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1.
Vet J ; 266: 105575, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33323169

ABSTRACT

The genetic and mutational basis of canine lymphoma remains poorly understood. Several genes, including TRAF3 and POT1, are mutated in canine B-cell lymphoma (cBCL), and are likely involved in the pathogenesis of this disease. The purpose of this study was to assess the prevalence of TRAF3 and POT1 mutations in a cohort of dogs with cBCL, compared to dogs with non-cBCL diseases (including four dogs with T-cell lymphoma [cTCL]). Forty-nine dogs were included (n = 24 cBCL; n = 25 non-cBCL). Eleven dogs had matched non-tumour DNA assessed to determine if mutations were germline or somatic. All dogs had TRAF3 and POT1 assessed by Sanger sequencing. The prevalence of deleterious TRAF3 and POT1 mutations in cBCL was 36% and 17%, respectively. A deleterious TRAF3 mutation was suspected to be germline in 1/5 cases with matched non-tumour DNA available for comparison. Deleterious mutations were not found in specimens from the non-cBCL group. Several synonymous variants were identified in both genes in cBCL and non-cBCL samples, which likely represent polymorphisms. These results indicate TRAF3 and POT1 mutations are common in cBCL. Deleterious TRAF3 and POT1 mutations were only identified in dogs with cBCL, and not in dogs with non-cBCL diseases, suggesting they are important in the pathogenesis of cBCL. Future studies to investigate the prognostic and therapeutic implications of these mutations are required.


Subject(s)
Dog Diseases/genetics , Lymphoma, B-Cell/veterinary , Mutation , TNF Receptor-Associated Factor 3/genetics , Telomere-Binding Proteins/genetics , Animals , Dogs , Lymphoma, B-Cell/genetics , Lymphoma, T-Cell/veterinary , Polymerase Chain Reaction/veterinary , Prevalence , Sequence Analysis, DNA
2.
Tissue Antigens ; 86(2): 98-113, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26189878

ABSTRACT

Familial aggregation, coupled with ethnic variation in incidence, suggests that inherited susceptibility plays a role in the development of lymphoma, and the search for genetic risk factors has highlighted the contribution of the human leukocyte antigen (HLA) complex. In a landmark study published almost 50 years ago, Hodgkin lymphoma (HL) was the first disease to be associated with HLA variation. It is now clear that Epstein-Barr virus (EBV)-positive and -negative HL are strongly associated with specific HLA polymorphisms but these differ by EBV status of the tumours. HLA class I alleles are consistently associated with EBV-positive HL while a polymorphism in HLA class II is the strongest predictor of risk of EBV-negative HL. Recent investigations, particularly genome-wide association studies (GWAS), have also revealed associations between HLA and common types of non-Hodgkin lymphoma (NHL). Follicular lymphoma is strongly associated with two distinct haplotypes in HLA class II whereas diffuse large B-cell lymphoma is most strongly associated with HLA-B*08. Although chronic lymphocytic leukaemia is associated with variation in HLA class II, the strongest signals in GWAS are from non-HLA polymorphisms, suggesting that inherited susceptibility is explained by co-inheritance of multiple low risk variants. Associations between B-cell derived lymphoma and HLA variation suggest that antigen presentation, or lack of, plays an important role in disease pathogenesis but the precise mechanisms have yet to be elucidated.


Subject(s)
Epstein-Barr Virus Infections/genetics , Genetic Predisposition to Disease , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class I/genetics , Hodgkin Disease/genetics , Lymphoma, Non-Hodgkin/genetics , Alleles , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/pathology , Gene Expression , Genome-Wide Association Study , Haplotypes , Herpesvirus 4, Human/pathogenicity , Herpesvirus 4, Human/physiology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Hodgkin Disease/complications , Hodgkin Disease/immunology , Hodgkin Disease/pathology , Humans , Lymphoma, Non-Hodgkin/complications , Lymphoma, Non-Hodgkin/immunology , Lymphoma, Non-Hodgkin/pathology , Polymorphism, Single Nucleotide
3.
Int J Cancer ; 121(2): 442-7, 2007 Jul 15.
Article in English | MEDLINE | ID: mdl-17390376

