Current Allergy and Asthma Reports

, Volume 10, Issue 5, pp 320–325 | Cite as

Immune Dysregulation in the Pathogenesis of Pulmonary Alveolar Proteinosis

Article

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare disease of the lung characterized by the accumulation of surfactant-derived lipoproteins within pulmonary alveolar macrophages and alveoli, resulting in respiratory insufficiency and increased infections. The disease is caused by a disruption in surfactant catabolism by alveolar macrophages due to loss of functional granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling. The underlying molecular mechanisms causing deficiencies in GM-CSF signaling are as follows: 1) high levels of neutralizing GM-CSF autoantibodies observed in autoimmune PAP; 2) mutations in CSF2RA, the gene encoding the α chain of the GM-CSF receptor, observed in hereditary PAP; and 3) reduced numbers and function of alveolar macrophages as a result of other clinical diseases seen in secondary PAP. Recent studies investigating the biology of GM-CSF have revealed that not only does this cytokine have an indispensable role in lung physiology, but it is also a critical regulator of innate immunity and lung host defense.

Keywords

Pulmonary alveolar proteinosis PAP GM-CSF GM-CSF receptor Alveolar macrophages Surfactant homeostasis Immune deficiency Autoimmunity 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Trapnell BC, Whitsett JA, Nakata K: Pulmonary alveolar proteinosis. N Engl J Med 2003, 349:2527–2539.CrossRefPubMedGoogle Scholar
  2. 2.
    • Carey B, Trapnell BC: The molecular basis of pulmonary alveolar proteinosis. Clin Immunol 2010, 135:223–235. This review provides an updated and comprehensive summary of the current literature in the field of PAP.CrossRefPubMedGoogle Scholar
  3. 3.
    Trapnell BC, Carey BC, Uchida K, Suzuki T: Pulmonary alveolar proteinosis, a primary immunodeficiency of impaired GM-CSF stimulation of macrophages. Curr Opin Immunol 2009, 21:514–521.CrossRefPubMedGoogle Scholar
  4. 4.
    Kitamura, T, Tanaka N, Watanabe J, et al.: Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med 1999, 190:875–880.CrossRefPubMedGoogle Scholar
  5. 5.
    Bonfield TL, Russell D, Burgess S, et al.: Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis. Am J Respir Cell Mol Biol 2002, 27:481–486.PubMedGoogle Scholar
  6. 6.
    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.CrossRefPubMedGoogle Scholar
  7. 7.
    •• Martinez-Moczygemba M, Doan ML, Elidemir O, et al.: Pulmonary alveolar proteinosis caused by deletion of the GM-CSFRalpha gene in the X chromosome pseudoautosomal region 1. J Exp Med 2008, 205:2711–2716. This study was the first to report the identification of a genetic deletion in the human GM-CSFRα gene contributing to hereditary PAP and reduced immune responsiveness. This study helped define PAP as a primary immunodeficiency disease of impaired GM-CSF stimulation of macrophages.CrossRefPubMedGoogle Scholar
  8. 8.
    •• Suzuki T, Sakagami T, Rubin BK, et al.: Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA. J Exp Med 2008, 205:2703–2710. This study was the first to report the identification of specific point mutations in the human GM-CSFRα gene leading to decreased GM-CSFR binding affinity to GM-CSF and thus contributing to hereditary PAP. This study helped define PAP as a primary immunodeficiency disease of impaired GM-CSF stimulation of macrophages.CrossRefPubMedGoogle Scholar
  9. 9.
    Dirksen U, Nishinakamura R, Groneck P, et al.: Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J Clin Invest 1997, 100:2211–2217.CrossRefPubMedGoogle Scholar
  10. 10.
    Dirksen U, Hattenhorst U, Schneider P, et al.: Defective expression of granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 receptor common beta chain in children with acute myeloid leukemia associated with respiratory failure. Blood 1998, 92:1097–1103.PubMedGoogle Scholar
  11. 11.
    Robb L, Drinkwater C, Metcalf D, et al.: Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. Proc Natl Acad Sci U S A 1995, 92:9565–9569.CrossRefPubMedGoogle Scholar
  12. 12.
    Nishinakamura R, Nakayama N, Hirabayashi Y, et al.: Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor exhibit lung pathology and impaired immune response, while beta IL3 receptor-deficient mice are normal. Immunity 1995, 2:211–222.CrossRefPubMedGoogle Scholar
  13. 13.
    Hamvas A, Cole FS, Nogee LM: Genetic disorders of surfactant proteins. Neonatology 2007, 91:311–317.CrossRefPubMedGoogle Scholar
  14. 14.
    Nogee LM, Dunbar AE III, Wert SE, et al.: A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med 2001, 344:573–579.CrossRefPubMedGoogle Scholar
  15. 15.
    Nogee LM, Garnier G, Dietz HC, et al.: A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest 1994, 93:1860–1863.CrossRefPubMedGoogle Scholar
  16. 16.
    Nogee LM, deMello DE, Dehner LP, Colten HR: Deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med 1993, 328:406–410.CrossRefPubMedGoogle Scholar
  17. 17.
    Rubin E, Weisbrod GL, Sanders DE: Pulmonary alveolar proteinosis: relationship to silicosis and pulmonary infection. Radiology 1980, 135:35–41.PubMedGoogle Scholar
  18. 18.
