Increased mortality from infection in patients with pulmonary alveolar proteinosis occurs in association with high levels of autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). We tested the hypothesis that neutrophil functions are impaired in patients with pulmonary alveolar proteinosis and that GM-CSF autoantibodies cause the dysfunction.

We studied 12 subjects with pulmonary alveolar proteinosis, 61 healthy control subjects, and 12 control subjects with either cystic fibrosis or end-stage liver disease. We also studied GM-CSF^−/− mice and wild-type mice. We evaluated basal neutrophil functions, neutrophil functions after priming by GM-CSF to augment antimicrobial functions, and the effects of highly purified GM-CSF autoantibodies on neutrophil functions in vitro and in vivo.

Neutrophils from subjects with pulmonary alveolar proteinosis had normal ultrastructure and differentiation markers but impaired basal functions and antimicrobial functions after GM-CSF priming. GM-CSF^−/− mice also had reduced basal neutrophil functions, but functions after GM-CSF priming were unimpaired. The neutrophil dysfunction characteristic of pulmonary alveolar proteinosis was reproduced in a dose-dependent fashion in blood specimens from healthy control subjects after incubation with affinity-purified GM-CSF autoantibodies isolated from patients with pulmonary alveolar proteinosis. The injection of mouse GM-CSF antibodies into wild-type mice also caused neutrophil dysfunction.

The antimicrobial functions of neutrophils are impaired in patients with pulmonary alveolar proteinosis, owing to the presence of GM-CSF autoantibodies. The effects of these autoantibodies show that GM-CSF is an essential regulator of neutrophil functions.