ABSTRACT

A proportion of Hodgkin lymphoma (HL) cases are causally associated with the Epstein-Barr virus (EBV) but the aetiology of the remaining cases remains obscure. Over the last 3 decades several studies have found an association between HL and measles virus (MV) including a recent cohort study describing the detection of MV antigens in Hodgkin and Reed-Sternberg cells, the tumour cells in HL. In the present study we looked at the relationship between history of MV infection and risk of developing HL in a population-based, case/control study of HL. In addition we used immunohistochemistry and RT-PCR to look for direct evidence of MV in HL biopsies. There was no significant difference in the proportion of cases reporting previous measles compared to controls in the entire data set or when young adults were considered separately. Using a robust immunohistochemical assay for MV infection, we failed to find evidence of MV in biopsies from 97 cases of HL and RT-PCR studies similarly gave negative results. This study therefore provides no evidence that MV is directly involved in the development of HL. However, when age at first reported MV infection was investigated, significant differences emerged with children infected before school-age having higher risk, especially of EBV-ve HL, when compared with children infected at older ages; the interpretation of these latter results is unclear.


Subject(s)
Hodgkin Disease/virology , Measles virus/growth & development , Measles/virology , Adolescent , Adult , Animals , Case-Control Studies , Cell Line, Tumor , Chlorocebus aethiops , Female , Hodgkin Disease/complications , Hodgkin Disease/pathology , Humans , Immunohistochemistry , Lymph Nodes/pathology , Lymph Nodes/virology , Male , Measles/complications , Measles virus/genetics , Measles virus/metabolism , Middle Aged , Odds Ratio , RNA, Viral/genetics , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Vero Cells , Viral Proteins/metabolism
4.
Dev Biol (Basel) ; 123: 77-88; discussion 119-32, 2006.
Article in English | MEDLINE | ID: mdl-16566437

ABSTRACT

The potential use of novel cell substrates from diverse animal species raises concerns about the transmission of hitherto unknown viral agents. Viruses that do not cause a cytopathic effect in cell culture may escape detection by conventional methods and molecular methods may therefore prove useful for screening for hitherto unknown viruses. This review describes currently used molecular methods for virus discovery, including degenerate PCR assays, representational difference analysis and rolling circle amplification, and summarises the advantages and disadvantages of each technique.


Subject(s)
Drug Contamination/prevention & control , Vaccines/adverse effects , Viral Vaccines/standards , Viruses/isolation & purification , Amino Acid Sequence , Animals , Base Sequence , Cell Line , Gene Amplification , Genome, Viral , Herpesviridae/genetics , Molecular Sequence Data , Nucleic Acid Hybridization , Polymerase Chain Reaction/methods , Polyomavirus/genetics , Viruses/genetics
5.
J Clin Pathol ; 57(1): 87-9, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14693845

ABSTRACT

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare malignancy derived from professional antigen presenting cells. This report describes a case of IDCS arising in the salivary gland associated lymphoid tissue of the parotid gland of a 51 year woman, presenting with a painless neck swelling. Histologically, sheets of S100(+)/Ccd68(+)/CD45(+)/CD34(-)/CD1a(-) spindle cells were surrounded with an inflammatory infiltrate with no evidence of B or T cell clonal proliferations. No evidence of either human herpesvirus 8 or Epstein-Barr virus could be detected by quantitative polymerase chain reaction in the tumour cells with serological evidence of previous Epstein-Barr virus infection. The patient remains well and disease free 24 months after presentation without specific treatment.


Subject(s)
Parotid Neoplasms/pathology , Sarcoma/pathology , DNA, Viral/analysis , Dendritic Cells/pathology , Female , Follow-Up Studies , Herpesvirus 4, Human/isolation & purification , Herpesvirus 8, Human/isolation & purification , Humans , Middle Aged , Parotid Neoplasms/virology , Sarcoma/virology
6.
J Clin Pathol ; 56(11): 811-6, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14600123

