Skip to main content

Advertisement

SpringerLink
Log in

Idiopathic Pulmonary Fibrosis is Associated with Circulating Antiepithelial Antibodies

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Purpose

Idiopathic pulmonary fibrosis (IPF) is a restrictive fibrotic lung disease of uncertain etiology. Alveolar epithelial injury may be one of the inciting triggers in the pathogenesis of this disorder. We hypothesized that circulating antibodies to alveolar epithelial and endothelial cells may be involved in the pathogenesis of IPF.

Methods

Antibodies to alveolar epithelial and endothelial cells were analyzed by indirect immunofluorescence using alveolar epithelial cells (A549) and human umbilical vein endothelial cells respectively. IgG and IgM antibodies in patients’ serum were evaluated. Patterns of immunofluorescence, including membranous, cytoplasmic, and nuclear staining, were analyzed by fluorescence microscopy. The severity of immunofluorescence was divided into mild, moderate, and severe categories. Fifty-six patients (IPF = 28, non-IPF ILD = 9, non-ILD control = 19) were evaluated for antiepithelial antibodies, and 28 patients (IPF = 12, non-IPF ILD = 3, non-ILD control = 13) were studied for antiendothelial antibodies.

Results

Compared with control subjects, serum from IPF patients displayed significantly higher IgG binding to alveolar epithelial cells (P = 0.041) with a membranous pattern of immunofluorescence. However, there was no significant difference in immunofluorescence with IgG on endothelial cells (P = 0.165). In terms of IgM antibodies, there was no differential fluorescence observed for either epithelial or endothelial cells.

Conclusions

There is evidence of increased IgG antibodies directed against alveolar epithelium in IPF. These antibodies may play a significant role in the pathogenesis of this fibrotic disorder. The findings of this study suggest further evaluation of the role of immune mediated alveolar epithelial injury in IPF.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Lynch JP III, Wurfel M, Flaherty K, White E, Martinez F, Travis W, Raghu G (2001) Usual interstitial pneumonia. Semin Respir Crit Care Med 22(4):357–386

    Article  PubMed  Google Scholar 

  2. King TE Jr, Safrin S, Starko KM, Brown KK, Noble PW, Raghu G, Schwartz DA (2005) Analyses of efficacy end points in a controlled trial of interferon-gamma1b for idiopathic pulmonary fibrosis. Chest 127(1):171–177

    Article  PubMed  CAS  Google Scholar 

  3. King TE Jr, Behr J, Brown KK, Du Bois RM, Lancaster L, de Andrade JA, Stahler G, Leconte I, Roux S, Raghu G (2008) BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 177(1):75–81

    Article  PubMed  CAS  Google Scholar 

  4. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE Jr (2004) A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med 350(2):125–133

    Article  PubMed  CAS  Google Scholar 

  5. Raghu G, Brown KK, Costabel U, Cottin V, Du Bois RM, Lasky JA, Thomeer M, Utz JP, Khandker RK, McDermott L, Fatenejad S (2008) Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am J Respir Crit Care Med 178(9):948–955

    Article  PubMed  CAS  Google Scholar 

  6. Carrington CB, Gaensler EA, Coutu RE, FitzGerald MX, Gupta RG (1978) Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 298(15):801–809

    Article  PubMed  CAS  Google Scholar 

  7. Katzenstein AA, Askin FB (1982) Surgical pathology of non-neoplastic lung disease. Major Probl Pathol 13:1–430

    PubMed  CAS  Google Scholar 

  8. Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, Gadgil A, George MP, Gibson KF, Choi AM, Kaminski N, Zhang Y, Duncan SR (2007) Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol 179(4):2592–2599

    PubMed  CAS  Google Scholar 

  9. Fujita J, Dobashi N, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Okada H, Takahara J (1999) Elevation of anti-cytokeratin 19 antibody in sera of the patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders. Lung 177(5):311–319

    Article  PubMed  CAS  Google Scholar 

  10. Fujita J, Takeuchi T, Dobashi N, Ohtsuki Y, Tokuda M, Takahara J (1999) Detection of anti-ADAM 10 antibody in serum of a patient with pulmonary fibrosis associated with dermatomyositis. Ann Rheum Dis 58(12):770–772

    Article  PubMed  CAS  Google Scholar 

  11. Erlinger R, Rauh G, Behr J, Schumacher U, Welsch U, Zollner N (1991) Similar frequency of autoantibodies against pneumocytes type II and Clara cells in patients with interstitial lung diseases and healthy persons. Klin Wochenschr 69(7):297–302

