The nature and role of autoimmunity in cystic fibrosis lung immunopathology

Abstract

Cystic Fibrosis (CF) arises due to the altered activity of the CF transmembrane regulator (CFTR) protein. While the lung disease in CF is associated with chronic infection by Pseudomonas aeruginosa (PA), identical CFTR mutations exhibit considerable clinical variability. To elucidate this, we evaluated the autoantibody response to bactericidal permeability-increasing protein (BPI) and anti-citrullinated proteins (ACPA) in CF patients (n=38) and compared it with the autoantibody profile in sera from Rheumatoid Arthritis (RA) patients (n=50), given the association of airway inflammation with ACPA induction in RA. The presence of ACPA was restricted to RA patients; no antibodies to BPI were seen. In contrast, 42% of CF patients had anti-BPI IgG, but no ACPA. Contrary to ACPA, the autoantibodies to BPI did not bind to post-translationally modified epitopes but mapped to the protein C-terminus (CT-BPI). Patients with high levels of anti-BPI IgG exhibited worse lung function (lower FEV1), the presence of anti-Cif antibodies (CFTR inhibitory factor), and the absence of the homozygous F508del CFTR mutation. Neutrophil incubation with PA led to the cleavage of BPI into a ~32kDa fragment corresponding to CT-BPI, in an elastase dependent process. In addition, anti-BPI IgG levels were higher in patients harboring the more pathogenic (mucoid) PA strain infection. These findings prompt the model that autoantibody responses reflect greater impairment of PA clearance, which is the hallmark of this chronic inflammatory disorder. Alternatively, given that no clear association between bacterial colonization and CF disease severity exists, the model that autoantibodies independently exacerbate CF lung pathology merits consideration.