Skip to main content
PMC home page
Thorax logoLink to Thorax
. 2005 Jan;60(1):39–44. doi: 10.1136/thx.2004.021329

Anti-GM-CSF antibodies in paediatric pulmonary alveolar proteinosis

P Latzin 1, M Tredano 1, Y Wust 1, J de Blic 1, T Nicolai 1, B Bewig 1, F Stanzel 1, D Kohler 1, M Bahuau 1, M Griese 1
PMCID: PMC1747161  PMID: 15618581

Abstract

Background: Auto-antibodies against granulocyte-macrophage colony stimulating factor (GM-CSF) may be central to the pathogenesis of adult sporadic pulmonary alveolar proteinosis (PAP). The role of anti-GM-CSF auto-antibodies in paediatric forms of PAP is as yet unclear.

Methods: Anti-GM-CSF auto-antibodies were determined with the help of an antigen capture assay using serum and/or bronchoalveolar lavage (BAL) fluid from 27 patients with PAP (nine adults, 15 children, three neonates) and from 185 children with different diseases as disease controls (various pulmonary conditions and patients with malignancies).

Results: Anti-GM-CSF auto-antibodies were detected in the serum of five of seven adult PAP patients. They were not found in the serum of any of the children or neonates with PAP nor in any of the disease control patients. Raised anti-GM-CSF titres were found in BAL fluid from three of four adult patients with PAP. Anti-GM-CSF auto-antibodies were detected in BAL fluid of only one of the 15 children (age at diagnosis 11 years, age at BAL 24 years) and in none of the neonates with PAP, nor in any of the disease control patients.

Conclusions: The presence of anti-GM-CSF auto-antibodies seems to define an autoimmune disease underlying most of the adult sporadic type of PAP, but age at diagnosis may cause an overlap with children in some rare instances. In most of the children and all of the neonates the anti-GM-CSF titres were not significantly increased, indicating that alternative explanations are needed for the pathogenesis of the disease in these patients.