    Ruben FL, Talamo TS: Secondary pulmonary alveolar proteinosis occurring in two patients with acquired immune deficiency syndrome. Am J Med 1986, 80:1187–1190.CrossRefPubMedGoogle Scholar
  19. 19.
    Abdul Rahman JA, Moodley UP, Phillips MJ: Pulmonary alveolar proteinosis associated with psoriasis and complicated by mycobacterial infection: successful treatment with granulocyte-macrophage colony stimulating factor after a partial response to whole lung lavage. Respirology 2004, 9:419–422.Google Scholar
  20. 20.
    Cordonnier C, Fleury-Feith J, Escudier E, et al.: Secondary alveolar proteinosis is a reversible cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 1994, 149:788–794.PubMedGoogle Scholar
  21. 21.
    Iyonaga K, Suga M, Yamamoto T, et al.: Elevated bronchoalveolar concentrations of MCP-1 in patients with pulmonary alveolar proteinosis. Eur Respir J 1999, 14:383–389.CrossRefPubMedGoogle Scholar
  22. 22.
    Paine R 3rd, Morris SB, Jin H, et al.: Impaired functional activity of alveolar macrophages from GM-CSF-deficient mice. Am J Physiol Lung Cell Mol Physiol 2001, 281:L1210–L1218.PubMedGoogle Scholar
  23. 23.
    Stanley E, Lieschke GJ, Grail D, et al.: Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A 1994, 91:5592–5596.CrossRefPubMedGoogle Scholar
  24. 24.
    Zsengeller ZK, Reed JA, Bachurski CJ, et al.: Adenovirus-mediated granulocyte-macrophage colony-stimulating factor improves lung pathology of pulmonary alveolar proteinosis in granulocyte-macrophage colony-stimulating factor-deficient mice. Hum Gene Ther 1998, 9:2101–2109.CrossRefPubMedGoogle Scholar
  25. 25.
    Nishinakamura R, Wiler R, Dirksen U, et al.: The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation. J Exp Med 1996, 183:2657–2662.CrossRefPubMedGoogle Scholar
  26. 26.
    Reed JA, Ikegami M, Cianciolo ER, et al.: Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice. Am J Physiol 1999, 276:L556–L563.PubMedGoogle Scholar
  27. 27.
    Shibata Y, Berclaz PY, Chroneos ZC, et al.: GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity 2001, 15:557–567.Google Scholar
  28. 28.
    Miyajima A, Kitamura T, Harada N, et al.: Cytokine receptors and signal transduction. Annu Rev Immunol 1992, 10:295–331.CrossRefPubMedGoogle Scholar
  29. 29.
    Stone KD, Prussin C, Metcalfe DD: IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 2010, 125(2 Suppl 2):S73–S80.PubMedGoogle Scholar
  30. 30.
    Blanchard C, Rothenberg ME: Biology of the eosinophil. Adv Immunol 2009, 101:81–121.CrossRefPubMedGoogle Scholar
  31. 31.
    Metcalf D: Hematopoietic cytokines. Blood 2008, 111:485–491.CrossRefPubMedGoogle Scholar
  32. 32.
    Mellman I, Steinman RM: Dendritic cells: specialized and regulated antigen processing machines. Cell 2001, 106:255–258.CrossRefPubMedGoogle Scholar
  33. 33.
    Shibasaki T, Katayama N, Ohishi K, et al.: IL-3 cannot replace GM-CSF in inducing human monocytes to differentiate into Langerhans cells. Int J Oncol 2007, 30:549–555.PubMedGoogle Scholar
  34. 34.
    Fleetwood AJ, Cook AD, Hamilton JA: Functions of granulocyte-macrophage colony-stimulating factor. Crit Rev Immunol 2005, 25:405–428.CrossRefPubMedGoogle Scholar
  35. 35.
    Hamilton JA, Anderson GP: GM-CSF biology. Growth Factors 2004, 22:225–233.CrossRefPubMedGoogle Scholar
  36. 36.
    Seymour JF, Lieschke GJ, Grail D, et al.: Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood 1997, 90:3037–3049.PubMedGoogle Scholar
  37. 37.
    •• Hansen G, Hercus TR, McClure BJ, et al.: The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 2008, 134:496–507. This seminal paper reported the crystal structure of the ligated GM-CSFR, revealing an unexpected higher-order dodecamer complex of the receptor. The findings presented in this report provided a structural basis for understanding the mechanism of activation of βc-sharing cytokine receptors.CrossRefPubMedGoogle Scholar
  38. 38.
    •• Hercus TR, Thomas D, Guthridge MA, et al.: The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood 2009, 114:1289–1298. This updated and comprehensive review discusses the findings reported in the article by Hansen et al. [37••] and elegantly links GM-CSFR structure to cell signaling in health and disease. The authors delineate how the new insights in GM-CSFR activation can be used for the development of new therapeutics targeted at cancer and inflammatory diseases.CrossRefPubMedGoogle Scholar
  39. 39.
    Martinez-Moczygemba M, Huston DP: Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol 2003, 112:653–665.CrossRefPubMedGoogle Scholar
  40. 40.
    Guthridge MA, Powell JA, Barry EF, et al.: Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch. EMBO J 2006, 25:479–489.CrossRefPubMedGoogle Scholar
  41. 41.
    • Sakagami T, Uchida K, Suzuki T, et al.: Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis. N Engl J Med 2009, 361:2679–2681. This is the first direct demonstration of passive transfer of human anti–GM-CSF antibodies causing PAP.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Margarita Martinez-Moczygemba
    • 1
  • David P. Huston
    • 1
  1. 1.Departments of Microbial and Molecular Pathogenesis and MedicineCollege of Medicine and Clinical Science and Translational Research Institute, Texas A&M Health Science CenterHoustonUSA

Personalised recommendations