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
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
N Engl J Med. 2007 Feb 8;356(6):567-79. doi: 10.1056/NEJMoa062505.
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.
肺泡蛋白沉积症患者因感染导致的死亡率增加与抗粒细胞-巨噬细胞集落刺激因子（GM-CSF）的自身抗体水平升高有关。我们检验了以下假设：肺泡蛋白沉积症患者的中性粒细胞功能受损，且GM-CSF自身抗体导致了这种功能障碍。
我们研究了12例肺泡蛋白沉积症患者、61名健康对照者以及12例患有囊性纤维化或终末期肝病的对照者。我们还研究了GM-CSF基因敲除小鼠和野生型小鼠。我们评估了基础中性粒细胞功能、GM-CSF激发以增强抗菌功能后的中性粒细胞功能，以及高度纯化的GM-CSF自身抗体在体外和体内对中性粒细胞功能的影响。
肺泡蛋白沉积症患者的中性粒细胞具有正常的超微结构和分化标志物，但基础功能以及GM-CSF激发后的抗菌功能受损。GM-CSF基因敲除小鼠的基础中性粒细胞功能也降低，但GM-CSF激发后的功能未受损。从肺泡蛋白沉积症患者分离的亲和纯化GM-CSF自身抗体与健康对照者的血液标本孵育后，以剂量依赖方式再现了肺泡蛋白沉积症特征性的中性粒细胞功能障碍。向野生型小鼠注射小鼠GM-CSF抗体也导致中性粒细胞功能障碍。
肺泡蛋白沉积症患者的中性粒细胞抗菌功能受损，原因是存在GM-CSF自身抗体。这些自身抗体的作用表明GM-CSF是中性粒细胞功能的重要调节因子。
