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Altered antibody isotype in cystic fibrosis: possible role in opsonic deficiency
Insights
Patients with cystic fibrosis (CF) and Pseudomonas aeruginosa (PA) colonization exhibit reduced opsonic capacity for PA phagocytosis. Altered antibody (Ab) isotype levels, particularly IgG2 and IgG3, correlate with this deficiency, impacting immune response in CF patients.
Area of Science:
- Immunology
- Microbiology
- Pulmonology
Background:
- Cystic fibrosis (CF) patients colonized with Pseudomonas aeruginosa (PA) may have impaired alveolar macrophage phagocytosis of PA.
- This deficiency might be linked to altered antibody (Ab) isotype responses targeting PA's lipopolysaccharide (LPS).
Purpose of the Study:
- To investigate the role of altered antibody isotype in the opsonic deficiency observed in CF patients colonized with PA.
- To compare serum antibody levels, distribution, and opsonic capacity in colonized CF patients, uncolonized CF patients, and healthy controls.
Main Methods:
- Enzyme-linked immunosorbent assays (ELISAs) were used to measure serum IgG and IgG subclass (IgG1-4) antibodies to PA LPS.
- Monoclonal secondary antibodies were employed in ELISAs.
- An in vitro murine alveolar macrophage phagocytic assay was used to assess serum opsonic capacity.
Main Results:
- Colonized CF patients showed significantly higher PA LPS IgG Ab levels and IgG subclasses compared to controls.
- A shift towards IgG3 was observed in colonized patients, while uncolonized CF patients had lower IgG2 and higher IgG4 levels compared to controls.
- Serum from colonized CF patients demonstrated diminished opsonic capacity for PA phagocytosis, with some sera showing inhibitory activity.
Conclusions:
- Altered antibody isotype distribution, particularly deficiencies in IgG2 and elevations in IgG3/IgG4, is associated with impaired opsonic capacity in CF patients colonized with PA.
- These antibody alterations may contribute to the reduced phagocytic activity against PA in the CF lung.
- Serum opsonic capacity involves non-complement cofactors for optimal activity.
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 phenomenon by measuring serum levels and distribution of IgG and IgG subclass Ab (IgG1, 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 less than 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 less than 0.02). A surprising finding was that uncolonized patients with CF had lower levels (p less than 0.05) and proportion (p less than 0.002) of PA LPS IgG2 Ab than controls, with an apparent shift to higher levels and proportion of PA LPS IgG4 (p less than 0.01). Serum from colonized patients with CF showed diminished opsonic capacity for phagocytosis of PA compared to uncolonized patients and controls (p less than 0.005), with 42% showing inhibitory activity. Functional Ab was also found to be inhibitory at high (greater than 500 ng/ml) concentrations. Serum opsonic capacity appeared to include a noncomplement cofactor for optimal activity.(ABSTRACT TRUNCATED AT 250 WORDS)