Correspondence

Human GM-CSF Autoantibodies and Reproduction of Pulmonary Alveolar Proteinosis

N Engl J Med 2009; 361:2679-2681December 31, 2009

Article

To the Editor:

Idiopathic pulmonary alveolar proteinosis is a rare disease in which surfactant lipids and proteins accumulate in pulmonary alveolar macrophages and alveoli, resulting in respiratory insufficiency and, in severe cases, respiratory failure.1 Granulocyte–macrophage colony-stimulating factor (GM-CSF) autoantibodies occur in these patients2 and may mediate the pathogenesis of this disease, but they are also present in healthy persons and in immune globulin prepared from plasma obtained from healthy persons. Since GM-CSF is required for surfactant catabolism by alveolar macrophages in mice, we hypothesized that high levels of GM-CSF autoantibodies (i.e., levels sufficient to eliminate endogenous GM-CSF priming of myeloid cells) could cause idiopathic pulmonary alveolar proteinosis by impairing surfactant clearance by alveolar macrophages.3 We previously found that high levels of GM-CSF autoantibodies are specifically associated with idiopathic pulmonary alveolar proteinosis4 and can be isolated in pure form from these patients.5

We administered highly purified GM-CSF autoantibodies derived from a patient with idiopathic pulmonary alveolar proteinosis to healthy nonhuman primates (Macaca fascicularis). These autoantibodies were administered intravenously, and serum levels of 40 μg per milliliter or more were maintained for 10 months. A marked reduction in levels of GM-CSF–stimulated CD11b in blood leukocytes indicated that GM-CSF signaling was blocked; these results were identical to those in patients with idiopathic pulmonary alveolar proteinosis.5 A diffuse, patchy distribution of lung lesions composed of well-preserved alveoli filled with eosinophilic, lipoproteinaceous material and enlarged, foamy alveolar macrophages developed in the macaques that received GM-CSF autoantibodies (Figure 1AFigure 1Effects of Human GM-CSF Autoantibodies in Nonhuman Primates.). Alveolar macrophages and intraalveolar material stained positively for surfactant protein B (Figure 1B) and lipid (Figure 1C). Ultrastructural evaluation revealed that alveolar macrophages were engorged with lipid droplets and lamellar inclusion bodies (Figure 1D), the numbers of which were both significantly increased as compared with those of a control primate that was injected with saline (Figure 1E). The bronchoalveolar-lavage fluid had a milky appearance and increased amounts of surfactant phospholipids and surfactant proteins as compared with the control fluid, which was normal in appearance and composition (not shown). GM-CSF autoantibodies from a patient with idiopathic pulmonary alveolar proteinosis or from a primate injected with patient-derived GM-CSF autoantibodies blocked the GM-CSF–stimulated increase in cell-surface CD11b levels in leukocytes (Figure 1F).5 Together, these results show that GM-CSF autoantibodies reproduce the pathologic manifestations of idiopathic pulmonary alveolar proteinosis and provide strong evidence of causality in human idiopathic pulmonary alveolar proteinosis, including disease association, isolation in pure form, reproduction of disease in healthy macaques, and reisolation from previously healthy macaques who were injected with GM-CSF autoantibodies. The term “autoimmune pulmonary alveolar proteinosis” can now be used instead of “idiopathic pulmonary alveolar proteinosis” to describe this disease. These observations have potential therapeutic implications for pulmonary alveolar proteinosis and for the potential use of GM-CSF autoantibodies to treat inflammatory and autoimmune disorders.

Takuro Sakagami, M.D., Ph.D.
Kanji Uchida, M.D., Ph.D.
Takuji Suzuki, M.D., Ph.D.
Brenna C. Carey, Ph.D.
Robert E. Wood, M.D., Ph.D.
Susan E. Wert, Ph.D.
Jeffrey A. Whitsett, M.D.
Bruce C. Trapnell, M.D.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH

Maurizio Luisetti, M.D.
University of Pavia, Pavia, Italy
bruce.trapnell@cchmc.org

Supported in part by grants from the National Heart, Lung, and Blood Institute (HL085453, to Dr. Trapnell) and the National Center for Research Resources and the Office of Rare Diseases of the National Institutes of Health (RR019498, to Dr. Trapnell).

Dr. Wood reports receiving grant support from Olympus. No other potential conflict of interest relevant to this letter was reported.

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Citing Articles (5)

Citing Articles

1. 1

   J Pidala, F Khalil, H Fernandez. (2011) Pulmonary alveolar proteinosis following allogeneic hematopoietic cell transplantation. Bone Marrow Transplantation 46:11, 1480-1483
   CrossRef

2. 2

   Maurizio Luisetti, Philipp Kroneberg, Takuji Suzuki, Zamir Kadija, Bernhard Muellinger, Ilaria Campo, Juliane Gleske, Giuseppe Rodi, William C. Zimlich, Francesca Mariani, Fabio Ferrari, Manuel Frey, Bruce C. Trapnell. (2011) Physical properties, lung deposition modeling, and bioactivity of recombinant GM-CSF aerosolised with a highly efficient nebulizer. Pulmonary Pharmacology & Therapeutics 24:1, 123-127
   CrossRef

3. 3

   Xinlun Tian, Jinmei Luo, Kai-Feng Xu, Lan Wang, Jiong Zhou, Ruie Feng, Yaosong Gui, Juan Wang, Wenbing Xu, Yi Xiao, Yuanjue Zhu. (2011) Impaired lipid metabolism in idiopathic pulmonary alveolar proteinosis. Lipids in Health and Disease 10:1, 54
   CrossRef

4. 4

   Shinya Urano, Chinatsu Kaneko, Takahito Nei, Natsuki Motoi, Ryushi Tazawa, Masato Watanabe, Masahiro Tomita, Takahiro Adachi, Hiroko Kanazawa, Koh Nakata. (2010) A cell-free assay to estimate the neutralizing capacity of granulocyte–macrophage colony-stimulating factor autoantibodies. Journal of Immunological Methods 360:1-2, 141-148
   CrossRef

5. 5

   Brenna Carey, Bruce C. Trapnell. (2010) The molecular basis of pulmonary alveolar proteinosis. Clinical Immunology 135:2, 223-235
   CrossRef