ABSTRACT

AIMS: The epidemiological and pathological features of Hodgkin lymphoma (HL) are complex. The Epstein-Barr virus (EBV) is consistently associated with a proportion of cases, and these cases are thought to represent a distinct aetiological subgroup of HL. The aim of the present analysis was to determine the age and sex specific incidence of EBV associated and non-associated HL, analysed separately, using data derived from a population based study-the Scotland and Newcastle epidemiological study of Hodgkin's disease (SNEHD). This study also provided a unique opportunity to evaluate accuracy in the current diagnosis and classification of HL. METHODS: SNEHD analysed consecutive cases of HL diagnosed in the study area between 1993 and 1997. Diagnostic biopsy material was retrieved, EBV status of tumours was determined, and histological review was performed. RESULTS: In total, 622 cases were eligible for the study, and EBV studies and histopathological review were performed on biopsy material from 537 and 549 cases, respectively. Accuracy in the overall diagnosis of HL and classification of nodular sclerosis HL was good, but diagnosis of HL in the elderly and classification of other subtypes was less reliable. One third of classic HL cases were EBV associated, and age specific incidence curves for EBV associated and non-associated cases were distinct. CONCLUSIONS: Comparison of age specific incidence curves for EBV associated and non-associated HL supports the hypothesis that these are two distinct aetiological entities. Accuracy in the diagnosis of HL is generally good, but certain subgroups of cases continue to present diagnostic difficulties.


Subject(s)
Epstein-Barr Virus Infections/complications , Hodgkin Disease/virology , Adolescent , Adult , Age Distribution , Aged , Biopsy , Case-Control Studies , England/epidemiology , Epstein-Barr Virus Infections/epidemiology , Female , Hodgkin Disease/epidemiology , Hodgkin Disease/pathology , Humans , Incidence , Male , Middle Aged , Scotland/epidemiology
7.
Ann Oncol ; 13 Suppl 1: 23-9, 2002.
Article in English | MEDLINE | ID: mdl-12078898

ABSTRACT

Hodgkin's lymphoma (HL) is unusual among human malignancies in that the epidemiology suggests an infectious aetiology. The Epstein-Barr virus (EBV) is associated with a proportion of cases and this association is believed to be causal. In these cases the Hodgkin and Reed-Sternberg (HRS) cells express the EBV-encoded proteins LMP1 and LMP2, which can mimic CD40 and the B cell receptor, respectively, and therefore may play a critical role in facilitating the survival of HRS cells. EBV-associated and non-EBV-associated HL cases have different epidemiological features and recent data suggest that delayed exposure to EBV is a risk factor for the development of EBV-associated HL in young adults. We suggest that HL can be divided into four entities on the basis of EBV status and age at presentation, with three groups of EBV-associated cases and a single group of EBV-negative cases. The aetiology of the latter cases is obscure although involvement of an infectious agent(s) is suspected.


Subject(s)
Herpesvirus 4, Human/physiology , Hodgkin Disease/virology , Reed-Sternberg Cells/virology , Hodgkin Disease/metabolism , Humans , Models, Biological , Reed-Sternberg Cells/metabolism , Viral Matrix Proteins/metabolism
8.
J Clin Pathol ; 55(1): 61-3, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11825927

ABSTRACT

Lymphoma of the salivary gland accounts for 5% of cases of extranodal lymphoma and 10% of malignant salivary gland tumours. Most primary salivary gland lymphomas are B marginal zone lymphomas arising on a background of sialadenitis associated with autoimmune disorders such as Sjorgen's syndrome. Primary T cell lymphoma of the salivary gland is rare. This report describes a case of primary T cell lymphoma arising in the parotid gland of an elderly white man, which was notable for its striking resemblance to a B cell extranodal marginal zone lymphoma. Immunohistochemistry and gene rearrangement studies confirmed the clonal T cell nature of the tumour. There was no molecular evidence of Epstein-Barr virus (EBV) infection of neoplastic or surroundings cells. Only 14 cases of primary T cell lymphoma of the salivary glands have been recorded in the literature, most being from the Orient and having extremely variable prognosis. Those with a T/natural killer cell phenotype are associated with EBV infection. This case highlights the fact that T cell lymphoma in the salivary gland can mimic closely the morphological features of B cell extranodal marginal zone lymphoma.


Subject(s)
Lymphoma, T-Cell/pathology , Parotid Neoplasms/pathology , Aged , Diagnosis, Differential , Humans , Lymphoma, B-Cell/diagnosis , Male
9.
Cancer Res ; 61(16): 6219-26, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11507075