Full Text

The Full Text of this article is available as a PDF (140.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barraclough R. M., Gillies A. J. Pulmonary alveolar proteinosis: a complete response to GM-CSF therapy. Thorax. 2001 Aug;56(8):664–665. doi: 10.1136/thorax.56.8.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bewig B., Wang X. D., Kirsten D., Dalhoff K., Schäfer H. GM-CSF and GM-CSF beta c receptor in adult patients with pulmonary alveolar proteinosis. Eur Respir J. 2000 Feb;15(2):350–357. doi: 10.1034/j.1399-3003.2000.15b22.x. [DOI] [PubMed] [Google Scholar]
  3. Bonfield Tracey L., Farver Carol F., Barna Barbara P., Malur Anagha, Abraham Susamma, Raychaudhuri Baisakhi, Kavuru Mani S., Thomassen Mary Jane. Peroxisome proliferator-activated receptor-gamma is deficient in alveolar macrophages from patients with alveolar proteinosis. Am J Respir Cell Mol Biol. 2003 Jun 12;29(6):677–682. doi: 10.1165/rcmb.2003-0148OC. [DOI] [PubMed] [Google Scholar]
  4. Bonfield Tracey L., Kavuru Mani S., Thomassen Mary Jane. Anti-GM-CSF titer predicts response to GM-CSF therapy in pulmonary alveolar proteinosis. Clin Immunol. 2002 Dec;105(3):342–350. doi: 10.1006/clim.2002.5301. [DOI] [PubMed] [Google Scholar]
  5. Bonfield Tracey L., Russell Debra, Burgess Sujata, Malur Anagha, Kavuru Mani S., Thomassen Mary Jane. Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis. Am J Respir Cell Mol Biol. 2002 Oct;27(4):481–486. doi: 10.1165/rcmb.2002-0023OC. [DOI] [PubMed] [Google Scholar]
  6. Dirksen U., Nishinakamura R., Groneck P., Hattenhorst U., Nogee L., Murray R., Burdach S. Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J Clin Invest. 1997 Nov 1;100(9):2211–2217. doi: 10.1172/JCI119758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dranoff G., Crawford A. D., Sadelain M., Ream B., Rashid A., Bronson R. T., Dickersin G. R., Bachurski C. J., Mark E. L., Whitsett J. A. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science. 1994 Apr 29;264(5159):713–716. doi: 10.1126/science.8171324. [DOI] [PubMed] [Google Scholar]
  8. Huffman J. A., Hull W. M., Dranoff G., Mulligan R. C., Whitsett J. A. Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice. J Clin Invest. 1996 Feb 1;97(3):649–655. doi: 10.1172/JCI118461. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Kitamura T., Tanaka N., Watanabe J., Uchida, Kanegasaki S., Yamada Y., Nakata K. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte/macrophage colony-stimulating factor. J Exp Med. 1999 Sep 20;190(6):875–880. doi: 10.1084/jem.190.6.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kitamura T., Uchida K., Tanaka N., Tsuchiya T., Watanabe J., Yamada Y., Hanaoka K., Seymour J. F., Schoch O. D., Doyle I. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):658–662. doi: 10.1164/ajrccm.162.2.9910032. [DOI] [PubMed] [Google Scholar]
  11. Mahut B., Delacourt C., Scheinmann P., de Blic J., Mani T. M., Fournet J. C., Bellon G. Pulmonary alveolar proteinosis: experience with eight pediatric cases and a review. Pediatrics. 1996 Jan;97(1):117–122. [PubMed] [Google Scholar]
  12. Nogee L. M., Wert S. E., Proffit S. A., Hull W. M., Whitsett J. A. Allelic heterogeneity in hereditary surfactant protein B (SP-B) deficiency. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):973–981. doi: 10.1164/ajrccm.161.3.9903153. [DOI] [PubMed] [Google Scholar]
  13. Nogee L. M., de Mello D. E., Dehner L. P., Colten H. R. Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med. 1993 Feb 11;328(6):406–410. doi: 10.1056/NEJM199302113280606. [DOI] [PubMed] [Google Scholar]
  14. Parto K., Svedström E., Majurin M. L., Härkönen R., Simell O. Pulmonary manifestations in lysinuric protein intolerance. Chest. 1993 Oct;104(4):1176–1182. doi: 10.1378/chest.104.4.1176. [DOI] [PubMed] [Google Scholar]
  15. Ragnhammar P., Friesen H. J., Frödin J. E., Lefvert A. K., Hassan M., Osterborg A., Mellstedt H. Induction of anti-recombinant human granulocyte-macrophage colony-stimulating factor (Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients. Blood. 1994 Dec 15;84(12):4078–4087. [PubMed] [Google Scholar]
  16. Schoch O. D., Schanz U., Koller M., Nakata K., Seymour J. F., Russi E. W., Boehler A. BAL findings in a patient with pulmonary alveolar proteinosis successfully treated with GM-CSF. Thorax. 2002 Mar;57(3):277–280. doi: 10.1136/thorax.57.3.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Seymour J. F., Begley C. G., Dirksen U., Presneill J. J., Nicola N. A., Moore P. E., Schoch O. D., van Asperen P., Roth B., Burdach S. Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired pulmonary alveolar proteinosis. Blood. 1998 Oct 15;92(8):2657–2667. [PubMed] [Google Scholar]
  18. Seymour J. F., Doyle I. R., Nakata K., Presneill J. J., Schoch O. D., Hamano E., Uchida K., Fisher R., Dunn A. R. 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 Mar;58(3):252–257. doi: 10.1136/thorax.58.3.252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Seymour J. F., Presneill J. J., Schoch O. D., Downie G. H., Moore P. E., Doyle I. R., Vincent J. M., Nakata K., Kitamura T., Langton D. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med. 2001 Feb;163(2):524–531. doi: 10.1164/ajrccm.163.2.2003146. [DOI] [PubMed] [Google Scholar]
  20. Seymour John F., Presneill Jeffrey J. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med. 2002 Jul 15;166(2):215–235. doi: 10.1164/rccm.2109105. [DOI] [PubMed] [Google Scholar]
  21. Shah P. L., Hansell D., Lawson P. R., Reid K. B., Morgan C. Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis. Thorax. 2000 Jan;55(1):67–77. doi: 10.1136/thorax.55.1.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shulenin Sergey, Nogee Lawrence M., Annilo Tarmo, Wert Susan E., Whitsett Jeffrey A., Dean Michael. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med. 2004 Mar 25;350(13):1296–1303. doi: 10.1056/NEJMoa032178. [DOI] [PubMed] [Google Scholar]
  23. Stanley E., Lieschke G. J., Grail D., Metcalf D., Hodgson G., Gall J. A., Maher D. W., Cebon J., Sinickas V., Dunn A. R. 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 Jun 7;91(12):5592–5596. doi: 10.1073/pnas.91.12.5592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Trapnell Bruce C., Whitsett Jeffrey A., Nakata Koh. Pulmonary alveolar proteinosis. N Engl J Med. 2003 Dec 25;349(26):2527–2539. doi: 10.1056/NEJMra023226. [DOI] [PubMed] [Google Scholar]
  25. Tredano Mohammed, Griese Matthias, Brasch Frank, Schumacher Silja, de Blic Jacques, Marque Stéphanie, Houdayer Claude, Elion Jacques, Couderc Rémy, Bahuau Michel. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease. Am J Med Genet A. 2004 Apr 1;126A(1):18–26. doi: 10.1002/ajmg.a.20670. [DOI] [PubMed] [Google Scholar]
  26. Wadhwa M., Bird C., Fagerberg J., Gaines-Das R., Ragnhammar P., Mellstedt H., Thorpe R. Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy. Clin Exp Immunol. 1996 May;104(2):351–358. doi: 10.1046/j.1365-2249.1996.11704.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. de Vega M. G., Sánchez-Palencia A., Ramírez A., Cervera S., Aneiros J. GM-CSF therapy in pulmonary alveolar proteinosis. Thorax. 2002 Sep;57(9):837–837. doi: 10.1136/thorax.57.9.837. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES