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GM-CSF Autoantibodies and Neutrophil Dysfunction in Pulmonary Alveolar Proteinosis.
Uchida, Kanji; Beck, David C.; Yamamoto, Takashi; Berclaz, Pierre-Yves; Abe, Shuichi; Staudt, Margaret K.; Carey, Brenna C.; Filippi, Marie-Dominique; Wert, Susan E.; Denson, Lee A.; Puchalski, Jonathan T.; Hauck, Diane M.; Trapnell, Bruce C.
[Article] New England Journal of Medicine. 356(6):567-579, February 8, 2007.

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Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

N Engl J Med 2007;356: 567-79.