Altered antibody isotype in cystic fibrosis: Possible role in opsonic deficiency

Abstract

Patients with cystic fibrosis (CF) whose respiratory tracts are colonized with Pseudomonas aeruginosa (PA) may develop a specific opsonic deficiency for alveolar macrophage phagocytosis of PA. We examined the possible role of altered antibody (Ab) isotype in this phenomenom by measuring serum levels and distribution of IgG and IgG subclass Ab (IgGl, IgG2, IgG3, and IgG4) to the major opsonic immunodeterminant, serotype-specific lipopolysaccharide (LPS), by means of enzyme-linked immunosorbent assays employing monoclonal secondary antibodies, and comparing these results to the serum opsonic capacity in an in vitro murine alveolar macrophage phagocytic assay. Twenty-one patients with CF who were colonized with PA had approximately a 30-fold elevation of PA LPS IgG Ab levels and higher IgG subclass 1-4 Ab compared to 10 uncolonized patients with CF and 11 healthy controls (p < 0.05-0.0005 depending on the isotype). Colonized patients with CF had a shift in PA LPS Ab distribution toward IgG3 compared to uncolonized patients with CF (p < 0.02). A surprising finding was that uncolonized patients with CF had lower levels (p < 0.05) and proportion (p < 0.002) of PA LPS IgG2 Ab than controls, with an apparent shift to higher levels and proportion of PA LPS IgG4 (p < 0.01). Serum from colonized patients with CF showed diminished opsonic capacity for phagocytosis of PA compared to uncolonized patients and controls (p < 0.005), with 42% showing inhibitory activity. Functional Ab was also found to be inhibitory at high (> 500 ng/ml) concentrations. Serum opsonic capacity appeared to include a noncomplement cofactor for optimal activity. Levels of PA LPS IgG4 but not IgGl-3 subclass Ab correlated inversely with opsonic capacity. We conclude that high levels of PA LPS IgG4 Ab may be inhibitory to normal pulmonary clearance of PA in colonized patients with CF, and that high levels of functional antibodies may also contribute to this specific acquired deficiency. The role of deficient IgG2 Ab responses to PA LPS and possibly other polysaccharide antigens in CF requires further study. © 1986 International Pediatric Research Foundation, Inc.