Patterns of Epstein-Barr virus infection in non-Hodgkin's lymphomas.
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Genes, Viral↗
Biomedical subjects
G Niedobitek
Publications and source records attributed to G Niedobitek.
Non-Hodgkin's lymphoma, coeliac disease, and Epstein-Barr virus: a study of 13 cases of enteropathy-associated T- and B-cell lymphoma.
A group of 166 patients with coeliac disease was followed for a period of up to 25 years. During this time, 17 patients developed intestinal tumours that were diagnosed as lymphoma, of which 15 cases were available for review. Eleven of the lymphomas were of T-cell type (enteropathy-associated T-cell lymphoma, EATL) and two were of B-cell type. Two cases were reclassified as undifferentiated carcinoma. The interval between the diagnosis of enteropathy and the onset of lymphoma varied from less than 2 months in four patients to more than 5 years in seven. Seven of the T-cell and both B-cell lymphomas were investigated for the presence of Epstein-Barr virus (EBV) by in situ hybridization (ISH) using probes against Epstein-Barr virus-encoded RNAs (EBERs) and by immunohistochemistry with EBV-specific monoclonal antibodies. All EATL cases were negative, suggesting that EBV is not an important factor in these cases. In one of the B-cell cases, EBV was detectable by ISH and immunohistochemistry in most tumour cells in the mesenteric lymph nodes, but not in any of the tumour cells in the primary ileal tumour, indicating that in this case EBV infection was a late event in the neoplastic process. These results show that lymphoma may develop any time after the onset of coeliac disease and that in our cases of EATL, EBV was not an important factor. In some cases of EBV-related neoplasia, virus infection may be a late event.
Adult↗
Absence of Epstein-Barr virus in testicular germ cell tumours: a study of 21 cases using in situ hybridisation.
Aim-To establish whether testicular germ cell tumours contain Epstein-Barr virus (EBV) and if so to provide further evidence for the hypothesis that EBV plays a direct role in the pathogenesis of testicular germ cell tumours.Method-Paraffin wax embedded tissue blocks from 21 germ cell tumours including 12 teratomas and nine classic seminomas were examined by in situ hybridisation for the expression of the small EBV encoded nuclear RNA transcripts (EBER-1 and -2) using isotopic and nonisotopic probes.Results-There was no EBER specific signal detectable in any of the testicular germ cell tumours examined by in situ hybridisation whilst a strong signal was observed in appropriate control sections.Conclusion-The absence of demonstrable EBER transcripts in testicular germ cell tumours make a direct role for EBV in the pathogenesis of these tumours unlikely. Other explanations for the epidemiological and serological evidence linking EBV with germ cell tumours need to be explored.
Journal Article↗
The expression of variant CD44 in nasopharyngeal carcinoma is unrelated to expression of LMP-1.
CD44 expression in undifferentiated nasopharyngeal carcinoma has been analyzed by sequencing cDNA clones and by immunohistochemical staining using monoclonal antibodies specific for defined variant exons. Both sequencing and antibody staining revealed expression of CD44 variants containing exon v6, which has been linked to tumor metastasis. Although nasopharyngeal carcinoma typically contains a mixture of epithelial tumor cells and infiltrating lymphocytes, the CD44 v6 variant expression could be assigned to the tumor cells in biopsies and in a mouse xenograft system. Consistent with earlier studies, biopsies from about 60% of Chinese nasopharyngeal carcinoma cases expressed the Epstein-Barr virus LMP-1 protein, although all contained EBV DNA and expressed the EBER genes. The antibody specific for CD44 exon v6 generally gave a focal pattern of staining in epithelial tumor cells, but the expression of this variant did not appear to be related to the expression of the LMP-1 protein in the tumor.
Base Sequence↗
Expression of immune regulatory molecules in Epstein-Barr virus-associated nasopharyngeal carcinomas with prominent lymphoid stroma. Evidence for a functional interaction between epithelial tumor cells and infiltrating lymphoid cells.
