The role for neutrophil extracellular traps in cystic fibrosis autoimmunity
Sladjana Skopelja, B. JoNell Hamilton, Jonathan D. Jones, Mei-Ling Yang, Mark Mamula, Alix Ashare, Alex H. Gifford, William F.C. Rigby
Sladjana Skopelja, B. JoNell Hamilton, Jonathan D. Jones, Mei-Ling Yang, Mark Mamula, Alix Ashare, Alex H. Gifford, William F.C. Rigby
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Research Article Immunology

The role for neutrophil extracellular traps in cystic fibrosis autoimmunity

Abstract

While respiratory failure in cystic fibrosis (CF) frequently associates with chronic infection by Pseudomonas 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 that P. aeruginosa–mediated NET formation results in BPI cleavage by P. aeruginosa elastase, which suggests a novel mechanism in the development of autoimmunity to BPI. In accordance with this model, autoantibodies associated with presence of P. aeruginosa on sputum culture. Finally, our results provide a role for autoimmunity in CF disease severity, as autoantibody levels associate with diminished lung function.

Authors

Sladjana Skopelja, B. JoNell Hamilton, Jonathan D. Jones, Mei-Ling Yang, Mark Mamula, Alix Ashare, Alex H. Gifford, William F.C. Rigby

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Figure 5

Anti-BPI IgG correlates with FEV1 and anti-Cif immune response to P.

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Anti-BPI IgG correlates with FEV1 and anti-Cif immune response to P. ae...
aeruginosain a US adult CF cohort. (A) Anti-CTBPI IgG levels determined by ELISA negatively correlate with pulmonary function in cystic fibrosis (CF) patients (FEV1 percent predicted), as determined by Pearson correlation analysis (n = 38, r = –0.664, P < 0.0001). P. aeruginosa infection status of patients is denoted: P. aeruginosa+ (white circle) and P. aeruginosa– (black circle). (B) Anti-BPI IgG titers were measured in representative CF bronchoalveolar lavage (BAL) samples that previously demonstrated serum anti-BPI reactivity by ELISA (ANOVA, n = 3), ***P < 0.001. (C) Higher anti-CTBPI IgG levels associate with positive P. aeruginosa sputum culture (PA+) in CF patients (n = 38), (D) particularly with presence of the mucoid P. aeruginosa strains (mPA) (n = 38). (E) Anti-BPI IgG titers are higher in CF patients that do not carry the F508del homozygous CFTR gene mutation (n = 38). (F) Anti-Cif (10 μg/ml) IgG levels are higher in CF patients with anti-BPI autoantibodies (Anti-BPI IgG+) compared with patients without reactivity to BPI (Anti-BPI IgG–) (n = 28). (C–F) Significance between two groups was determined by Student’s t test with Welch’s correction; *P < 0.05, **P < 0.01, ***P < 0.001; error bars represent mean ± SEM. FEV 1%, forced expiratory volume in 1 second percent predicted; Cif, CFTR inhibitory factor; BPI, bactericidal permeability-increasing protein.