Pseudomonas aeruginosa is the principle pathogen implicated in progressive and recurrent respiratory infections in cystic fibrosis. Recently, we described impaired serum-mediated killing of P. aeruginosa in patients with bronchiectasis that was associated with increased severity of respiratory infections. This inhibition was mediated by high titres of O-antigen-specific IgG2 antibodies. These ‘inhibitory antibodies’ (iAbs) have been found in patients with bronchiectasis (24%), cystic fibrosis (33%) and post lung transplant (30%). Importantly, three patients with P. aeruginosa infection and iAbs have been successfully treated with plasmapheresis. All patients had immediate benefit from this treatment with a significant drop in hospitalisations, antibiotic use and markers of inflammation.
Here we determine the mechanisms that underlie the inhibition phenotype. We demonstrate that inhibitory antibodies can be of other subtypes such as IgA, but must be of high affinity. Inhibition does not seem to be dependent on LPS serotype, with IAbs specific to all prevalent P. aeruginosa serotypes having been detected. Purified O-antigen of various serotypes can also induce ‘inhibitory antibodies’ in a mouse model. Finally, LPS density and length are critical factors in the inhibition phenotype. We have demonstrated that biotinylated O-antigen can be used to specifically remove inhibitory antibodies in patient serum, restoring the bactericidal effect. These results will improve methods to detect and treat inhibitory antibodies. Finding ways to remove or counteract this antibody can lead to improvement in health without the need for antibiotics.