ABSTRACT

Approximately 40% of Hodgkin's disease (HD) cases carry EBV in the malignant Hodgkin-Reed Sternberg (H-RS) cells, with expression of viral latent membrane proteins (LMPs) 1 and 2. These viral proteins are targets for CTLs in healthy EBV carriers, and their expression in EBV-associated HD raises the possibility of targeting them for a CTL-based immunotherapy. Here we characterize the CTL response to EBV latent antigens in both the blood and tumor-infiltrating lymphocytes of HD patients using two approaches: (a) in vitro reactivation of CTLs by stimulation with the autologous EBV-transformed lymphoblastoid cell line; and (b) an enzyme-linked immunospot assay to quantify frequencies of CTLs specific for known LMP1/2 epitopes. We detected EBV-specific CTLs in blood and biopsy samples from both EBV-negative and EBV-positive HD patients. However, as in healthy EBV carriers, LMP-specific CTL precursors occurred only at low frequency in the blood of HD patients, and with the exception of one EBV-negative HD case, were undetectable in the tumor. These data give rise to two considerations: (a) they may explain why EBV-positive tumor cells persist in the presence of an existing EBV-specific immune response; and (b) they provide a rationale for selectively boosting/eliciting LMP-specific CTL responses as a therapy for EBV-positive HD.


Subject(s)
Epstein-Barr Virus Infections/immunology , Herpesvirus 4, Human/immunology , Hodgkin Disease/immunology , Immunotherapy, Adoptive , T-Lymphocytes, Cytotoxic/immunology , Adolescent , Adult , Aged , Biopsy , Epitopes, T-Lymphocyte/immunology , Epstein-Barr Virus Infections/complications , Female , Hodgkin Disease/virology , Humans , Lymphocyte Activation/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Male , Middle Aged , Viral Matrix Proteins/blood , Viral Matrix Proteins/immunology
10.
Cancer Epidemiol Biomarkers Prev ; 10(6): 705-9, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11401923

ABSTRACT

Cases of Hodgkin's disease (HD) may be distinguished by whether they do [EBV-positive ((+ve)) cases] or do not [EBV-negative ((-ve)) cases] have evidence of EBV DNA in the Reed-Sternberg cells. Only one study has attempted to distinguish epidemiological risk factors for EBV(+ve) and EBV(-ve) HD, and none have compared inherited susceptibility. The present study involves a population-based case series of HD, diagnosed in patients between 16-24 years of age in the United Kingdom (n = 118), of whom 87% were classified by EBV status (EBV(+ve), 19, EBV(-ve), 84). History of infectious illness, EBV antibody titers, and HLA-DPB1 type have been compared in EBV(+ve) and EBV(-ve) cases. Reported infectious mononucleosis was more frequent in EBV(+ve) cases (odds ratio (OR), 5.10; 95% confidence interval (CI), 1.12-24.4). EBV antibody titers to viral capsid antigen were significantly higher in EBV(+ve) cases (P for trend = 0.02). Higher proportions of EBV(+ve) (43%) than EBV(-ve) (31%) cases typed positive for HLA-DPB1*0301, but this was not statistically significant; the association of infectious mononucleosis with EBV(+ve) cases was stronger in this HLA subgroup (OR, 17.1; 95%CI, 1.06-1177) than in other cases (OR, 1.24; 95% CI, 0.02-15.4). Although these results are based on small numbers of HD cases, they provide suggestive evidence that the etiology of EBV(+ve) HD may involve inherited susceptibility to EBV.


Subject(s)
Epstein-Barr Virus Infections/complications , Genetic Predisposition to Disease , HLA-DP Antigens/analysis , Herpesvirus 4, Human/pathogenicity , Hodgkin Disease/immunology , Hodgkin Disease/virology , Adolescent , Adult , Age of Onset , Epidemiologic Studies , Female , HLA-DP beta-Chains , Herpesvirus 4, Human/immunology , Hodgkin Disease/genetics , Humans , Male , Risk Factors
11.
Leukemia ; 15(3): 415-21, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11237065

ABSTRACT

There is epidemiological evidence that infection may play a role in the etiology of childhood leukemia in particular common B cell precursor acute lymphoblastic leukemia. A panel of 20 leukemic samples (panel 1) was examined for the presence of four lymphotropic herpesviruses using conventional molecular techniques. A second independent panel of 27 leukemic samples (panel 2), along with 28 control peripheral blood samples from children with other forms of cancer, was tested for the presence of the same four viruses using sensitive real-time quantitative PCR. While herpesvirus genomes were detected, they were present at very low levels; detection rates and levels were similar in the leukemic and control panels. In addition we surveyed 18 leukemic samples (five from panel 1, six from panel 2 and a further seven samples not previously analyzed) using a degenerate PCR assay capable of detecting the genomes of known herpesviruses plus putative new members of the family. No novel herpesvirus genomes were detected suggesting that a herpesvirus is unlikely to be etiologically involved as a transforming agent in common acute lymphoblastic leukemia.


