The Epstein-Barr virus (EBV) is a herpes virus which establishes a life-long persistent infection in over 90% of the human adult population world-wide. Based on its association with a variety of lymphoid and epithelial malignancies, EBV has been classified as a group 1 carcinogen by the International Agency for Research on Cancer. In this article we discuss the evidence supporting an aetiological role for EBV in the pathogenesis of human tumours. The biology of EBV infection will be described with special emphasis on viral transforming gene products. A brief survey of EBV-associated tumours is followed by a discussion of specific problems. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated tumours also in patients without clinically manifest immunodeficiencies. Finally, the timing of EBV infection in the pathogenesis of virus-associated malignancies is discussed. There is good evidence that EBV infection precedes expansion of the malignant cell populations in some virus-associated tumours. However, this is clearly not always the case and for some of these tumours there are indications that clonal genetic alterations may occur prior to EBV infection. Thus, whilst there is good evidence to suggest that EBV is a human carcinogen, its precise role(s) in the development of virus-associated human tumours requires clarification.

The Epstein-Barr virus (EBV) is a herpes virus which establishes a life-long persistent infection in over 90% of the human adult population world-wide. Based on its association with a variety of lymphoid and epithelial malignancies, EBV has been classified as a group 1 carcinogen by the International Agency for Research on Cancer. In this article we discuss the evidence supporting an aetiological role for EBV in the pathogenesis of human tumours. The biology of EBV infection will be described with special emphasis on viral transforming gene products. A brief survey of EBVassociated tumours is followed by a discussion of specific problems. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated tumours also in patients without clinically manifest immunodeficiencies. Finally, the timing of EBV infection in the pathogenesis of virus-associated malignancies is discussed. There is good evidence that EBV infection precedes expansion of the malignant cell populations in some virus-associated tumours. However, this is clearly not always the case and for some of these tumours there are indications that clonal genetic alterations may occur prior to EBV infection. Thus, whilst there is good evidence to suggest that EBV is a human carcinogen, its precise role(s) in the development of virus-associated human tumours requires clarification.

V(D)J recombination in lymphocytes is (Ig) and T-cell receptor (TCR) genes is mediated by the products of 2 recombinationactivating genes (RAG1 and RAG2) which recognize specific recombination signal sequences (RSS) flanking the V, D, and J gene segments. 1,2 The RAGs are transiently and coordinately expressed during B-cell and T-cell ontogeny in bone marrow and thymus, respectively. [3][4][5] Upon completion of V(D)J rearrangement, RAG expression is shut down. 3 IgM-expressing immature bone marrow B cells recognizing self antigens can re-express the RAGs, leading to further rearrangement of the light chain locus. 6 This process, termed receptor editing, is thought to play a role in the elimination of autoreactive B cells. 6 Mature lymphocytes were generally believed to be incapable of expressing the RAG, thus maintaining allelic exclusion. A number of recent studies, however, have raised the possibility that secondary V(D)J recombination may occur in peripheral lymphoid tissue B cells in the context of germinal center reactions. Thus, RAG transcripts and proteins have been detected in germinal center B cells from lymph nodes, spleens, and Peyer patches in mice. 7,8 Using polymerase chain reaction (PCR), RSS DNA strand breaks characteristic of V(D)J recombination were detected in interleukin 4 (IL-4)-stimulated mature mouse B cells and in germinal center B cells from immunized mice. 9,10 Han et al have suggested that reinduction of RAG expression may occur in germinal center B cells as a result of diminished or abolished antigen binding, thus rescuing cells which would otherwise have been lost to apoptotic cell death. 10 Although initial studies have used mouse models, subsequent reports have provided evidence that similar mechanisms may operate in humans. RAG1 and RAG2 transcripts have been detected in human germinal center B lymphocytes by reverse transcriptase (RT)-PCR. 11 In human tonsils, RSS DNA breaks were detectable in germinal center centrocytes but not in follicle mantle cells. 12 Moreover, RAG, terminal deoxynucleotidyl transferase (TdT), VpreB, and -like transcripts were detected in centrocytes by PCR analysis of fluorescence activated cell sorting (FACS) sorted cell populations. 12,13 Nevertheless, the exact nature and localization of RAG-expressing cells in peripheral lymphoid tissues is still controversial and immunohistochemical studies have not clarified this issue. Expression of RAG genes has been variably reported in the light zones of germinal centers, 8 in germinal center apoptotic bodies, 14 and in scattered cells of germinal center, mantle zone, and extrafollicular area. 13 To resolve this issue, we have examined the expression of RAGs and TdT in human lymphoreticular tissues using in situ hybridization and immunohistochemistry, respectively. Materials and methods TissuesFormalin-fixed and paraffin-embedded tonsillectomy specimens from 25 patients aged 3 to 49 years were studied. All cases showed prominent follicular hyperplasia but no evidence of neoplastic disease. In addition, paraffin ...

These data indicate that tonsillar enlargement in paediatric liver transplant patients does not necessarily imply a diagnosis of PTLD. Furthermore, the presence of increased numbers of EBV infected cells in tonsils from liver transplant recipients by itself does not indicate an increased risk of developing PTLD.

Summary. We report the case of a young Caucasian man who presented with polyneuropathy and severe, ultimately fatal, congestive heart failure in the context of a chronic active Epstein±Barr virus (EBV) infection. Post-mortem examination revealed both monoclonal and polyclonal proliferation of EBV-positive atypical T lymphocytes within different organs. Predominant infiltration of the nervous system and heart with extensive myocardial scarring accounted for the clinical symptoms. The remarkable features of this case are (i) the occurrence in a Caucasian patient, (ii) the absence of detectable immunodeficiency, and (iii) the myocardial destruction by EBV-infected monoclonal T cells.