Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Apr;84(7):920–925. doi: 10.1054/bjoc.2000.1687

The latency pattern of Epstein–Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas

Z-G Xu 1, K Iwatsuki 2, N Oyama 1, M Ohtsuka 1, M Satoh 1, S Kikuchi 1, H Akiba 1, F Kaneko 1
PMCID: PMC2363835  PMID: 11286472

Abstract

The nasal type, extranodal natural killer or T(NK/T)-cell lymphoma is usually associated with latent Epstein–Barr virus (EBV) infection. In order to elucidate the EBV gene expression patterns in vivo, we examined eight patients with cutaneous EBV-related NK/T-cell lymphomas, including six patients with a NK-cell phenotype and two patients with a T-cell phenotype. The implication of EBV in the skin lesions was determined by the presence of EBV-DNA, EBV-encoded nuclear RNA (EBER) and a clonality of EBV-DNA fragments containing the terminal repeats. Transcripts of EBV-encoded genes were screened by reverse transcription- polymerase chain reaction (RT-PCR), and confirmed by Southern blot hybridization. The expression of EBV-related antigens was examined by immunostaining using paraffin-embedded tissue sections and cell pellets of EBV-positive cell lines. Our study demonstrated that all samples from the patients contained EBV nuclear antigen (EBNA)-1 mRNA which was transcribed using the Q promoter, whereas both the Q promoter and another upstream promoter (Cp/Wp) were used in EBV-positive cell lines, B95.8, Raji and Jiyoye. Latent membrane protein-1 (LMP-1) mRNA was detected in seven of eight patients and all cell lines, whereas EBNA-2 transcripts were found only in the cell lines. Immunostaining showed no LMP-1, EBNA-2 or ZEBRA antigens in the paraffin-embedded tissue sections, although they were positive in the cell line cells. Latent BHRF1 transcripts encoding bcl-2 homologue and BCRF1 transcripts encoding viral interleukin (vIL)-10 were detected in one and two of eight patients, respectively. A patient with NK-cell lymphoma expressing both transcripts died of rapid progression of the illness. Our results indicate that the restricted expression of the latency-associated EBV genes and the production of vIL-10 and bcl-2 homologue may favour tumour growth, evading the host immune surveillance. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: Epstein–Barr virus, NK/T-cell lymphomas, latency, viral IL-10, bcl-2 homologue, LMP, EBNA

Full Text

The Full Text of this article is available as a PDF (194.6 KB).

Selected References

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

  1. Blay J. Y., Burdin N., Rousset F., Lenoir G., Biron P., Philip T., Banchereau J., Favrot M. C. Serum interleukin-10 in non-Hodgkin's lymphoma: a prognostic factor. Blood. 1993 Oct 1;82(7):2169–2174. [PubMed] [Google Scholar]
  2. Brooks L., Yao Q. Y., Rickinson A. B., Young L. S. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J Virol. 1992 May;66(5):2689–2697. doi: 10.1128/jvi.66.5.2689-2697.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chan J. K., Sin V. C., Wong K. F., Ng C. S., Tsang W. Y., Chan C. H., Cheung M. M., Lau W. H. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood. 1997 Jun 15;89(12):4501–4513. [PubMed] [Google Scholar]
  4. Cohen J. I., Lekstrom K. Epstein-Barr virus BARF1 protein is dispensable for B-cell transformation and inhibits alpha interferon secretion from mononuclear cells. J Virol. 1999 Sep;73(9):7627–7632. doi: 10.1128/jvi.73.9.7627-7632.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Deacon E. M., Pallesen G., Niedobitek G., Crocker J., Brooks L., Rickinson A. B., Young L. S. Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med. 1993 Feb 1;177(2):339–349. doi: 10.1084/jem.177.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Hamilton-Dutoit S. J., Rea D., Raphael M., Sandvej K., Delecluse H. J., Gisselbrecht C., Marelle L., van Krieken H. J., Pallesen G. Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency. Am J Pathol. 1993 Oct;143(4):1072–1085. [PMC free article] [PubMed] [Google Scholar]
  8. Harabuchi Y., Yamanaka N., Kataura A., Imai S., Kinoshita T., Mizuno F., Osato T. Epstein-Barr virus in nasal T-cell lymphomas in patients with lethal midline granuloma. Lancet. 1990 Jan 20;335(8682):128–130. doi: 10.1016/0140-6736(90)90002-m. [DOI] [PubMed] [Google Scholar]
  9. Harris N. L., Jaffe E. S., Diebold J., Flandrin G., Muller-Hermelink H. K., Vardiman J., Lister T. A., Bloomfield C. D. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999 Dec;17(12):3835–3849. doi: 10.1200/JCO.1999.17.12.3835. [DOI] [PubMed] [Google Scholar]
  10. Henderson S., Huen D., Rowe M., Dawson C., Johnson G., Rickinson A. Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8479–8483. doi: 10.1073/pnas.90.18.8479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Henderson S., Rowe M., Gregory C., Croom-Carter D., Wang F., Longnecker R., Kieff E., Rickinson A. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991 Jun 28;65(7):1107–1115. doi: 10.1016/0092-8674(91)90007-l. [DOI] [PubMed] [Google Scholar]
  12. Hsu D. H., de Waal Malefyt R., Fiorentino D. F., Dang M. N., Vieira P., de Vries J., Spits H., Mosmann T. R., Moore K. W. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science. 1990 Nov 9;250(4982):830–832. doi: 10.1126/science.2173142. [DOI] [PubMed] [Google Scholar]
  13. Iwatsuki K., Ohtsuka M., Harada H., Han G., Kaneko F. Clinicopathologic manifestations of Epstein-Barr virus-associated cutaneous lymphoproliferative disorders. Arch Dermatol. 1997 Sep;133(9):1081–1086. [PubMed] [Google Scholar]
  14. Jaffe E. S., Chan J. K., Su I. J., Frizzera G., Mori S., Feller A. C., Ho F. C. Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol. 1996 Jan;20(1):103–111. doi: 10.1097/00000478-199601000-00012. [DOI] [PubMed] [Google Scholar]
  15. Jaffe E. S., Costa J., Fauci A. S., Cossman J., Tsokos M. Malignant lymphoma and erythrophagocytosis simulating malignant histiocytosis. Am J Med. 1983 Nov;75(5):741–749. doi: 10.1016/0002-9343(83)90402-3. [DOI] [PubMed] [Google Scholar]
  16. Kerr B. M., Lear A. L., Rowe M., Croom-Carter D., Young L. S., Rookes S. M., Gallimore P. H., Rickinson A. B. Three transcriptionally distinct forms of Epstein-Barr virus latency in somatic cell hybrids: cell phenotype dependence of virus promoter usage. Virology. 1992 Mar;187(1):189–201. doi: 10.1016/0042-6822(92)90307-b. [DOI] [PubMed] [Google Scholar]
  17. Levitskaya J., Coram M., Levitsky V., Imreh S., Steigerwald-Mullen P. M., Klein G., Kurilla M. G., Masucci M. G. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature. 1995 Jun 22;375(6533):685–688. doi: 10.1038/375685a0. [DOI] [PubMed] [Google Scholar]
  18. Miller G. The switch between latency and replication of Epstein-Barr virus. J Infect Dis. 1990 May;161(5):833–844. doi: 10.1093/infdis/161.5.833. [DOI] [PubMed] [Google Scholar]
  19. Miyazaki I., Cheung R. K., Dosch H. M. Viral interleukin 10 is critical for the induction of B cell growth transformation by Epstein-Barr virus. J Exp Med. 1993 Aug 1;178(2):439–447. doi: 10.1084/jem.178.2.439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Moore K. W., Vieira P., Fiorentino D. F., Trounstine M. L., Khan T. A., Mosmann T. R. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science. 1990 Jun 8;248(4960):1230–1234. doi: 10.1126/science.2161559. [DOI] [PubMed] [Google Scholar]
  21. Ohtsuka M., Iwatsuki K., Kaneko R., Akiba H., Kikuchi S., Harada H., Kaneko F. Epstein-Barr virus-associated lymphoid hyperplasia of the eyelid characterized by intramuscular infiltration. Br J Dermatol. 1999 Feb;140(2):358–359. doi: 10.1046/j.1365-2133.1999.02677.x. [DOI] [PubMed] [Google Scholar]
  22. Oudejans J. J., Jiwa M., van den Brule A. J., Grässer F. A., Horstman A., Vos W., Kluin P. M., van der Valk P., Walboomers J. M., Meijer C. J. Detection of heterogeneous Epstein-Barr virus gene expression patterns within individual post-transplantation lymphoproliferative disorders. Am J Pathol. 1995 Oct;147(4):923–933. [PMC free article] [PubMed] [Google Scholar]
  23. Oudejans J. J., van den Brule A. J., Jiwa N. M., de Bruin P. C., Ossenkoppele G. J., van der Valk P., Walboomers J. M., Meijer C. J. BHRF1, the Epstein-Barr virus (EBV) homologue of the BCL-2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes. Blood. 1995 Sep 1;86(5):1893–1902. [PubMed] [Google Scholar]
  24. Raab-Traub N., Flynn K. The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell. 1986 Dec 26;47(6):883–889. doi: 10.1016/0092-8674(86)90803-2. [DOI] [PubMed] [Google Scholar]
  25. Rickinson A. B., Young L. S., Rowe M. Influence of the Epstein-Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J Virol. 1987 May;61(5):1310–1317. doi: 10.1128/jvi.61.5.1310-1317.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Rowe M., Rowe D. T., Gregory C. D., Young L. S., Farrell P. J., Rupani H., Rickinson A. B. Differences in B cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 1987 Sep;6(9):2743–2751. doi: 10.1002/j.1460-2075.1987.tb02568.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sample J., Brooks L., Sample C., Young L., Rowe M., Gregory C., Rickinson A., Kieff E. Restricted Epstein-Barr virus protein expression in Burkitt lymphoma is due to a different Epstein-Barr nuclear antigen 1 transcriptional initiation site. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6343–6347. doi: 10.1073/pnas.88.14.6343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schaefer B. C., Woisetschlaeger M., Strominger J. L., Speck S. H. Exclusive expression of Epstein-Barr virus nuclear antigen 1 in Burkitt lymphoma arises from a third promoter, distinct from the promoters used in latently infected lymphocytes. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6550–6554. doi: 10.1073/pnas.88.15.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Su I. J., Hsieh H. C. Clinicopathological spectrum of Epstein-Barr virus-associated T cell malignancies. Leuk Lymphoma. 1992 May;7(1-2):47–53. doi: 10.3109/10428199209053601. [DOI] [PubMed] [Google Scholar]
  30. Su I. J., Hsieh H. C., Lin K. H., Uen W. C., Kao C. L., Chen C. J., Cheng A. L., Kadin M. E., Chen J. Y. Aggressive peripheral T-cell lymphomas containing Epstein-Barr viral DNA: a clinicopathologic and molecular analysis. Blood. 1991 Feb 15;77(4):799–808. [PubMed] [Google Scholar]
  31. Sugiura M., Imai S., Tokunaga M., Koizumi S., Uchizawa M., Okamoto K., Osato T. Transcriptional analysis of Epstein-Barr virus gene expression in EBV-positive gastric carcinoma: unique viral latency in the tumour cells. Br J Cancer. 1996 Aug;74(4):625–631. doi: 10.1038/bjc.1996.412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Tao Q., Robertson K. D., Manns A., Hildesheim A., Ambinder R. F. Epstein-Barr virus (EBV) in endemic Burkitt's lymphoma: molecular analysis of primary tumor tissue. Blood. 1998 Feb 15;91(4):1373–1381. [PubMed] [Google Scholar]
  33. 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]
  34. Xu Z. G., Iwatsuki K., Ohtsuka M., Oyama N., Matsui T., Kaneko F. Polymorphism analysis of Epstein-Barr virus isolates from patients with cutaneous natural killer/T-cell lymphoproliferative disorders: A possible relation to the endemic occurrence of these diseases in Japan. J Med Virol. 2000 Oct;62(2):239–246. doi: 10.1002/1096-9071(200010)62:2<239::aid-jmv16>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  35. Young L., Alfieri C., Hennessy K., Evans H., O'Hara C., Anderson K. C., Ritz J., Shapiro R. S., Rickinson A., Kieff E. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med. 1989 Oct 19;321(16):1080–1085. doi: 10.1056/NEJM198910193211604. [DOI] [PubMed] [Google Scholar]
  36. Zeidler R., Eissner G., Meissner P., Uebel S., Tampé R., Lazis S., Hammerschmidt W. Downregulation of TAP1 in B lymphocytes by cellular and Epstein-Barr virus-encoded interleukin-10. Blood. 1997 Sep 15;90(6):2390–2397. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES