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Blood, 1 February 2004, Vol. 103, No. 3, pp. 1089-1098. Prepublished online as a Blood First Edition Paper on September 25, 2003; DOI 10.1182/blood-2003-05-1565. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1565v1 103/3/1089    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Uchida, K. Articles by Keicho, N. Search for Related Content PubMed PubMed Citation Articles by Uchida, K. Articles by Keicho, N. Related Collections Hematopoiesis and Stem Cells Immunobiology Phagocytes Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES 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 From the Department of Respiratory Diseases, Research Institute, International Medical Center of Japan, Tokyo; Department of Anesthesiology, Tokyo University Graduate School of Medicine; Bio-Product Technology Laboratory, Chugai Pharmaceutical, Tokyo; Department of Pathology, Tokyo Medical and Dental University School of Medicine; Department of Anesthesiology, Yokohama-city University School of Medicine, Kanagawa, Japan; Cincinnati Children's Hospital Medical Center, OH; and Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia. Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mice results in pulmonary alveolar proteinosis (PAP) from impaired surfactant catabolism by alveolar macrophages (AMs). Recently, we have shown that neutralizing anti-GM-CSF autoantibodies develop specifically in patients with idiopathic pulmonary alveolar proteinosis (iPAP). Analogous to murine PAP models, it is plausible that the autoantibodies reduce GM-CSF activity, resulting in AM dysfunction and surfactant accumulation. To examine this hypothesis, we estimated the neutralizing activity of the autoantibodies in the lungs of patients and characterized their biologic properties. GM-CSF bioactivity was completely abrogated in the bronchoalveolar lavage fluid (BALF) of patients with iPAP but not in healthy subjects. Autoantibodies were present in the alveoli in high concentrations and colocalized with GM-CSF. They recognized human GM-CSF with high avidity (KAV = 20.0 ± 7.5 pM) and high specificity, reacting with its superstructure and neutralizing GM-CSF activity to a level 4000 to 58 000 times the levels of GM-CSF normally present in the lung. Although target epitopes varied among patients, GM-CSF amino acids 78 to 94 were consistently recognized. Thus, autoantibodies bind GM-CSF with high specificity and high affinity, exist abundantly in the lung, and effectively block GM-CSF binding to its receptor, inhibiting AM differentiation and function. Our data strengthen the evidence associating anti-GM-CSF autoantibodies with the pathogenesis of this disease. (Blood. 2004;103:1089-1098) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Luisetti, G. Rodi, C. Perotti, I. Campo, F. Mariani, E. Pozzi, and B. C. Trapnell Plasmapheresis for treatment of pulmonary alveolar proteinosis Eur. Respir. J., May 1, 2009; 33(5): 1220 - 1222. [Abstract] [Full Text] [PDF] K. Uchida, K. Nakata, T. Suzuki, M. Luisetti, M. Watanabe, D. E. Koch, C. A. Stevens, D. C. Beck, L. A. Denson, B. C. Carey, et al. Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects Blood, March 12, 2009; 113(11): 2547 - 2556. [Abstract] [Full Text] [PDF] A. A. Frazier, T. J. Franks, E. O. Cooke, T.-L. H. Mohammed, R. D. Pugatch, and J. R. Galvin From the Archives of the AFIP: Pulmonary Alveolar Proteinosis RadioGraphics, May 1, 2008; 28(3): 883 - 899. [Abstract] [Full Text] [PDF] Y. Inoue, B. C. Trapnell, R. Tazawa, T. Arai, T. Takada, N. Hizawa, Y. Kasahara, K. Tatsumi, M. Hojo, T. Ichiwata, et al. Characteristics of a Large Cohort of Patients with Autoimmune Pulmonary Alveolar Proteinosis in Japan Am. J. Respir. Crit. Care Med., April 1, 2008; 177(7): 752 - 762. [Abstract] [Full Text] [PDF] K. Bendtzen, M. Svenson, M. B. Hansen, T. Busch, S. Bercker, U. Kaisers, K. Uchida, D. C. Beck, and B. C. Trapnell GM-CSF Autoantibodies in Pulmonary Alveolar Proteinosis N. Engl. J. Med., May 10, 2007; 356(19): 2001 - 2002. [Full Text] [PDF] K. Uchida, D. C. Beck, T. Yamamoto, P.-Y. Berclaz, S. Abe, M. K. Staudt, B. C. Carey, M.-D. Filippi, S. E. Wert, L. A. Denson, et al. GM-CSF Autoantibodies and Neutrophil Dysfunction in Pulmonary Alveolar Proteinosis N. Engl. J. Med., February 8, 2007; 356(6): 567 - 579. [Abstract] [Full Text] [PDF] P.-Y. Berclaz, B. Carey, M.-D. Fillipi, K. Wernke-Dollries, N. Geraci, S. Cush, T. Richardson, J. Kitzmiller, M. O'Connor, C. Hermoyian, et al. GM-CSF Regulates a PU.1-Dependent Transcriptional Program Determining the Pulmonary Response to LPS Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 114 - 121. [Abstract] [Full Text] [PDF] F-C Lin, G-D Chang, M-S Chern, Y-C Chen, and S-C Chang Clinical significance of anti-GM-CSF antibodies in idiopathic pulmonary alveolar proteinosis Thorax, June 1, 2006; 61(6): 528 - 534. [Abstract] [Full Text] [PDF] M. E. Wylam, R. Ten, U. B. S. Prakash, H. F. Nadrous, M. L. Clawson, and P. M. Anderson Aerosol granulocyte-macrophage colony-stimulating factor for pulmonary alveolar proteinosis. Eur. Respir. J., March 1, 2006; 27(3): 585 - 593. [Abstract] [Full Text] [PDF] S. Y. Patel, L. Ding, M. R. Brown, L. Lantz, T. Gay, S. Cohen, L. A. Martyak, B. Kubak, and S. M. Holland Anti-IFN-{gamma} Autoantibodies in Disseminated Nontuberculous Mycobacterial Infections J. Immunol., October 1, 2005; 175(7): 4769 - 4776. [Abstract] [Full Text] [PDF] R. Tazawa, E. Hamano, T. Arai, H. Ohta, O. Ishimoto, K. Uchida, M. Watanabe, J. Saito, M. Takeshita, Y. Hirabayashi, et al. Granulocyte-Macrophage Colony-Stimulating Factor and Lung Immunity in Pulmonary Alveolar Proteinosis Am. J. Respir. Crit. Care Med., May 15, 2005; 171(10): 1142 - 1149. [Abstract] [Full Text] [PDF] R. Chiarini, O. Moran, and R. P. Revoltella Identification of an Antigenic Domain Near the C Terminus of Human Granulocyte-Macrophage Colony-stimulating Factor and Its Spatial Localization J. Biol. 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