Undifferentiated nasopharyngeal carcinomas (UNPC) are characterized by an association with Epstein-Barr virus and an abundant lymphoid stroma. The role of this lymphoid stroma is uncertain but is mostly thought to represent an immune response against viral or tumor antigens. We have analyzed the expression of immune regulatory receptor/ligand pairs in snap-frozen biopsies of 20 UNPCs. All cases were Epstein-Barr virus positive and the virus-encoded latent membrane protein, LMP1, was expressed in 6 cases. By immunohistochemistry, we have demonstrated the expression of CD70 and CD40 in the tumor cells of 16 and 18 cases, respectively. Infiltrating lymphoid cells expressing CD27, the CD70 receptor, and the CD40 ligand were present in all cases. The Bcl-2 protein was detected in 17 cases. Unexpectedly, tumor cells of 5 cases expressed at least one member of the B7 family (CD80, CD86, and B7-3) and many lymphoid cells expressing the corresponding counter-receptor, CD28, were detected in all cases. Interestingly, 5 of 6 LMP1-positive cases also expressed B7, whereas all 14 LMP1-negative cases were also B7 negative. Our results indicate that T cells and carcinoma cells communicate in the microenvironment of UNPCs and suggest that the presence of a lymphoid stroma may be a requirement for UNPC growth at least in certain stages of tumor development.
Carcinoma↗
Monoclonal antibodies directed against the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1): immunohistologic detection of EBNA1 in the malignant cells of Hodgkin's disease.
Monoclonal antibodies directed against the Epstein-Barr virus nuclear protein 1 (EBNA1) were used to examine conventional paraffin sections from a series of EBV-associated lymphoproliferative disorders by immunohistochemistry. The presence of latent EBV infection in tumor cells was determined by in situ hybridization for the Epstein-Barr virus early RNAs (EBERs). Of those EBER-positive cases a total of 28 of 40 cases of Hodgkin's disease, 3 of 3 cases of Burkitt's lymphoma, and 8 of 8 cases of human immunodeficiency virus-associated cerebral B-cell lymphoma expressed detectable amounts of EBNA1. In the positive cases, expression was confined to the tumor cells. No reactivity was detected in EBV-negative cases of the above tumors or in 8 cases of EBV-negative cases of large cell anaplastic non-Hodgkin lymphoma. This report provides the first unequivocal evidence for the expression of the EBNA1 protein in the tumor cells of Hodgkin's disease and validates an important reagent with which to analyze the role of EBV in various virus-associated malignancies.
Amino Acid Sequence↗
Epstein-Barr virus persistence and virus-associated tumours.
The Epstein-Barr virus (EBV) has been implicated in the aetiology of many human lymphoid and epithelial malignancies. Although EBV is B lymphotropic in vitro, it has been hypothesised that oropharyngeal epithelium is important in primary EBV infection, replication, and persistence in vivo, and that infection of B lymphocytes is secondary. This hypothesis has been challenged by several recent studies. On the basis of current evidence, we propose that primary EBV infection and virus persistence are mediated through B lymphocytes, and that latent infection of epithelial cells is accidental and irrelevant to virus persistence, although important in the development of certain carcinomas. To what extent T cells are involved in EBV persistence remains uncertain. Clarification of the possible part played by EBV in the development of virus-associated tumours requires a better understanding of the mode of EBV persistence and the identification of the stage in the carcinogenic process at which EBV infection occurs.
B-Lymphocytes↗
Epstein-Barr virus in inflammatory diseases of the liver and liver allografts: an in situ hybridization study.