    Article  PubMed  CAS  Google Scholar 

  12. Meliconi R, Bestagno M, Sturani C, Negri C, Galavotti V, Sala C, Facchini A, Ciarrocchi G, Gasbarrini G, Astaldi Ricotti GC (1989) Autoantibodies to DNA topoisomerase II in cryptogenic fibrosing alveolitis and connective tissue disease. Clin Exp Immunol 76(2):184–189

    PubMed  CAS  Google Scholar 

  13. Meliconi R, Negri C, Borzi RM, Facchini A, Sturani C, Fasano L, Fabbri M, Astaldi Ricotti GC (1993) Antibodies to topoisomerase II in idiopathic pulmonary fibrosis. Clin Rheumatol 12(3):311–315

    Article  PubMed  CAS  Google Scholar 

  14. Wallace WA, Roberts SN, Caldwell H, Thornton E, Greening AP, Lamb D, Howie SE (1994) Circulating antibodies to lung protein(s) in patients with cryptogenic fibrosing alveolitis. Thorax 49(3):218–224

    Article  PubMed  CAS  Google Scholar 

  15. Taille C, Grootenboer-Mignot S, Boursier C, Michel L, Debray MP, Fagart J, Barrientos L, Mailleux A, Cigna N, Tubach F, Marchal-Somme J, Soler P, Chollet-Martin S, Crestani B (2011) Identification of periplakin as a new target for autoreactivity in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 183(6):759–766

    Article  PubMed  CAS  Google Scholar 

  16. American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS) [Review] [234 refs]. Am J Respir Crit Care Med 161(2 Pt 1):646–664

    Google Scholar 

  17. Kim JH, Jang YS, Eom KS, Hwang YI, Kang HR, Jang SH, Kim CH, Park YB, Lee MG, Hyun IG, Jung KS, Kim DG (2007) Transforming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J Korean Med Sci 22(5):898–904

    Article  PubMed  CAS  Google Scholar 

  18. Strieter RM (2005) Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest 128(5 Suppl 1):526S–532S

    Article  PubMed  Google Scholar 

  19. Dobashi N, Fujita J, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Tokuda M, Hojo S, Bandou S, Ueda Y, Takahara J (2000) Circulating cytokeratin 8: anti-cytokeratin 8 antibody immune complexes in sera of patients with pulmonary fibrosis. Respiration 67(4):397–401

    Article  PubMed  CAS  Google Scholar 

  20. Dobashi N, Fujita J, Murota M, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ueda R, Bandoh S, Kamei T, Nishioka M, Ishida T, Takahara J (2000) Elevation of anti-cytokeratin 18 antibody and circulating cytokeratin 18: anti-cytokeratin 18 antibody immune complexes in sera of patients with idiopathic pulmonary fibrosis. Lung 178(3):171–179

    Article  PubMed  CAS  Google Scholar 

  21. Dobashi N, Fujita J, Ohtsuki Y, Yamadori I, Yoshinouchi T, Kamei T, Takahara J (1999) Elevated serum and BAL cytokeratin 19 fragment in pulmonary fibrosis and acute interstitial pneumonia. Eur Respir J 14(3):574–578

    Article  PubMed  CAS  Google Scholar 

  22. Fujita J, Bandoh S, Ohtsuki Y, Dobashi N, Hiroi M, Takeuchi T, Fukunaga Y, Miyaue H, Onishi S, Ishida T, Takahara J (2000) The role of anti-epithelial cell antibodies in the pathogenesis of bilateral radiation pneumonitis caused by unilateral thoracic irradiation. Respir Med 94(9):875–880

    Article  PubMed  CAS  Google Scholar 

  23. Fujita J, Ohtsuki Y, Bandoh S, Takashima H, Ueda Y, Wu F, Tojo Y, Kubo A, Ishida T (2004) Elevation of cytokeratin 19 fragment (CYFRA 21-1) in serum of patients with radiation pneumonitis: possible marker of epithelial cell damage. Respir Med 98(4):294–300

    Article  PubMed  CAS  Google Scholar 

  24. Ward PA (1979) Immune complex injury of the lung. Am J Pathol 97(1):85–92

    PubMed  CAS  Google Scholar 

  25. Magro CM, Ross P, Marsh CB, Allen JN, Liff D, Knight DA, Waldman WJ, Cowden DJ (2007) The role of anti-endothelial cell antibody-mediated microvascular injury in the evolution of pulmonary fibrosis in the setting of collagen vascular disease. Am J Clin Pathol 127(2):237–247

    Article  PubMed  CAS  Google Scholar 

  26. Magro CM, Waldman WJ, Knight DA, Allen JN, Nadasdy T, Frambach GE, Ross P, Marsh CB (2006) Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies. Hum Immunol 67(4–5):284–297

    Article  PubMed  CAS  Google Scholar 

  27. Magro CM, Allen J, Pope-Harman A, Waldman WJ, Moh P, Rothrauff S, Ross P Jr (2003) The role of microvascular injury in the evolution of idiopathic pulmonary fibrosis. Am J Clin Pathol 119(4):556–567

    Article  PubMed  Google Scholar 

  28. Bellon B, Bernaudin JF, Mandet C, Chamak B, Kuhn J, Druet P (1982) Immune complex-mediated lung injury produced by horseradish peroxidase (HRP) and anti-HRP antibodies in rats. Am J Pathol 107(1):16–24

    PubMed  CAS  Google Scholar 

  29. Dall’Aglio PP, Pesci A, Bertorelli G, Brianti E, Scarpa S (1988) Study of immune complexes in bronchoalveolar lavage fluids. Respiration 54(Suppl 1):36–41

    Article  PubMed  Google Scholar 

  30. Dreisin RB, Schwarz MI, Theofilopoulos AN, Stanford RE (1978) Circulating immune complexes in the idiopathic interstitial pneumonias. N Engl J Med 298(7):353–357

    Article  PubMed  CAS  Google Scholar 

  31. Haslam PL, Thompson B, Mohammed I, Townsend PJ, Hodson ME, Holborow EJ, Turner-Warwick M (1979) Circulating immune complexes in patients with cryptogenic fibrosing alveolitis. Clin Exp Immunol 37(3):381–390

    PubMed  CAS  Google Scholar 

  32. Bournazos S, Bournazou I, Murchison JT, Wallace WA, McFarlane P, Hirani N, Simpson AJ, Dransfield I, Hart SP (2010) Fcgamma receptor IIIb (CD16b) polymorphisms are associated with susceptibility to idiopathic pulmonary fibrosis. Lung 188(6):475–481

    Article  PubMed  CAS  Google Scholar 

  33. Bournazos S, Grinfeld J, Alexander KM, Murchison JT, Wallace WA, McFarlane P, Hirani N, Simpson AJ, Dransfield I, Hart SP (2010) Association of FcgammaR IIa R131H polymorphism with idiopathic pulmonary fibrosis severity and progression. BMC Pulm Med 10:51

    Article  PubMed  Google Scholar 

  34. Wallace WA, Schofield JA, Lamb D, Howie SE (1994) Localisation of a pulmonary autoantigen in cryptogenic fibrosing alveolitis. Thorax 49(11):1139–1145

    Article  PubMed  CAS  Google Scholar 

  35. Marrack P, Kappler J, Kotzin BL (2001) Autoimmune disease: why and where it occurs. Nat Med 7(8):899–905

    Article  PubMed  CAS  Google Scholar 

  36. Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Cramer D, Renzoni EA, Hansell DM, Du Bois RM, Wells AU (2010) Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J 35(4):830–836

    Article  PubMed  CAS  Google Scholar 

  37. Takabatake N, Arao T, Sata M, Abe S, Inoue S, Shibata Y, Takeishi Y, Kubota I (2005) Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy. Eur J Nucl Med Mol Imaging 32(2):221–228

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

None for any of the authors.

Author information

Authors and Affiliations

  1. Division of Cardiovascular and Respiratory Studies, Castle Hill Hospital, Castle Road, Cottingham, HU16 5JQ, UK

    Ahmed Fahim & Michael G. Crooks

  2. Hull York Medical School, Cottingham, UK

    Mei C. Chong

  3. Division of Cardiovascular and Respiratory Studies, Centre for Cardiovascular and Metabolic Research, Hull York Medical School, Castle Hill Hospital, Castle Road, Cottingham, HU16 5JQ, UK

    Simon P. Hart

Authors
  1. Ahmed Fahim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei C. Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael G. Crooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon P. Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmed Fahim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fahim, A., Chong, M.C., Crooks, M.G. et al. Idiopathic Pulmonary Fibrosis is Associated with Circulating Antiepithelial Antibodies. Lung 190, 451–458 (2012). https://doi.org/10.1007/s00408-012-9390-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-012-9390-z

Keywords

Search

Navigation