1887

Journal of General Virology header logo

Volume 95, Issue 9

Epstein–Barr virus, the germinal centre and the development of Hodgkin’s lymphoma Free

Abstract

The relationship between Epstein-Barr virus (EBV) and the germinal centre (GC) of the asymptomatic host remains an enigma. The occasional appearance of EBV-positive germinal centres in some patients, particularly those with a history of immunosuppression, suggests that EBV numbers in the GC are subject to immune control. The relationship, if any, between lymphoid hyperplasia with EBV-positive germinal centres and subsequent or concurrent lymphomagenesis remains to be clarified. As far as the development of EBV-associated Hodgkin's lymphoma is concerned, the suppression of virus replication, mediated by LMP1 on the one hand, and the loss of B-cell receptor signalling on the other, appears to be an important pathogenic mechanism. A further important emerging concept is that alterations in the microenvironment of the EBV-infected B-cell may be important for lymphomagenesis.

  • Received:
  • Accepted:
  • Published Online:
© 2014 The Authors
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.066712-0
2014-09-01
2024-04-24
Loading full text...

Full text loading...

/deliver/fulltext/jgv/95/9/1861.html?itemId=/content/journal/jgv/10.1099/vir.0.066712-0&mimeType=html&fmt=ahah

References

  1. Adler B., Schaadt E., Kempkes B., Zimber-Strobl U., Baier B., Bornkamm G. W. 2002; Control of Epstein-Barr virus reactivation by activated CD40 and viral latent membrane protein 1. Proc Natl Acad Sci U S A 99:437–442 [View Article][PubMed]
     [Google Scholar]
  2. Amoroso R., Fitzsimmons L., Thomas W. A., Kelly G. L., Rowe M., Bell A. I. 2011; Quantitative studies of Epstein-Barr virus-encoded microRNAs provide novel insights into their regulation. J Virol 85:996–1010 [View Article][PubMed]
     [Google Scholar]
  3. Anagnostopoulos I., Hummel M., Kreschel C., Stein H. 1995; Morphology, immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus. Blood 85:744–750[PubMed]
     [Google Scholar]
  4. Anderton E., Yee J., Smith P., Crook T., White R. E., Allday M. J. 2008; Two Epstein-Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumour-suppressor Bim: clues to the pathogenesis of Burkitt’s lymphoma. Oncogene 27:421–433 [View Article][PubMed]
     [Google Scholar]
  5. Araujo I., Foss H. D., Hummel M., Anagnostopoulos I., Barbosa H. S., Bittencourt A., Stein H. 1999; Frequent expansion of Epstein-Barr virus (EBV) infected cells in germinal centres of tonsils from an area with a high incidence of EBV-associated lymphoma. J Pathol 187:326–330 [View Article][PubMed]
     [Google Scholar]
  6. Armstrong A. A., Alexander F. E., Cartwright R., Angus B., Krajewski A. S., Wright D. H., Brown I., Lee F., Kane E., Jarrett R. F. 1998; Epstein-Barr virus and Hodgkin’s disease: further evidence for the three disease hypothesis. Leukemia 12:1272–1276 [View Article][PubMed]
     [Google Scholar]
  7. Babcock G. J., Decker L. L., Volk M., Thorley-Lawson D. A. 1998; EBV persistence in memory B-cells in vivo. Immunity 9:395–404 [View Article][PubMed]
     [Google Scholar]
  8. Babcock G. J., Hochberg D., Thorley-Lawson A. D. 2000; The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B-cell. Immunity 13:497–506 [View Article][PubMed]
     [Google Scholar]
  9. Balfour H. H. Jr, Odumade O. A., Schmeling D. O., Mullan B. D., Ed J. A., Knight J. A., Vezina H. E., Thomas W., Hogquist K. A. 2013; Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. J Infect Dis 207:80–88 [View Article][PubMed]
     [Google Scholar]
  10. Bargou R. C., Emmerich F., Krappmann D., Bommert K., Mapara M. Y., Arnold W., Royer H. D., Grinstein E., Greiner A.other authors 1997; Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 100:2961–2969 [View Article][PubMed]
     [Google Scholar]
  11. Bechtel D., Kurth J., Unkel C., Küppers R. 2005; Transformation of BCR-deficient germinal-center B-cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 106:4345–4350 [View Article][PubMed]
     [Google Scholar]
  12. Bräuninger A., Spieker T., Mottok A., Baur A. S., Küppers R., Hansmann M. L. 2003; Epstein-Barr virus (EBV)-positive lymphoproliferations in post-transplant patients show immunoglobulin V gene mutation patterns suggesting interference of EBV with normal B-cell differentiation processes. Eur J Immunol 33:1593–1602 [View Article][PubMed]
     [Google Scholar]
  13. Bräuninger A., Schmitz R., Bechtel D., Renné C., Hansmann M. L., Küppers R. 2006; Molecular biology of Hodgkin’s and Reed/Sternberg cells in Hodgkin’s lymphoma. Int J Cancer 118:1853–1861 [View Article][PubMed]
     [Google Scholar]
  14. Cader F. Z., Vockerodt M., Bose S., Nagy E., Brundler M. A., Kearns P., Murray P. G. 2013; The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 122:4237–4245 [View Article][PubMed]
     [Google Scholar]
  15. Caldwell R. G., Wilson J. B., Anderson S. J., Longnecker R. 1998; Epstein-Barr virus LMP2A drives B-cell development and survival in the absence of normal B-cell receptor signals. Immunity 9:405–411 [View Article][PubMed]
     [Google Scholar]
  16. Casola S., Otipoby K. L., Alimzhanov M., Humme S., Uyttersprot N., Kutok J. L., Carroll M. C., Rajewsky K. 2004; B-cell receptor signal strength determines B-cell fate. Nat Immunol 5:317–327 [View Article][PubMed]
     [Google Scholar]
  17. Chaganti S., Bell A. I., Pastor N. B., Milner A. E., Drayson M., Gordon J., Rickinson A. B. 2005; Epstein-Barr virus infection in vitro can rescue germinal center B-cells with inactivated immunoglobulin genes. Blood 106:4249–4252 [View Article][PubMed]
     [Google Scholar]
  18. Chaganti S., Heath E. M., Bergler W., Kuo M., Buettner M., Niedobitek G., Rickinson A. B., Bell A. I. 2009; Epstein-Barr virus colonization of tonsillar and peripheral blood B-cell subsets in primary infection and persistence. Blood 113:6372–6381 [View Article][PubMed]
     [Google Scholar]
  19. Countryman J., Miller G. 1985; Activation of expression of latent Epstein-Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA. Proc Natl Acad Sci U S A 82:4085–4089 [View Article][PubMed]
     [Google Scholar]
  20. Crawford D. H., Ando I. 1986; EB virus induction is associated with B-cell maturation. Immunology 59:405–409[PubMed]
     [Google Scholar]
  21. Dojcinov S. D., Venkataraman G., Pittaluga S., Wlodarska I., Schrager J. A., Raffeld M., Hills R. K., Jaffe E. S. 2011; Age-related EBV-associated lymphoproliferative disorders in the Western population: a spectrum of reactive lymphoid hyperplasia and lymphoma. Blood 117:4726–4735 [View Article][PubMed]
     [Google Scholar]
  22. Dutton A., Reynolds G. M., Dawson C. W., Young L. S., Murray P. G. 2005; Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin’s lymphoma cells through a mechanism involving Akt kinase and mTOR. J Pathol 205:498–506 [View Article][PubMed]
     [Google Scholar]
  23. Engels N., Yigit G., Emmerich C. H., Czesnik D., Schild D., Wienands J. 2012; Epstein-Barr virus LMP2A signaling in statu nascendi mimics a B-cell antigen receptor-like activation signal. Cell Commun Signal 10:9 [View Article][PubMed]
     [Google Scholar]
  24. Flavell K. J., Biddulph J. P., Powell J. E., Parkes S. E., Redfern D., Weinreb M., Nelson P., Mann J. R., Young L. S., Murray P. G. 2001; South Asian ethnicity and material deprivation increase the risk of Epstein-Barr virus infection in childhood Hodgkin’s disease. Br J Cancer 85:350–356 [View Article][PubMed]
     [Google Scholar]
  25. Gires O., Zimber-Strobl U., Gonnella R., Ueffing M., Marschall G., Zeidler R., Pich D., Hammerschmidt W. 1997; Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J 16:6131–6140 [View Article][PubMed]
     [Google Scholar]
  26. Glaser S. L., Lin R. J., Stewart S. L., Ambinder R. F., Jarrett R. F., Brousset P., Pallesen G., Gulley M. L., Khan G.other authors 1997; Epstein-Barr virus-associated Hodgkin’s disease: epidemiologic characteristics in international data. Int J Cancer 70:375–382 [View Article][PubMed]
     [Google Scholar]
  27. He B., Raab-Traub N., Casali P., Cerutti A. 2003; EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching. J Immunol 171:5215–5224 [View Article][PubMed]
     [Google Scholar]
  28. Hochberg D., Middeldorp J. M., Catalina M., Sullivan J. L., Luzuriaga K., Thorley-Lawson D. A. 2004; Demonstration of the Burkitt’s lymphoma Epstein-Barr virus phenotype in dividing latently infected memory cells in vivo. Proc Natl Acad Sci U S A 101:239–244 [View Article][PubMed]
     [Google Scholar]
  29. Hudnall S. D., Ge Y., Wei L., Yang N. P., Wang H. Q., Chen T. 2005; Distribution and phenotype of Epstein-Barr virus-infected cells in human pharyngeal tonsils. Mod Pathol 18:519–527 [View Article][PubMed]
     [Google Scholar]
  30. Jarrett R. F., Gallagher A., Jones D. B., Alexander F. E., Krajewski A. S., Kelsey A., Adams J., Angus B., Gledhill S., Wright D. H. 1991; Detection of Epstein-Barr virus genomes in Hodgkin’s disease: relation to age. J Clin Pathol 44:844–848 [View Article][PubMed]
     [Google Scholar]
  31. Kieff E., Rickinson A. B. 2001; Epstein–Barr virus and its replication. In Fields Virology, 4th edn. pp. 2511–2573 Edited by Knipe D. M., Howley P. M. Philadelphia: Lippincott Williams & Wilkins;
     [Google Scholar]
  32. Klein U., Dalla-Favera R. 2008; Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 8:22–33 [View Article][PubMed]
     [Google Scholar]
  33. Kube D., Holtick U., Vockerodt M., Ahmadi T., Haier B., Behrmann I., Heinrich P. C., Diehl V., Tesch H. 2001; STAT3 is constitutively activated in Hodgkin cell lines. Blood 98:762–770 [View Article][PubMed]
     [Google Scholar]
  34. Küppers R. 2005; Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer 5:251–262 [View Article][PubMed]
     [Google Scholar]
  35. Kurth J., Spieker T., Wustrow J., Strickler G. J., Hansmann L. M., Rajewsky K., Küppers R. 2000; EBV-infected B-cells in infectious mononucleosis: viral strategies for spreading in the B-cell compartment and establishing latency. Immunity 13:485–495 [View Article][PubMed]
     [Google Scholar]
  36. Kurth J., Hansmann M. L., Rajewsky K., Küppers R. 2003; Epstein-Barr virus-infected B-cells expanding in germinal centers of infectious mononucleosis patients do not participate in the germinal center reaction. Proc Natl Acad Sci U S A 100:4730–4735 [View Article][PubMed]
     [Google Scholar]
  37. Laichalk L. L., Thorley-Lawson D. A. 2005; Terminal differentiation into plasma cells initiates the replicative cycle of Epstein-Barr virus in vivo. J Virol 79:1296–1307 [View Article][PubMed]
     [Google Scholar]
  38. Lin K. I., Lin Y., Calame K. 2000; Repression of c-myc is necessary but not sufficient for terminal differentiation of B lymphocytes in vitro. Mol Cell Biol 20:8684–8695 [View Article][PubMed]
     [Google Scholar]
  39. MacLennan I. C. 1994; Germinal centers. Annu Rev Immunol 12:117–139 [View Article][PubMed]
     [Google Scholar]
  40. Mancao C., Altmann M., Jungnickel B., Hammerschmidt W. 2005; Rescue of “crippled” germinal center B-cells from apoptosis by Epstein-Barr virus. Blood 106:4339–4344 [View Article][PubMed]
     [Google Scholar]
  41. Martín P., Gomez-Lozano N., Montes S., Salas C., Provencio M., Bellas C. 2011; Epstein-Barr virus in the germinal centres of adenopathies affected by classic Hodgkin lymphoma. Histopathology 59:349–352[PubMed]
     [Google Scholar]
  42. Martín P., Coronado M. J., Bellas C. 2012; Evidence of the intersection of Epstein-Barr virus with germinal center. APMIS 120:253–254 [View Article][PubMed]
     [Google Scholar]
  43. Maruo S., Zhao B., Johannsen E., Kieff E., Zou J., Takada K. 2011; Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. Proc Natl Acad Sci U S A 108:1919–1924 [View Article][PubMed]
     [Google Scholar]
  44. Miller C. L., Lee J. H., Kieff E., Longnecker R. 1994; An integral membrane protein (LMP2) blocks reactivation of Epstein-Barr virus from latency following surface immunoglobulin crosslinking. Proc Natl Acad Sci U S A 91:772–776 [View Article][PubMed]
     [Google Scholar]
  45. Niedobitek G., Herbst H., Young L. S., Brooks L., Masucci M. G., Crocker J., Rickinson A. B., Stein H. 1992; Patterns of Epstein-Barr virus infection in non-neoplastic lymphoid tissue. Blood 79:2520–2526[PubMed]
     [Google Scholar]
  46. Niedobitek G., Agathanggelou A., Herbst H., Whitehead L., Wright D. H., Young L. S. 1997; Epstein-Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV-infected cells. J Pathol 182:151–159 [View Article][PubMed]
     [Google Scholar]
  47. Niedobitek G., Agathanggelou A., Steven N., Young L. S. 2000; Epstein-Barr virus (EBV) in infectious mononucleosis: detection of the virus in tonsillar B lymphocytes but not in desquamated oropharyngeal epithelial cells. Mol Pathol 53:37–42 [View Article][PubMed]
     [Google Scholar]
  48. Oyama T., Ichimura K., Suzuki R., Suzumiya J., Ohshima K., Yatabe Y., Yokoi T., Kojima M., Kamiya Y.other authors 2003; Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol 27:16–26 [View Article][PubMed]
     [Google Scholar]
  49. Oyama T., Yamamoto K., Asano N., Oshiro A., Suzuki R., Kagami Y., Morishima Y., Takeuchi K., Izumo T.other authors 2007; Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res 13:5124–5132 [View Article][PubMed]
     [Google Scholar]
  50. Panagopoulos D., Victoratos P., Alexiou M., Kollias G., Mosialos G. 2004; Comparative analysis of signal transduction by CD40 and the Epstein-Barr virus oncoprotein LMP1 in vivo. J Virol 78:13253–13261 [View Article][PubMed]
     [Google Scholar]
  51. Prince S., Keating S., Fielding C., Brennan P., Floettmann E., Rowe M. 2003; Latent membrane protein 1 inhibits Epstein-Barr virus lytic cycle induction and progress via different mechanisms. J Virol 77:5000–5007 [View Article][PubMed]
     [Google Scholar]
  52. Rickinson A., Kieff E. 2001; Epstein–Barr virus. In Fields Virology, 4th edn. pp. 2575–2627 Edited by Knipe D. M., Howley P. M. Philadelphia: Lippincott Williams & Wilkins;
     [Google Scholar]
  53. Roughan J. E., Thorley-Lawson D. A. 2009; The intersection of Epstein-Barr virus with the germinal center. J Virol 83:3968–3976 [View Article][PubMed]
     [Google Scholar]
  54. Roughan J. E., Torgbor C., Thorley-Lawson D. A. 2010; Germinal center B-cells latently infected with Epstein-Barr virus proliferate extensively but do not increase in number. J Virol 84:1158–1168 [View Article][PubMed]
     [Google Scholar]
  55. Schaadt E., Baier B., Mautner J., Bornkamm G. W., Adler B. 2005; Epstein-Barr virus latent membrane protein 2A mimics B-cell receptor-dependent virus reactivation. J Gen Virol 86:551–559 [View Article][PubMed]
     [Google Scholar]
  56. Skalska L., White R. E., Franz M., Ruhmann M., Allday M. J. 2010; Epigenetic repression of p16(INK4A) by latent Epstein-Barr virus requires the interaction of EBNA3A and EBNA3C with CtBP. PLoS Pathog 6:e1000951 [View Article][PubMed]
     [Google Scholar]
  57. Swanson-Mungerson M. A., Caldwell R. G., Bultema R., Longnecker R. 2005; Epstein-Barr virus LMP2A alters in vivo and in vitro models of B-cell anergy, but not deletion, in response to autoantigen. J Virol 79:7355–7362 [View Article][PubMed]
     [Google Scholar]
  58. Takada K., Shimizu N., Sakuma S., Ono Y. 1986; Trans activation of the latent Epstein-Barr virus (EBV) genome after transfection of the EBV DNA fragment. J Virol 57:1016–1022[PubMed]
     [Google Scholar]
  59. Thorley-Lawson D. A. 2001; Epstein-Barr virus: exploiting the immune system. Nat Rev Immunol 1:75–82 [View Article][PubMed]
     [Google Scholar]
  60. Thorley-Lawson D. A., Gross A. 2004; Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350:1328–1337 [View Article][PubMed]
     [Google Scholar]
  61. Thorley-Lawson D. A., Duca K. A., Shapiro M. 2008; Epstein-Barr virus: a paradigm for persistent infection – for real and in virtual reality. Trends Immunol 29:195–201 [View Article][PubMed]
     [Google Scholar]
  62. Vockerodt M., Morgan S. L., Kuo M., Wei W., Chukwuma M. B., Arrand J. R., Kube D., Gordon J., Young L. S.other authors 2008; The Epstein–Barr virus oncoprotein, latent membrane protein-1, reprograms germinal centre B-cells towards a Hodgkin’s Reed–Sternberg-like phenotype. J Pathol 216:83–92 [View Article][PubMed]
     [Google Scholar]
  63. Vockerodt M., Wei W., Nagy E., Prouzova Z., Schrader A., Kube D., Rowe M., Woodman C. B., Murray P. G. 2013; Suppression of the LMP2A target gene, EGR-1, protects Hodgkin’s lymphoma cells from entry to the EBV lytic cycle. J Pathol 230:399–409 [View Article][PubMed]
     [Google Scholar]
  64. Vrzalikova K., Vockerodt M., Leonard S., Bell A., Wei W., Schrader A., Wright K. L., Kube D., Rowe M.other authors 2011; Down-regulation of BLIMP1 by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B-cells: implications for the pathogenesis of EBV-associated B-cell lymphomas. Blood 117:5907–5917 [View Article][PubMed]
     [Google Scholar]
  65. Weiss L. M., Movahed L. A., Warnke R. A., Sklar J. 1989; Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin’s disease. N Engl J Med 320:502–506 [View Article][PubMed]
     [Google Scholar]
  66. White R. E., Rämer P. C., Naresh K. N., Meixlsperger S., Pinaud L., Rooney C., Savoldo B., Coutinho R., Bödör C.other authors 2012; EBNA3B-deficient EBV promotes B-cell lymphomagenesis in humanized mice and is found in human tumors. J Clin Invest 122:1487–1502 [View Article][PubMed]
     [Google Scholar]
  67. Wu T. C., Mann R. B., Charache P., Hayward S. D., Staal S., Lambe B. C., Ambinder R. F. 1990; Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin’s disease. Int J Cancer 46:801–804 [View Article][PubMed]
     [Google Scholar]
  68. Young L. S., Murray P. G. 2003; Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene 22:5108–5121 [View Article][PubMed]
     [Google Scholar]
  69. Young L. S., Rickinson A. B. 2004; Epstein-Barr virus: 40 years on. Nat Rev Cancer 4:757–768 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.066712-0
Loading
Epstein–Barr virus, the germinal centre and the development of Hodgkin’s lymphoma
J. Gen. Virol. 95, 1861 (2014); https://doi.org/10.1099/vir.0.066712-0
/content/journal/jgv/10.1099/vir.0.066712-0
/content/journal/jgv/10.1099/vir.0.066712-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error