Idiopathic Pulmonary Alveolar Proteinosis as an Autoimmune Disease with Neutralizing Antibody against Granulocyte/Macrophage Colony-Stimulating Factor

doi:10.1084/jem.190.6.875

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© The Rockefeller University Press, 0022-1007/1999/9/875/ $5.00
The Journal of Experimental Medicine, Volume 190, Number 6, September 20, 1999 875-880

Brief Definitive Report

Idiopathic Pulmonary Alveolar Proteinosis as an Autoimmune Disease with Neutralizing Antibody against Granulocyte/Macrophage Colony-Stimulating Factor

Takayuki Kitamura^a, Naohiko Tanaka^a^,b, Junichi Watanabe^a, Uchida^a, Shiro Kanegasaki^a, Yoshitsugu Yamada^a, and Koh Nakata

^a The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
^b Kitasato University School of Medicine, Kanagawa 228-8655, Japan
Laboratory of Culture Collection, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan.81-3-5449-525481-3-5449-5391

kinkabu{at}hgc.ims.u-tokyo.ac.jp

Idiopathic pulmonary alveolar proteinosis (I-PAP) is a raredisease of unknown etiology in which the alveoli fill with lipoproteinaceousmaterial. We report here that I-PAP is an autoimmune diseasewith neutralizing antibody of immunoglobulin G isotype againstgranulocyte/macrophage colony-stimulating factor (GM-CSF). Theantibody was found to be present in all specimens of bronchoalveolarlavage fluid obtained from 11 I-PAP patients but not in samplesfrom 2 secondary PAP patients, 53 normal subjects, and 14 patientswith other lung diseases. It specifically bound GM-CSF and neutralizedbioactivity of the cytokine in vitro. The antibody was alsofound in sera from all I-PAP patients examined but not in serafrom a secondary PAP patient or normal subjects, indicatingthat it exists systemically in I-PAP patients. As lack of GM-CSFsignaling causes PAP in congenital cases and PAP-like diseasein murine models, our findings strongly suggest that neutralizationof GM-CSF bioactivity by the antibody causes dysfunction ofalveolar macrophages, which results in reduced surfactant clearance.

Key Words: autoantibody • granulocyte/macrophage colony-stimulating factor • pulmonary alveolar proteinosis • alveolar macrophage • surfactant protein

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