated NET formation results in BPI cleavage byP.aeruginosaelastase, which suggests a novel mechanism in the development of autoimmunity to BPI. In accordance with this model, autoantibodies associated with presence ofP.aeruginosaon sputum culture. Finally, our results provide a role for autoimmunity in CF disease severity, as autoantibody levels associate with diminished lung function.
authors: Department of Microbiology and Immunology and.
authors: Sladjana
authors: S
authors: Skopelja
authors: Department of Microbiology and Immunology and.
authors: B JoNell
authors: BJ
authors: Hamilton
authors: Division of Rheumatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors: Jonathan D
authors: JD
authors: Jones
authors: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Mei-Ling
authors: ML
authors: Yang
authors: Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors: Mark
authors: M
authors: Mamula
authors: Department of Microbiology and Immunology and.|Division of Pulmonology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors: Alix
authors: A
authors: Ashare
authors: Division of Pulmonology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors: Alex H
authors: AH
authors: Gifford
authors: Department of Microbiology and Immunology and.|Division of Rheumatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors: William Fc
authors: WF
authors: Rigby
mesh_terms: D000293:Adolescent; D000328:Adult; D000075422:Anti-Citrullinated Protein Antibodies / Q000097:blood; D023181:Antimicrobial Cationic Peptides / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015551:Autoimmunity; D001798:Blood Proteins / Q000276:immunology; D003429:Cross Reactions; D003550:Cystic Fibrosis / Q000276:immunology*; D065206:Extracellular Traps / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D011552:Pseudomonas Infections / Q000276:immunology; D011550:Pseudomonas aeruginosa; D055815:Young Adult
chemical_list: D000075422:Anti-Citrullinated Protein Antibodies; D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D008565:Membrane Proteins; C021623:bactericidal permeability increasing protein