Correspondence
GM-CSF Autoantibodies in Pulmonary Alveolar Proteinosis
N Engl J Med 2007; 356:2001-2002May 10, 2007
- Article
To the Editor:
Uchida et al. (Feb. 8 issue)1 report that in patients with pulmonary alveolar proteinosis, neutrophil functions are impaired because of autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF). Although this may be true, neutralizing GM-CSF autoantibodies are found at high levels in a small proportion (<5%) of healthy persons. The Gammagard immune globulin used as a “negative” control by Uchida et al. contains these autoantibodies.2,3 Pulmonary alveolar proteinosis has been described in patients without autoantibodies against GM-CSF,4 and pathological specimens from patients with this condition may respond to preparations of immunoglobulin containing these autoantibodies.5 When primed with 10 ng of GM-CSF per milliliter, whole-blood neutrophils from patients with pulmonary alveolar proteinosis were severely impaired, presumably because most GM-CSF adhered to autoantibodies in the blood. However, without investigating whether GM-CSF at high autoantibody-saturating doses can salvage neutrophil functions in pulmonary alveolar proteinosis, one cannot exclude the possibility that neutrophil dysfunction in pulmonary alveolar proteinosis involves additional factors.
5 ReferencesKlaus Bendtzen, M.D., D.M.Sc.
Morten Svenson, Ph.D.
Morten B. Hansen, M.D., D.M.Sc.
Rigshospitalet National University Hospital, DK-2100 Copenhagen, Denmark
kben@mail.dk 1
Uchida K ,Beck DC ,Yamamoto T , et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med 2007;356:567-579
Full Text | Web of Science | Medline2
Svenson M ,Hansen MB ,Ross C , et al. Antibody to granulocyte-macrophage colony-stimulating factor is a dominant anti-cytokine activity in human IgG preparations. Blood 1998;91:2054-2061
Web of Science | Medline3
Bendtzen K ,Hansen MB ,Ross C ,Svenson M . High-avidity autoantibodies to cytokines. Immunol Today 1998;19:209-211
CrossRef | Medline4
Lin FC ,Chang GD ,Chern MS ,Chen YC ,Chang SC . Clinical significance of anti-GM-CSF antibodies in idiopathic pulmonary alveolar proteinosis. Thorax 2006;61:528-534
CrossRef | Web of Science | Medline5
Cho K ,Nakata K ,Ariga T , et al. Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration. Respirology 2006;11:Suppl:S74-S77
CrossRef | Web of Science | Medline
To the Editor:
Uchida and colleagues postulate the use of a humanized monoclonal GM-CSF antibody for the treatment of the acute respiratory distress syndrome (ARDS), which they regard as a chronic inflammatory disorder. We believe this proposal is incorrect. First, ARDS has an acute onset and is related to sepsis in most cases.1 Second, elevated concentrations of GM-CSF in bronchoalveolar-lavage specimens have been found to correlate positively with survival,2 suggesting a beneficial effect of GM-CSF in ARDS. In patients with severe sepsis and acute respiratory dysfunction (40% of patients with ARDS), the administration of GM-CSF at low doses over a period of 5 days improved gas exchange in parallel with a reduction in alveolar neutrophils.3 In light of these findings, the use of human recombinant GM-CSF rather than its antibody might offer a valuable new option for ARDS treatment.
3 ReferencesThilo Busch, Ph.D.
Sven Bercker, M.D.
Udo Kaisers, M.D.
