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Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-05-1565.
Submitted May 27, 2003
Accepted September 16, 2003
High affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis
Kanji Uchida, Koh Nakata*, Bruce C Trapnell, Takahiro Terakawa, Emi Hamano, Ayako Mikami, Ikumi Matsushita, John F Seymour, Masayoshi Oh-eda, Ikuo Ishige, Yoshinobu Eishi, Takayuki Kitamura, Yoshitsugu Yamada, Kazuo Hanaoka, and Naoto Keicho
Department of Respiratory Diseases, International Medical Center of Japan, Tokyo, Japan
Department of Anesthesiology, Tokyo University Graduate School of Medicine, Tokyo, Japan
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Bio-Product Technology Lab, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Department of Pathology, Tokyo Medical and Dental University, Tokyo, Japan
Department of Anesthesiology, Yokohama City University School of Medicine, Kanagawa, Japan
* Corresponding author; email: knak{at}ri.imcj.go.jp.
Deficiency of granulocyte macrophage-colony stimulating factor (GM-CSF) in mice results in pulmonary alveolar proteinosis (PAP) due to impaired surfactant catabolism by alveolar macrophages (AMs). Recently, we have shown that neutralizing anti-GM-CSF autoantibodies (autoAbs) occur specifically in individuals with idiopathic pulmonary alveolar proteinosis (iPAP). Analogous to murine PAP models, it is plausible that the autoAbs reduce GM-CSF activity resulting in AM dysfunction and surfactant accumulation. To examine this hypothesis, we estimated the neutralizing activity of the autoAbs in the lung of patients and characterized their biological properties. GM-CSF bioactivity was completely abrogated in bronchoalveolar lavage fluid (BALF) of iPAP but not in normal subjects. The autoAbs were present in the alveoli in high concentrations and colocalized with GM-CSF. The autoAbs recognized human GM-CSF with high avidity (KAV=20.0±7.5pM) and high specificity, reacting with its superstructure, eliciting 10-500 times greater neutralizing activities than commercial Abs. Although target epitopes varied among patients, GM-CSF amino acids 78-94 were consistently recognized. Thus, the autoAbs bind GM-CSF with high specificity and high affinity, abundantly exist in the lung, and effectively block GM-CSF binding to its receptor, inhibiting AM differentiation and function. Our data strengthen the evidence associating these anti-GM-CSF autoAbs with the pathogenesis of this disease.
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