The Epstein-Barr virus is associated with a broad spectrum of lymphoproliferative diseases in liver allograft recipients. To investigate the effects of primary infection in children following liver transplantation and the possible role of Epstein-Barr virus in the pathogenesis of unexplained chronic hepatitis after transplantation, we used an in situ hybridization technique to detect small virus encoded nuclear RNAs in posttransplant specimens. For comparison, other posttransplant complications and diseases occurring in the nontransplanted liver were studied with the same method. We examined 114 specimens in the following categories: (a) children with primary Epstein-Barr virus infection after transplant (n = 25), (b) chronic hepatitis more than 12 mo after transplant (n = 14), (c) rejection (n = 15), (d) normal/near-normal histology more than 12 mo after transplant (n = 13) (e) end-stage acute liver disease (n = 9) and (f) end-stage cirrhosis (n = 38). Thirty-three of 114 specimens had labeling of occasional portal and parenchymal lymphoid cells. These were present in each of the six main diagnostic categories listed above: 2 of 25, pediatric; 6 of 14, chronic hepatitis; 4 of 15, rejection; 1 of 13, normal; 4 of 9, acute; and 16 of 38, cirrhosis. In none of the patients with Epstein-Barr virus-infected cells did lymphoproliferative disease subsequently develop. In conclusion, we have been unable to show an obvious association between Epstein-Barr virus infection and graft dysfunction after liver transplantation. Our results suggest that immunological response to primary infection in children after liver transplantation may be adequate.(ABSTRACT TRUNCATED AT 250 WORDS)
Biopsy↗
Latent Epstein-Barr virus infection in cottontop tamarins. A possible model for Epstein-Barr virus infection in humans.
The association of Epstein-Barr virus (EBV) with a growing number of human malignancies underlines the importance of efforts aimed at preventing the infection with this potential carcinogen and of establishing animal models for human virus-associated tumors. Cottontop tamarins have been used in EBV vaccine studies because virus infection regularly induces lymphomas similar to those seen in human immunocompromised individuals. In recent years, several vaccines based on the gp340/220 envelope protein of EBV have been developed and shown to prevent the development of EBV-associated lymphomas in this model. Using in situ hybridization and immunohistology, we have characterized EBV infection in one nonimmunized and three immunized animals after challenge with a standard tumorigenic dose of EBV. In the nonimmunized animal, EBV-infected lymphoid cells were detected in numerous tissues showing no obvious lymphoma infiltration. Surprisingly, variable numbers of virus-carrying cells were also found in all three immunized animals that were protected against the development of virus-associated lymphoma. This observation demonstrates that vaccination does not induce sterilizing immunity against EBV infection in this model. Double labeling suggested a B cell phenotype of the majority of these cells. EBV infection of nonlymphoid cells was not observed. Analysis of viral gene expression in immunized animals suggested a restricted form of virus latency different from that seen in EBV-driven lymphomas in nonimmunized cottontop tamarins. These results raise the possibility that immunized cottontop tamarins protected against the development of EBV-driven lymphoma or animals exposed to a sublymphomagenic dose of virus may serve as a model for EBV infection in humans.
Animals↗
Analysis of Epstein-Barr virus infection in nasopharyngeal biopsies from a group at high risk of nasopharyngeal carcinoma.
Although Epstein-Barr virus (EBV) is consistently associated with the epithelial malignancy nasopharyngeal carcinoma (NPC), it is not clear to what extent the normal virus carrier state involves infection of nasopharyngeal epithelium. We attempted to examine this question by screening 26 nasopharyngeal punch biopsies from EBV-carrying Chinese Malaysians who had presented with clinical symptoms possibly indicative of NPC, but in whom histological analysis of an adjacent biopsy had revealed no evidence of tumour. Assays included (i) in situ hybridization with 35S-labelled riboprobes specific for EBERs (rather than with BamHI W DNA probes which can give false-positive results); (ii) cDNA amplification across defined splice junctions of the EBNA1 and BamHI A transcripts expressed in latently-infected NPC cells and of the BHRF1 lytic-cycle transcript; and (iii) immunostaining for the immediate early lytic-cycle protein BZLF1. Of the 26 biopsies examined, all 23 showing normal nasopharyngeal histology were consistently negative for both latent and lytic-cycle markers. The other 3 cases were all positive for EBNA1 and BamHI A transcripts; these RNAs were almost certainly of tumour rather than normal-cell origin since these particular biopsies were the only ones to reveal localized foci of EBER-positive NPC cells; such biopsies were again negative for lytic-cycle markers. We provisionally conclude that EBV infection of the normal nasopharynx is not a regular feature of the virus carrier state and that screening nasopharyngeal biopsies for viral RNA markers of the latent cycle could be useful in NPC diagnosis.
Base Sequence↗
Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells.
Epstein-Barr virus (EBV) is associated with a number of different human tumors and appears to play different pathogenetic roles in each case. Thus, immunoblastic B cell lymphomas of the immunosuppressed display the full pattern of EBV latent gene expression (expressing Epstein-Barr nuclear antigen [EBNA]1, 2, 3A, 3B, 3C, and -LP, and latent membrane protein [LMP]1, 2A, and 2B), just as do B lymphoblastoid cell lines transformed by the virus in vitro. In contrast, those EBV-associated tumors with a more complex, multistep pathogenesis show more restricted patterns of viral gene expression, limited in Burkitt's lymphoma to EBNA1 only and in nasopharyngeal carcinoma (NPC) to EBNA1 and LMP1, 2A, and 2B. Recent evidence has implicated EBV in the pathogenesis of another lymphoid tumor, Hodgkin's disease (HD), where the malignant Hodgkin's and Reed-Sternberg (HRS) cells are EBV genome positive in up to 50% of cases. Here we extend preliminary results on viral gene expression in HRS cells by adopting polymerase chain reaction-based and in situ hybridization assays capable of detecting specific EBV latent transcripts diagnostic of the different possible forms of EBV latency. We show that the transcriptional program of the virus in HRS cells is similar to that seen in NPC in several respects: (a) selective expression of EBNA1 mRNA from the BamHI F promoter; (b) downregulation of the BamHI C and W promoters and their associated EBNA mRNAs; (c) expression of LMP1 and, in most cases, LMP2A and 2B transcripts; and (d) expression of the "rightward-running" BamHI A transcripts once thought to be unique to NPC. This form of latency, consistently detected in EBV-positive HD irrespective of histological subtype, implies an active role for the virus in the pathogenesis of HD and also suggests that the tumor may remain sensitive to at least certain facets of the EBV-induced cytotoxic T cell response.
Antigens, Viral↗
Overexpression of p53 in Hodgkin's disease: lack of correlation with Epstein-Barr virus infection.
Recent work has shown that p53 gene mutations are frequently found in Epstein-Barr virus (EBV)-positive and EBV-negative cases of Burkitt's lymphoma but not in EBV-associated undifferentiated nasopharyngeal carcinomas (NPCs). Similar viral gene expression patterns are observed in undifferentiated NPCs and in EBV-positive cases of Hodgkin's disease (HD), suggesting that the contribution of the virus to the pathogenesis of these malignancies may also be similar. We have analysed 116 cases of HD for EBV association and for immunohistologically detectable overexpression of p53. p53 overexpression was detected in the tumour cell population of 37 (32 per cent) of the cases. Fifteen cases showed p53-specific labelling of more than 40 per cent of tumour cells; in six of these, virtually all tumour cells were stained. In eight cases, between 5 and 40 per cent of tumour cells were labelled, and in another 14 cases, less than 5 per cent of tumour cells expressed detectable amounts of p53. EBV-positive HD cases were found in all groups with different levels of p53 overexpression as well as amongst p53-negative cases. While a more detailed analysis of the p53 gene in HD is required, these data show that overexpression of p53 in HD is heterogeneous and that there is no simple correlation between EBV infection and p53 overexpression.
Gene Expression↗
P53 overexpression and Epstein-Barr virus infection in undifferentiated and squamous cell nasopharyngeal carcinomas.
We have analysed 22 nasopharyngeal carcinomas (NPCs) for expression of the small nuclear Epstein-Barr virus (EBV)-encoded RNAs (EBERs) and for immunohistologically detectable overexpression of p53. In situ hybridization demonstrated expression of the EBERs in 13 undifferentiated NPCs while nine squamous cell NPCs were EBER-negative. These results therefore confirm our previous DNA-DNA in situ hybridization studies and demonstrate that in the nasopharynx EBV is exclusively associated with undifferentiated but not with squamous cell carcinomas. p53 overexpression was demonstrated by immunohistology in 5 of 9 squamous cell NPCs and in 9 of 13 undifferentiated NPCs. Thus, there appears to be no correlation of p53 overexpression with EBV infection. These results are unexpected in the light of previous studies demonstrating that the p53 gene in primary undifferentiated NPC is consistently in the wild-type configuration. By contrast, analyses of squamous cell carcinomas of the head and neck have demonstrated that p53 overexpression in these cases is the result of p53 gene mutation. Whilst more detailed genetic analysis is required, our results suggest that mechanisms other than mutation of the p53 gene may be responsible for the stabilization of the protein in cases of undifferentiated NPC. It is tempting to speculate that an EBV-encoded protein may be involved.
Carcinoma↗
Epstein-Barr virus and Hodgkin's disease.
Seroepidemiological and molecular biological studies have established an association of Hodgkin's disease with Epstein-Barr virus. Recently, Epstein-Barr virus genomes and gene products have been detected in the neoplastic cells of approximately 50% of cases, most notably the latent membrane protein, which has transforming potential. However, Epstein-Barr virus was not restricted to neoplastic cells. In situ hybridization, employing probes for the small Epstein-Barr virus-encoded nuclear RNAs EBER1 and -2, helped to precisely characterize phenotype and distribution of all latently Epstein-Barr virus-infected cells, indicating the presence of usually small numbers of Epstein-Barr virus-infected, but latent membrane protein-negative, non-malignant B-cells of polyclonal origin in lymph nodes from Hodgkin's disease patients and normal controls. In contrast, the neoplastic cells and the Epstein-Barr virus genomes expressing latent membrane protein in these cells appear to be monoclonal in nature, which points to specific immunological deficiencies in Hodgkin's disease patients and suggests that Epstein-Barr virus may contribute to the etiology of a significant proportion of Hodgkin's disease cases.
Antigens, Viral↗
Epstein-Barr virus and carcinomas.
The Epstein-Barr virus, a human B lymphotropic herpes virus, is strongly associated with undifferentiated nasopharyngeal carcinoma, which is endemic in Southern China and North Africa. More recently, an association of the virus with certain other epithelial malignancies has been described, some of which are more common in Western countries. Also, the observation that oral hairy leukoplakia, an acquired immunodeficiency syndrome-related lesion of the tongue, supports Epstein-Barr virus replication in the epithelial cell compartment has further strengthened the notion that Epstein-Barr virus infection of epithelial cells may be an important phenomenon in vivo. The purpose of this article is to review the association of Epstein-Barr virus with nasopharyngeal carcinomas, to examine the evidence suggesting an association of the virus with other epithelial neoplasias and to discuss Epstein-Barr virus infection of non-neoplastic epithelial cells.
Epithelial Cells↗
Nasal T-cell lymphoma associated with Epstein-Barr virus infection.
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Adult↗
Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virus-associated hemophagocytic syndrome.
The clonal composition of EBV-infected cells was examined in three cases of EBV-associated hemophagocytic syndrome by analysis of the heterogeneity of terminal repetitive sequences in the EBV genome, indicating monoclonal expansion of EBV-infected cells in all cases. Involvement of T lymphoid cells was determined by in situ hybridization using 35S-labeled RNA probes specific for the small EBV-encoded nuclear RNAs, EBER1 and EBER2, in combination with immunostaining for the TCR-beta chain, CD45RO, CD20, CD30 and CD68 antigens in these three cases. The majority of lymphoid cells showing EBER transcripts were stained by antibodies against CD45RO and T cell receptor-beta. In contrast, EBER-specific signals were not detectable on B cells or hemophagocytic cells. These data support the concept that EBV-associated T cell proliferation is a primary feature of EBV-AHS.
Adolescent↗
Epstein-Barr virus and CD30+ malignant lymphomas.
Phenotypic, genotypic, and karyotypic analyses have indicated that Hodgkin's disease and CD30+ anaplastic large cell lymphoma may be conceived as malignancies derived from activated, cytokine-producing lymphoid cells, in many instances with an immature genotype. Most recently, Epstein-Barr virus (EBV) genomes and gene products, most notably the transformation-associated latent membrane protein (LMP), have been detected in approximately 50 and 20% of the cases, respectively. These findings suggest that EBV may superimpose an activated phenotype on an immature lymphoid cell, contributing to the pathoetiology of sizable proportions of these CD30+ malignancies.
Antigens, CD↗