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B cells under influence: transformation of B cells by Epstein–Barr virus

Nature Reviews Immunology volume 3, pages 801–812 (2003)Cite this article

Key Points

  • Epstein–Barr virus (EBV) infects nearly all humans worldwide and establishes a persistent infection.

  • The reservoir of EBV is B cells.

  • Although EBV normally persists as a harmless passenger, it might also promote the development of B-cell lymphomas.

  • Although EBV can adapt to normal B-cell developmental pathways, the virus can also have a marked influence on differentiation processes of B cells. In particular, EBV might replace the survival signals that are normally provided by the B-cell receptor (BCR), thereby allowing the survival of BCR-deficient B cells.

  • EBV-encoded proteins mimic key signalling pathways in B cells: latent membrane protein 1 (LMP1) mimics an active CD40 receptor, LMP2A mimics the BCR and EBV nuclear antigen 2 (EBNA2) signals in a manner similar to the Notch pathway.

  • The main types of EBV-associated B-cell lymphoma (Burkitt lymphoma, Hodgkin lymphoma and post-transplant lymphomas) all seem to derive mostly from (distinct subsets of) germinal-centre B cells, pointing to a particular role for the germinal-centre reaction in the pathogenesis of these tumours.

Abstract

Epstein–Barr virus (EBV) is an extremely successful virus, infecting more than 90% of the human population worldwide. After primary infection, the virus persists for the life of the host, usually as a harmless passenger residing in B cells. However, EBV can transform B cells, which can result in the development of malignant lymphomas. Intriguingly, the three main types of EBV-associated B-cell lymphoma — that is, Burkitt lymphoma, Hodgkin lymphoma and post-transplant lymphomas — seem to derive from germinal-centre B cells or atypical survivors of the germinal-centre reaction in most, if not all, cases, indicating that EBV-infected germinal-centre B cells are at particular risk for malignant transformation.

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Figure 1: Strategies of EBV-infected B cells during acute primary infection.
Figure 2: Scenarios for the development of EBV-associated lymphomas.

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References

  1. Rickinson, A. B. & Kieff, E. in Fields Virology (eds Knipe, D. M. & Howley, P. M.) 2575–2627 (Lippincott–Raven, Philadelphia, 2001).

    Google Scholar 

  2. Jenson, H. B. Acute Epstein–Barr virus infections. Bailliere's Clin. Infect. Dis. 3, 477–506 (1996).

    Google Scholar 

  3. Kilger, E., Kieser, A., Baumann, M. & Hammerschmidt, W. Epstein–Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J. 17, 1700–1709 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Caldwell, R. G., Wilson, J. B., Anderson, S. J. & Longnecker, R. Epstein–Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9, 405–411 (1998). This study shows that expression of latent membrane protein 2A (LMP2A) allows immunoglobulin-negative B cells to survive and colonize peripheral lymphoid organs, indicating that LMP2A can replace the survival signal normally supplied by the B-cell receptor (BCR).

    Article  CAS  PubMed  Google Scholar 

  5. Smith, P. Epstein–Barr virus complementary strand transcripts (CSTs/BARTs) and cancer. Semin. Cancer Biol. 11, 468–476 (2001).

    Article  CAS  Google Scholar 

  6. Khan, G., Miyashita, E. M., Yang, B., Babcock, G. J. & Thorley-Lawson, D. A. Is EBV persistence in vivo a model for B cell homeostasis? Immunity 5, 173–179 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Babcock, G. J., Hochberg, D. & Thorley-Lawson, D. A. 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 (2000). This paper shows that the expression pattern of Epstein–Barr virus (EBV)-encoded genes depends on the differentiation stage of the infected B cells. These findings are the basis for a model of viral strategies during persistent infection.

    Article  CAS  PubMed  Google Scholar 

  8. Thorley-Lawson, D. A. & Babcock, G. J. A model for persistent infection with Epstein–Barr virus: the stealth virus of human B cells. Life Sci. 65, 1433–1453 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Thorley-Lawson, D. A. Epstein–Barr virus: exploiting the immune system. Nature Rev. Immunol. 1, 75–82 (2001).

    Article  CAS  Google Scholar 

  10. Joseph, A. M., Babcock, G. J. & Thorley-Lawson, D. A. Cells expressing the Epstein–Barr virus growth program are present in and restricted to the naive B-cell subset of healthy tonsils. J. Virol. 74, 9964–9971 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Babcock, G. J., Decker, L. L., Volk, M. & Thorley-Lawson, D. A. EBV persistence in memory B cells in vivo. Immunity 9, 395–404 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Rowe, D. T. Epstein–Barr virus immortalization and latency. Front. Biosci. 4, D346–D371 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Cheung, R. K., Miyazaki, I. & Dosch, H. M. Unexpected patterns of Epstein–Barr virus gene expression during early stages of B cell transformation. Int. Immunol. 5, 707–716 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Ehlin-Henriksson, B., Gordon, J. & Klein, G. B-lymphocyte subpopulations are equally susceptible to Epstein–Barr virus infection, irrespective of immunoglobulin isotype expression. Immunol. 108, 427–430 (2003).

    Article  CAS  Google Scholar 

  15. Laichalk, L. L., Hochberg, D., Babcock, G. J., Freeman, R. B. & Thorley-Lawson, D. A. The dispersal of mucosal memory B cells: evidence from persistent EBV infection. Immunity 16, 745–754 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Araujo, I. et al. 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 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Meru, N. et al. Epstein–Barr virus infection in paediatric liver transplant recipients: detection of the virus in post-transplant tonsillectomy specimens. Mol. Pathol. 54, 265–269 (2001).

    Article  Google Scholar 

  18. Niedobitek, G. et al. Patterns of Epstein–Barr virus infection in non-neoplastic lymphoid tissue. Blood 79, 2520–2526 (1992).

    Article  CAS  PubMed  Google Scholar 

  19. Capello, D. et al. Molecular histogenesis of posttransplant lymphoproliferative disorders. Blood (in the press).

  20. Carbone, A. et al. BCL-6 protein expression in AIDS-related non-Hodgkin's lymphomas: inverse relationship with Epstein–Barr virus-encoded latent membrane protein-1 expression. Am. J. Pathol. 150, 155–165 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cattoretti, G. et al. Downregulation of BCL-6 gene expression by CD40 and EBV latent membrane protein-1 (LMP-1) and its block in lymphoma carrying BCL-6 rearrangements. Blood 90, 175a (1997).

    Google Scholar 

  22. Uchida, J. et al. Mimicry of CD40 signals by Epstein–Barr virus LMP1 in B lymphocyte responses. Science 286, 300–303 (1999). Evidence is provided that constitutive expression of LMP1 by mouse B cells on the one hand mimics CD40 signalling, but on the other hand also blocks B cells from differentiating into germinal-centre B cells.

    Article  CAS  PubMed  Google Scholar 

  23. Klein, G., Svedmyr, E., Jondal, M. & Persson, P. O. EBV-determined nuclear antigen (EBNA)-positive cells in the peripheral blood of infectious mononucleosis patients. Int. J. Cancer 17, 21–26 (1976).

    Article  CAS  PubMed  Google Scholar 

  24. Rickinson, A. B. & Moss, D. J. Human cytotoxic T lymphocyte responses to Epstein–Barr virus infection. Annu. Rev. Immunol. 15, 405–431 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Kurth, J. et al. EBV-infected B cells in infectious mononucleosis: viral strategies for spreading in the B cell compartment and establishing latency. Immunity 13, 485–495 (2000). This molecular analysis of EBV-infected B cells in infectious mononucleosis indicated the viral strategies during acute primary infection.

    Article  CAS  PubMed  Google Scholar 

  26. Kurth, J., Hansmann, M. -L., Rajewsky, K. & Küppers, R. 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. USA 100, 4730–4735 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Brink, A. A. et al. Presence of Epstein–Barr virus latency type III at the single cell level in post-transplantation lymphoproliferative disorders and AIDS related lymphomas. J. Clin. Pathol. 50, 911–918 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Niedobitek, G. et al. Epstein–Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV-infected cells. J. Pathol. 182, 151–159 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Bhatia, K. G., Gutierrez, M. I., Huppi, K., Siwarski, D. & Magrath, I. T. The pattern of p53 mutations in Burkitt's lymphoma differs from that of solid tumors. Cancer Res. 52, 4273–4276 (1992).

    CAS  PubMed  Google Scholar 

  30. Gaidano, G. et al. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc. Natl Acad. Sci. USA 88, 5413–5417 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cinti, C. et al. Genetic alterations of the retinoblastoma-related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt's lymphoma subtypes. Am. J. Pathol. 156, 751–760 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gregory, C. D. et al. Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype. J. Immunol. 139, 313–318 (1987).

    CAS  PubMed  Google Scholar 

  33. Ling, N. R. et al. A phenotypic study of cells from Burkitt lymphoma and EBV-B-lymphoblastoid lines and their relationship to cells in normal lymphoid tissues. Int. J. Cancer 43, 112–118 (1989).

    Article  CAS  PubMed  Google Scholar 

  34. Onizuka, T. et al. BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. Blood 86, 28–37 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Chapman, C. J., Mockridge, C. I., Rowe, M., Rickinson, A. B. & Stevenson, F. K. Analysis of VH genes used by neoplastic B cells in endemic Burkitt's lymphoma shows somatic hypermutation and intraclonal heterogeneity. Blood 85, 2176–2181 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Chapman, C. J., Zhou, J. X., Gregory, C., Rickinson, A. B. & Stevenson, F. K. VH and VL gene analysis in sporadic Burkitt's lymphoma shows somatic hypermutation, intraclonal heterogeneity, and a role for antigen selection. Blood 88, 3562–3568 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Harris, R. S., Croom-Carter, D. S., Rickinson, A. B. & Neuberger, M. S. Epstein–Barr virus and the somatic hypermutation of immunoglobulin genes in Burkitt's lymphoma cells. J. Virol. 75, 10488–10492 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sale, J. E. & Neuberger, M. S. TdT-accessible breaks are scattered over the immunoglobulin V domain in a constitutively hypermutating B cell line. Immunity 9, 859–869 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Goossens, T., Klein, U. & Küppers, R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc. Natl Acad. Sci. USA 95, 2463–2468 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Küppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580–5594 (2001).

    Article  PubMed  Google Scholar 

  41. Bornkamm, G. W. & Hammerschmidt, W. Molecular virology of Epstein–Barr virus. Philos. Trans. R. Soc. Lond. B Biol. Sci. 356, 437–459 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wilson, J. B., Bell, J. L. & Levine, A. J. Expression of Epstein–Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J. 15, 3117–3126 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kitagawa, N. et al. Epstein–Barr virus-encoded poly(A)− RNA supports Burkitt's lymphoma growth through interleukin-10 induction. EMBO J. 19, 6742–6750 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nanbo, A., Inoue, K., Adachi-Takasawa, K. & Takada, K. Epstein–Barr virus RNA confers resistance to interferon-α-induced apoptosis in Burkitt's lymphoma. EMBO J. 21, 954–965 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Niller, H. H. et al. The in vivo binding site for oncoprotein c-Myc in the promoter for Epstein–Barr virus (EBV) encoding RNA (EBER) 1 suggests a specific role for EBV in lymphomagenesis. Med. Sci. Monit. 9, HY1–9 (2003).

    CAS  PubMed  Google Scholar 

  46. Kiss, C. et al. T cell leukemia I oncogene expression depends on the presence of Epstein–Barr virus in the virus-carrying Burkitt lymphoma lines. Proc. Natl Acad. Sci. USA 100, 4813–4818 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kelly, G., Bell, A. & Rickinson, A. Epstein–Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Nature Med. 8, 1098–1104 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Pajic, A. et al. Antagonistic effects of c-myc and Epstein–Barr virus latent genes on the phenotype of human B cells. Int. J. Cancer 93, 810–816 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Jochner, N. et al. Epstein–Barr virus nuclear antigen 2 is a transcriptional suppressor of the immunoglobulin μ gene: implications for the expression of the translocated c-myc gene in Burkitt's lymphoma cells. EMBO J. 15, 375–382 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Weiss, L. M., Chan, J. K. C., MacLennan, K. & Warnke, R. A. in Hodgkin's disease (eds Mauch, P. M., Armitage, J. O., Diehl, V., Hoppe, R. T. & Weiss, L. M.) 101–120 (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  51. Harris, N. L. Hodgkin's lymphomas: classification, diagnosis, and grading. Semin. Hematol. 36, 220–232 (1999).

    CAS  PubMed  Google Scholar 

  52. Jarrett, R. F. & MacKenzie, J. Epstein–Barr virus and other candidate viruses in the pathogenesis of Hodgkin's disease. Semin. Hematol. 36, 260–269 (1999).

    CAS  PubMed  Google Scholar 

  53. Kanzler, H., Küppers, R., Hansmann, M. L. & Rajewsky, K. Hodgkin and Reed–Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J. Exp. Med. 184, 1495–1505 (1996).

    Article  CAS  PubMed  Google Scholar 

  54. Küppers, R. Molecular biology of Hodgkin's lymphoma. Adv. Cancer Res. 84, 277–312 (2002).

    Article  PubMed  Google Scholar 

  55. Marafioti, T. et al. Hodgkin and Reed–Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood 95, 1443–1450 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Liu, Y. J. et al. Mechanism of antigen-driven selection in germinal centres. Nature 342, 929–931 (1989).

    Article  CAS  PubMed  Google Scholar 

  57. Herbst, H. et al. Epstein–Barr virus latent membrane protein expression in Hodgkin and Reed–Sternberg cells. Proc. Natl Acad. Sci. USA 88, 4766–4770 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Niedobitek, G. et al. Immunohistochemical detection of the Epstein–Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis. Blood 90, 1664–1672 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Pallesen, G., Hamilton-Dutoit, S. J., Rowe, M. & Young, L. S. Expression of Epstein–Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 337, 320–322 (1991).

    Article  CAS  PubMed  Google Scholar 

  60. Schwering, I. et al. Loss of the B-lineage-specific gene expression program in Hodgkin and Reed–Sternberg cells of Hodgkin lymphoma. Blood 101, 1505–1512 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Engels, N. et al. Epstein–Barr virus latent membrane protein 2A (LMP2A) employs the SLP-65 signaling module. J. Exp. Med. 194, 255–264 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Knowles, D. M. The molecular genetics of post-transplantation lymphoproliferative disorders. Springer Sem. Immunopathol. 20, 357–373 (1998).

    Article  CAS  Google Scholar 

  63. Bräuninger, A. et al. Epstein–Barr virus (EBV)-positive lymphoproliferations in posttransplant patients show immunoglobulin V gene mutation patterns suggesting interference of EBV with normal B cell differentiation processes. Eur. J. Immunol. 33, 1593–1602 (2003).

    Article  PubMed  CAS  Google Scholar 

  64. Timms, J. M. et al. Target cells of Epstein–Barr-virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma. Lancet 361, 217–223 (2003). References 63 and 64 (as well as reference 19) show that post-transplant lymphomas derive from the transformation of diverse types of B cell, including selected and 'crippled' germinal-centre B cells.

    Article  PubMed  Google Scholar 

  65. Küppers, R., Klein, U., Hansmann, M. -L. & Rajewsky, K. Cellular origin of human B-cell lymphomas. N. Engl. J. Med. 341, 1520–1529 (1999).

    Article  PubMed  Google Scholar 

  66. Arbus, G. S. et al. Verotoxin targets lymphoma infiltrates of patients with post-transplant lymphoproliferative disease. Leuk. Res. 24, 857–864 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Randhawa, P. S. et al. Morphologic and immunophenotypic characterization of a cell line derived from liver tissue with Epstein–Barr virus associated post-transplant lymphoproliferative disease. In Vitro Cell. Dev. Biol. Anim. 30A, 400–406 (1994).

    Article  CAS  PubMed  Google Scholar 

  68. Randhawa, P. et al. In vitro culture of B-lymphocytes derived from Epstein–Barr-virus-associated posttransplant lymphoproliferative disease: cytokine production and effect of interferon-α. In Vitro Cell. Dev. Biol. Anim. 33, 803–808 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Armitage, J. M. et al. Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J. Heart Lung Transplant. 10, 877–886 (1991).

    CAS  PubMed  Google Scholar 

  70. Hopwood, P. & Crawford, D. H. The role of EBV in post-transplant malignancies: a review. J. Clin. Pathol. 53, 248–254 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Anagnostopoulos, I. et al. Heterogeneous Epstein–Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Blood 80, 1804–1812 (1992).

    Article  CAS  PubMed  Google Scholar 

  72. Weiss, L. M. et al. Detection and localization of Epstein–Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood 79, 1789–1795 (1992).

    Article  CAS  PubMed  Google Scholar 

  73. Bräuninger, A. et al. Survival and clonal expansion of mutating 'forbidden' (immunoglobulin receptor-deficient) Epstein–Barr virus-infected B cells in angioimmunoblastic T cell lymphoma. J. Exp. Med. 194, 927–940 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Lam, K. P., Kühn, R. & Rajewsky, K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).

    Article  CAS  PubMed  Google Scholar 

  75. Razzouk, B. I., Srinivas, S., Sample, C. E., Singh, V. & Sixbey, J. W. Epstein–Barr Virus DNA recombination and loss in sporadic Burkitt's lymphoma. J. Infect. Dis. 173, 529–535 (1996).

    Article  CAS  PubMed  Google Scholar 

  76. Gan, Y. J., Razzouk, B. I., Su, T. & Sixbey, J. W. A defective, rearranged Epstein–Barr virus genome in EBER-negative and EBER-positive Hodgkin's disease. Am. J. Pathol. 160, 781–786 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cabannes, E., Khan, G., Aillet, F., Jarrett, R. F. & Hay, R. T. Mutations in the IκBα gene in Hodgkin's disease suggest a tumour suppressor role for IκBα. Oncogene 18, 3063–3070 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Emmerich, F. et al. Overexpression of IκBα without inhibition of NF-κB activity and mutations in the IκBα gene in Reed–Sternberg cells. Blood 94, 3129–3134 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Joos, S. et al. Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 99, 1381–1387 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Jungnickel, B. et al. Clonal deleterious mutations in the IκBα gene in the malignant cells in Hodgkin's disease. J. Exp. Med. 191, 395–401 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Martin-Subero, J. I. et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 99, 1474–1477 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Fais, F. et al. Analysis of stepwise genetic changes in an AIDS-related Burkitt's lymphoma. Int. J. Cancer 88, 744–750 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Tinguely, M. et al. Molecular single cell analysis of a composite mantle cell and Hodgkin lymphoma shows a common origin and indicates Epstein–Barr virus infection of a Hodgkin/Reed–Sternberg cell precursor in a germinal center reaction. Am. J. Surg. Pathol. (in the press).

  84. Shaffer, A. L., Rosenwald, A. & Staudt, L. M. Lymphoid malignancies: the dark side of B-cell differentiation. Nature Rev. Immunol. 2, 920–932 (2002).

    Article  CAS  Google Scholar 

  85. Stevenson, F. K. et al. The occurrence and significance of V gene mutations in B cell-derived human malignancy. Adv. Cancer Res. 83, 81–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  86. Küppers, R. & Rajewsky, K. The origin of Hodgkin and Reed–Sternberg cells in Hodgkin's disease. Annu. Rev. Immunol. 16, 471–493 (1998).

    Article  PubMed  Google Scholar 

  87. Yates, J. L., Warren, N. & Sugden, B. Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells. Nature 313, 812–815 (1985).

    Article  CAS  PubMed  Google Scholar 

  88. Levitskaya, J. et al. Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature 375, 685–688 (1995).

    Article  CAS  PubMed  Google Scholar 

  89. Kieff, E. in Fields Virology (eds Fields, B. N., Knipe, D. M. & Howley, P. M.) 2343–2396 (Lippincott–Raven, Philadelphia, 1996).

    Google Scholar 

  90. Zimber-Strobl, U. & Strobl, L. J. EBNA2 and Notch signalling in Epstein–Barr virus mediated immortalization of B lymphocytes. Semin. Cancer Biol. 11, 423–434 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Wang, D., Liebowitz, D. & Kieff, E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell 43, 831–840 (1985).

    Article  CAS  PubMed  Google Scholar 

  92. Kulwichit, W. et al. Expression of the Epstein–Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc. Natl Acad. Sci. USA 95, 11963–11968 (1998). This study shows that transgenic mice expressing LMP1 in B cells develop lymphomas, establishing LMP1 as an oncogene for B cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mosialos, G. et al. The Epstein–Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. Cell 80, 389–399 (1995).

    Article  CAS  PubMed  Google Scholar 

  94. Brown, K. D., Hostager, B. S. & Bishop, G. A. Differential signaling and tumor necrosis factor receptor-associated factor (TRAF) degradation mediated by CD40 and the Epstein–Barr virus oncoprotein latent membrane protein 1 (LMP1). J. Exp. Med. 193, 943–954 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Alber, G. et al. Molecular mimicry of the antigen receptor signalling motif by transmembrane proteins of the Epstein–Barr virus and the bovine leukemia virus. Curr. Biol. 3, 333–339 (1993).

    Article  CAS  PubMed  Google Scholar 

  96. Miller, C. L. et al. Integral membrane protein 2 of Epstein–Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases. Immunity 2, 155–166 (1995).

    Article  CAS  PubMed  Google Scholar 

  97. Merchant, M. et al. The effects of the Epstein–Barr virus latent membrane protein 2A on B cell function. Int. Rev. Immunol. 20, 805–835 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Rajewsky, K. Clonal selection and learning in the antibody system. Nature 381, 751–758 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).

    CAS  PubMed  Google Scholar 

  100. Küppers, R., Zhao, M., Hansmann, M. L. & Rajewsky, K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 12, 4955–4967 (1993).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I am supported supported by the Deutsche Forschungsgemeinschaft and by the Hugo-Feger-Nachlass. I am grateful to K. Rajewsky and M.-L. Hansmann for stimulating discussions, and to J. Kurth, A. Bräuninger and G. Bornkamm for critical comments on the manuscript.

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  1. Institute for Genetics and Department of Internal Medicine I, University of Cologne, Cologne, 50931, Germany

    Ralf Küppers

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DATABASES

LocusLink

BCL6

BLNK

IFN-α

MYC

p53

RB2

TCL1

OMIM

Burkitt lymphoma

Hodgkin lymphoma

Entrez

EBV

Glossary

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS

(ITAMs). Structural motifs containing tyrosine residues, found in the cytoplasmic tails of several signalling molecules. The motif consists of Tyr-Xaa-Xaa-Leu/Ile, and the tyrosine is a target for phosphorylation by SRC tyrosine kinases and subsequent binding of proteins containing SH2 domains.

GERMINAL CENTRE

A structure found in the follicles of secondary lymphoid tissues (spleen, Peyer's patches and lymph nodes) that is composed of proliferating B cells that are induced to mutate rearranged variable regions of their heavy- and light-chain genes after contact with antigen and T helper cells. B cells that have modified B-cell receptors that cannot bind antigen die by apoptosis, whereas those that do bind antigen are positively selected to exit the germinal centre as memory cells.

SOMATIC HYPERMUTATION

(SHM). The process by which antigen-activated B cells in germinal centres mutate their rearranged immunoglobulin genes. The B cells are subsequently selected for those expressing the 'best' mutations on the basis of the ability of the surface immunoglobulin to bind antigen.

CLASS-SWITCH RECOMBINATION

Alters the immunoglobulin heavy-chain constant (CH)-region gene that will be expressed from the Cμ region to one of the other CH genes. This results in a switch of immunoglobulin isotype from IgM/IgD to IgG, IgA or IgE, without altering antigen specificity.

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Küppers, R. B cells under influence: transformation of B cells by Epstein–Barr virus. Nat Rev Immunol 3, 801–812 (2003). https://doi.org/10.1038/nri1201

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