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. 2000 Nov;55(11):958–961. doi: 10.1136/thorax.55.11.958

Involvement of Epstein-Barr virus latent membrane protein 1 in disease progression in patients with idiopathic pulmonary fibrosis

K Tsukamoto 1, H Hayakawa 1, A Sato 1, K Chida 1, H Nakamura 1, K Miura 1
PMCID: PMC1745627  PMID: 11050267

Abstract

BACKGROUND—The role of Epstein-Barr virus (EBV) in idiopathic pulmonary fibrosis (IPF) is uncertain. A study was undertaken to detect the virus in IPF as well as to clarify the influence of EBV on the clinical features of the disease.
METHODS—Twenty nine lung specimens were obtained from patients with IPF, as well as five specimens from patients with systemic sclerosis with pulmonary fibrosis (SSc) and 15 specimens from controls. EBV DNA and EBV latent membrane protein 1 (LMP1) were detected using the PCR method and immunohistochemical analysis, respectively.
RESULTS—EBV DNA was detected in 24 of 25 patients with IPF (96%), in all five patients with SSc (100%), and in 10 of 14 controls (71%). The detection ratio was significantly higher in patients with IPF than in controls (p = 0.047, odds ratio (OR) = 9.60, 95% confidence interval (CI) 0.9 to 96.9). Immunohistochemical analysis revealed that cuboidal epithelial cells were positively stained with anti-LMP1 antibody in nine of the 29 lung specimens from IPF patients. In contrast, neither the patients with SSc nor the control subjects showed positive staining. In the follow up periods LMP1 positive patients with IPF died more frequently from respiratory failure than LMP1 negative patients (4/9 versus 1/20; p = 0.022, OR =15.20, 95% CI 1.3 to 168.0).
CONCLUSIONS—EBV LMP1 positivity may be associated with more rapid disease progression in IPF.



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Selected References

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  1. Andiman W. A., Eastman R., Martin K., Katz B. Z., Rubinstein A., Pitt J., Pahwa S., Miller G. Opportunistic lymphoproliferations associated with Epstein-Barr viral DNA in infants and children with AIDS. Lancet. 1985 Dec 21;2(8469-70):1390–1393. doi: 10.1016/s0140-6736(85)92557-7. [DOI] [PubMed] [Google Scholar]
  2. Carrington C. B., Gaensler E. A., Coutu R. E., FitzGerald M. X., Gupta R. G. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med. 1978 Apr 13;298(15):801–809. doi: 10.1056/NEJM197804132981501. [DOI] [PubMed] [Google Scholar]
  3. Crystal R. G., Bitterman P. B., Rennard S. I., Hance A. J., Keogh B. A. Interstitial lung diseases of unknown cause. Disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med. 1984 Jan 26;310(4):235–244. doi: 10.1056/NEJM198401263100406. [DOI] [PubMed] [Google Scholar]
  4. Crystal R. G., Fulmer J. D., Roberts W. C., Moss M. L., Line B. R., Reynolds H. Y. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med. 1976 Dec;85(6):769–788. doi: 10.7326/0003-4819-85-6-769. [DOI] [PubMed] [Google Scholar]
  5. Dawson C. W., Rickinson A. B., Young L. S. Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation. Nature. 1990 Apr 19;344(6268):777–780. doi: 10.1038/344777a0. [DOI] [PubMed] [Google Scholar]
  6. Dreisin R. B., Schwarz M. I., Theofilopoulos A. N., Stanford R. E. Circulating immune complexes in the idiopathic interstitial pneumonias. N Engl J Med. 1978 Feb 16;298(7):353–357. doi: 10.1056/NEJM197802162980701. [DOI] [PubMed] [Google Scholar]
  7. Egan J. J., Stewart J. P., Hasleton P. S., Arrand J. R., Carroll K. B., Woodcock A. A. Epstein-Barr virus replication within pulmonary epithelial cells in cryptogenic fibrosing alveolitis. Thorax. 1995 Dec;50(12):1234–1239. doi: 10.1136/thx.50.12.1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fries K. L., Miller W. E., Raab-Traub N. Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene. J Virol. 1996 Dec;70(12):8653–8659. doi: 10.1128/jvi.70.12.8653-8659.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fåhraeus R., Rymo L., Rhim J. S., Klein G. Morphological transformation of human keratinocytes expressing the LMP gene of Epstein-Barr virus. Nature. 1990 May 31;345(6274):447–449. doi: 10.1038/345447a0. [DOI] [PubMed] [Google Scholar]
  10. Gilligan K., Rajadurai P., Resnick L., Raab-Traub N. Epstein-Barr virus small nuclear RNAs are not expressed in permissively infected cells in AIDS-associated leukoplakia. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8790–8794. doi: 10.1073/pnas.87.22.8790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hashimoto Y., Nawata Y., Kurasawa K., Takabayashi K., Oda K., Mikata A., Iwamoto I. Investigation of EB virus and cytomegalovirus in rapidly progressive interstitial pneumonitis in polymyositis/dermatomyositis by in situ hybridization and polymerase chain reaction. Clin Immunol Immunopathol. 1995 Dec;77(3):298–306. doi: 10.1006/clin.1995.1156. [DOI] [PubMed] [Google Scholar]
  12. Kaye K. M., Izumi K. M., Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9150–9154. doi: 10.1073/pnas.90.19.9150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kobayashi J., Kitamura S. KL-6: a serum marker for interstitial pneumonia. Chest. 1995 Aug;108(2):311–315. doi: 10.1378/chest.108.2.311. [DOI] [PubMed] [Google Scholar]
  14. Liebowitz D., Wang D., Kieff E. Orientation and patching of the latent infection membrane protein encoded by Epstein-Barr virus. J Virol. 1986 Apr;58(1):233–237. doi: 10.1128/jvi.58.1.233-237.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Lung M. L., Lam W. K., So S. Y., Lam W. P., Chan K. H., Ng M. H. Evidence that respiratory tract is major reservoir for Epstein-Barr virus. Lancet. 1985 Apr 20;1(8434):889–892. doi: 10.1016/s0140-6736(85)91671-x. [DOI] [PubMed] [Google Scholar]
  16. Matusiewicz S. P., Williamson I. J., Sime P. J., Brown P. H., Wenham P. R., Crompton G. K., Greening A. P. Plasma lactate dehydrogenase: a marker of disease activity in cryptogenic fibrosing alveolitis and extrinsic allergic alveolitis? Eur Respir J. 1993 Oct;6(9):1282–1286. [PubMed] [Google Scholar]
  17. Peterson M. W., Monick M., Hunninghake G. W. Prognostic role of eosinophils in pulmonary fibrosis. Chest. 1987 Jul;92(1):51–56. doi: 10.1378/chest.92.1.51. [DOI] [PubMed] [Google Scholar]
  18. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  19. Stewart J. P., Egan J. J., Ross A. J., Kelly B. G., Lok S. S., Hasleton P. S., Woodcock A. A. The detection of Epstein-Barr virus DNA in lung tissue from patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1336–1341. doi: 10.1164/ajrccm.159.4.9807077. [DOI] [PubMed] [Google Scholar]
  20. Takei M., Mitamura K., Fujiwara S., Horie T., Ryu J., Osaka S., Yoshino S., Sawada S. Detection of Epstein-Barr virus-encoded small RNA 1 and latent membrane protein 1 in synovial lining cells from rheumatoid arthritis patients. Int Immunol. 1997 May;9(5):739–743. doi: 10.1093/intimm/9.5.739. [DOI] [PubMed] [Google Scholar]
  21. Tung K. T., Wells A. U., Rubens M. B., Kirk J. M., du Bois R. M., Hansell D. M. Accuracy of the typical computed tomographic appearances of fibrosing alveolitis. Thorax. 1993 Apr;48(4):334–338. doi: 10.1136/thx.48.4.334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Vergnon J. M., Vincent M., de Thé G., Mornex J. F., Weynants P., Brune J. Cryptogenic fibrosing alveolitis and Epstein-Barr virus: an association? Lancet. 1984 Oct 6;2(8406):768–771. doi: 10.1016/s0140-6736(84)90702-5. [DOI] [PubMed] [Google Scholar]
  23. Wang D., Liebowitz D., Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985 Dec;43(3 Pt 2):831–840. doi: 10.1016/0092-8674(85)90256-9. [DOI] [PubMed] [Google Scholar]
  24. Wang D., Liebowitz D., Wang F., Gregory C., Rickinson A., Larson R., Springer T., Kieff E. Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J Virol. 1988 Nov;62(11):4173–4184. doi: 10.1128/jvi.62.11.4173-4184.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Wangoo A., Shaw R. J., Diss T. C., Farrell P. J., du Bois R. M., Nicholson A. G. Cryptogenic fibrosing alveolitis: lack of association with Epstein-Barr virus infection. Thorax. 1997 Oct;52(10):888–891. doi: 10.1136/thx.52.10.888. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Watters L. C., King T. E., Schwarz M. I., Waldron J. A., Stanford R. E., Cherniack R. M. A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am Rev Respir Dis. 1986 Jan;133(1):97–103. doi: 10.1164/arrd.1986.133.1.97. [DOI] [PubMed] [Google Scholar]
  27. Watters L. C., Schwarz M. I., Cherniack R. M., Waldron J. A., Dunn T. L., Stanford R. E., King T. E. Idiopathic pulmonary fibrosis. Pretreatment bronchoalveolar lavage cellular constituents and their relationships with lung histopathology and clinical response to therapy. Am Rev Respir Dis. 1987 Mar;135(3):696–704. doi: 10.1164/arrd.1987.135.3.696. [DOI] [PubMed] [Google Scholar]
  28. Wen S., Shimizu N., Yoshiyama H., Mizugaki Y., Shinozaki F., Takada K. Association of Epstein-Barr virus (EBV) with Sjögren's syndrome: differential EBV expression between epithelial cells and lymphocytes in salivary glands. Am J Pathol. 1996 Nov;149(5):1511–1517. [PMC free article] [PubMed] [Google Scholar]
  29. Zhang Q., Brooks L., Busson P., Wang F., Charron D., Kieff E., Rickinson A. B., Tursz T. Epstein-Barr virus (EBV) latent membrane protein 1 increases HLA class II expression in an EBV-negative B cell line. Eur J Immunol. 1994 Jun;24(6):1467–1470. doi: 10.1002/eji.1830240635. [DOI] [PubMed] [Google Scholar]

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