University of Leipzig, D-04103 Leipzig, Germany1
Rubenfeld GD ,Caldwell E ,Peabody E , et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005;353:1685-1693
Full Text | Web of Science | Medline2
Matute-Bello G ,Liles WC ,Radella F II , et al. Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med 2000;28:1-7
CrossRef | Web of Science | Medline3
Presneill JJ ,Harris T ,Stewart AG ,Cade JF ,Wilson JW . A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med 2002;166:138-143
CrossRef | Web of Science | Medline
Author/Editor Response
With regard to the comments by Bendtzen and colleagues, their previous report showed increased autoantibodies against GM-CSF in 4 of 1258 apparently healthy donors, and another study1 showed non-neutralizing autoantibodies in 38 patients and neutralizing autoantibodies in 3 among 425 patients who had autoimmune diseases without evidence of pulmonary alveolar proteinosis. We calculate that the levels of total autoantibodies in these latter three patients were 2.9, 8.6, and 17.3 μg per milliliter, respectively. Our data are consistent with previous reports that autoantibody levels are markedly elevated in patients with primary pulmonary alveolar proteinosis (mean [±SE] value in a total of 158 patients, 113±7 μg per milliliter)2,3 and are very low (≤1 μg per milliliter) in patients with secondary pulmonary alveolar proteinosis, congenital pulmonary alveolar proteinosis, or other lung diseases and in healthy controls.3 The autoantibody level is only 11 μg per milligram of protein in Gammagard (equivalent to approximately 2 to 3 μg per millilter in serum). In pulmonary alveolar proteinosis, polyclonal autoantibodies are both neutralizing and non-neutralizing, and levels of autoantibodies do not correlate with disease severity.2,4
These puzzling observations are explained by the concept of a “critical threshold” level of neutralizing autoantibodies (not total autoantibodies) that is required to reduce GM-CSF bioactivity to a level that impairs myeloid-cell functions.2 Assuming that 50% of autoantibodies are neutralizing, we estimate that the critical threshold level is between 8 and 22 μg per milliliter. Our hypothesis is supported by the dose-dependent rescue of neutrophil function (the CD11b stimulation index) at higher concentrations of GM-CSF. In a group of five patients with pulmonary alveolar proteinosis, all had an increase in the CD11b stimulation index, reaching 93±11% of the control value at 100 ng per milliliter or more.
With regard to the comments by Busch and colleagues, GM-CSF has both short-term and long-term effects on myeloid cells, as well as direct effects on respiratory epithelium. ARDS is a heterogeneous syndrome with distinct phases, including exudative, proliferative, and fibrotic phases. Similarly, the distinct phases of sepsis are the at-risk, hyperinflammatory, and immunoparalytic phases. We propose that although a subgroup of patients with ARDS may benefit from augmentation of GM-CSF bioactivity,5 another subgroup may benefit from neutralization of GM-CSF bioactivity.
5 ReferencesKanji Uchida, M.D., Ph.D.
David C. Beck, M.D., Ph.D.
Bruce C. Trapnell, M.D.
Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
bruce.trapnell@cchmc. org 1
Meager A ,Wadhwa M ,Bird C , et al. Spontaneously occurring neutralizing antibodies against granulocyte-macrophage colony-stimulating factor in patients with autoimmune disease. Immunology 1999;97:526-532
CrossRef | Web of Science | Medline2
Uchida K ,Nakata K ,Trapnell BC , et al. High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis. Blood 2004;103:1089-1098
CrossRef | Web of Science | Medline3
Trapnell BC ,Whitsett JA ,Nakata K . Pulmonary alveolar proteinosis. N Engl J Med 2003;349:2527-2539
Full Text | Web of Science | Medline4
Seymour JF ,Doyle IR ,Nakata K , et al. Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 2003;58:252-257
CrossRef | Web of Science | Medline5
Trapnell BC . Granulocyte macrophage-colony stimulating factor augmentation therapy in sepsis: is there a role? Am J Respir Crit Care Med 2002;166:129-130
CrossRef | Web of Science | Medline
- Citing Articles (7)
Citing Articles
1
K. Uchida, B. Carey, T. Suzuki, K. Nakata, B. Trapnell. (2010) Response: Granulocyte/macrophage colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy persons. Blood 115:2, 431-433
CrossRef2
Sakagami, Takuro, Uchida, Kanji, Suzuki, Takuji, Carey, Brenna C., Wood, Robert E., Wert, Susan E., Whitsett, Jeffrey A., Trapnell, Bruce C., , Luisetti, Maurizio, . (2009) Human GM-CSF Autoantibodies and Reproduction of Pulmonary Alveolar Proteinosis. New England Journal of Medicine 361:27, 2679-2681
Full Text3
Bruce C Trapnell, Brenna C Carey, Kanji Uchida, Takuji Suzuki. (2009) Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages. Current Opinion in Immunology 21:5, 514-521
CrossRef4
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, N. Keicho, J. P. Krischer, Y. Yamada, B. C. Trapnell. (2009) Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood 113:11, 2547-2556
CrossRef5
Carina de Lemos Rieper, Pia Galle, Morten Bagge Hansen. (2009) Characterization and potential clinical applications of autoantibodies against cytokines. Cytokine & Growth Factor Reviews 20:1, 61-75
CrossRef6
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, N. Keicho, J. P. Krischer, Y. Yamada, B. C. Trapnell. (2009) Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. Blood 113:11, 2547
CrossRef7
Sapandeep K. Singh, Dalia G. Galicia, David P. Huston. (2007) Clinical trials report. Current Allergy and Asthma Reports 7:5, 319-322
CrossRef