Subject(s)
Genome, Viral , Herpesviridae/isolation & purification , Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology , Adolescent , Blotting, Southern , Child , Child, Preschool , Cloning, Molecular , DNA Primers , Herpesviridae/genetics , Humans , Infant , Polymerase Chain Reaction
12.
Br J Haematol ; 112(1): 161-6, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11167797

ABSTRACT

Peripheral blood from patients with a novel tropical splenic lymphoma, characterized by splenomegaly and circulating naïve CD5-negative villous B lymphocytes, has been screened for evidence of an association with the B-lymphotropic viruses, Epstein--Barr virus (EBV), hepatitis C virus (HCV) and human herpesvirus 8 (HHV8). No increased prevalence of EBV, HCV and HHV8 was demonstrated using serological and molecular techniques, compared with a geographical, age-matched control group. However, lymphoma patients had markedly raised EBV antibody levels without a concomitant increase in the rate of detection of viral genomes in the peripheral blood. This phenomenon also occurred in patients with hyper-reactive malarial splenomegaly, a condition that occurs in the same geographical area and that is clinically indistinguishable from tropical splenic lymphoma, adding further weight to the suggestion that there may be an aetiological association between these two disorders.


Subject(s)
Antibodies, Viral/blood , Herpesvirus 4, Human/immunology , Lymphoma, B-Cell/virology , Splenic Neoplasms/virology , Adolescent , Adult , Aged , Case-Control Studies , Chi-Square Distribution , Female , Gene Rearrangement, B-Lymphocyte , Hepacivirus/immunology , Herpesvirus 8, Human/immunology , Humans , Malaria/virology , Male , Middle Aged , Serologic Tests , Tropical Medicine
13.
Br J Cancer ; 82(5): 1117-21, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10737396

ABSTRACT

A UK population-based case-control study of Hodgkin's disease (HD) in young adults (16-24 years) included 118 cases and 237 controls matched on year of birth, gender and county of residence. The majority (103) of the cases were classified by Epstein-Barr virus (EBV) status (EBV present in Reed-Stenberg cells), with 19 being EBV-positive. Analyses using conditional logistic regression are presented of subject reports of prior infectious disease (infectious mononucleosis (IM), chicken pox, measles, mumps, pertussis and rubella). In these analyses HD cases are compared with matched controls, EBV-positive cases and EBV-negative cases are compared separately with their controls and formal tests of differences of association by EBV status are applied. A prior history of IM was positively associated with HD (odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.10-5.33) and with EBV-positive HD (OR = 9.16, 95% CI = 1.07-78.31) and the difference between EBV-positive and EBV-negative HD was statistically significant (P = 0.013). The remaining infectious illnesses (combined) were negatively associated with HD, EBV-positive HD and EBV-negative HD (in the total series, for > or =2 episodes compared with < or =1, OR = 0.45, 95% CI = 0.25-0.83). These results support previous evidence that early exposure to infection protects against HD and that IM increases subsequent risk; the comparisons of EBV-positive and EBV-negative HD are new and generate hypotheses for further study.


Subject(s)
Epstein-Barr Virus Infections/complications , Herpesvirus 4, Human , Hodgkin Disease/virology , Adolescent , Adult , Case-Control Studies , Female , HLA-DP Antigens/genetics , Hodgkin Disease/epidemiology , Hodgkin Disease/genetics , Humans , Male , Risk Factors , United Kingdom/epidemiology
14.
Br J Cancer ; 81(5): 898-9, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10555765

ABSTRACT

Epidemiological evidence suggests that childhood leukaemia, and possibly common acute lymphoblastic leukaemia in particular, may have an infectious aetiology. Smith (1997 J Immunother 20: 89-100) recently suggested that the critical infectious event occurs during pregnancy, and identified the polyoma virus JC as a candidate agent. In the present study we investigated whether genomes from the JC virus, and closely related BK virus, could be detected in leukaemic cells. No positive results were obtained suggesting that JC virus is unlikely to play a direct role in leukaemogenesis.


Subject(s)
BK Virus/isolation & purification , JC Virus/isolation & purification , Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology , BK Virus/genetics , Child , Child, Preschool , DNA, Viral/isolation & purification , Female , Humans , Infant , JC Virus/genetics , Male , Polymerase Chain Reaction
15.
Blood ; 94(6): 2090-101, 1999 Sep 15.
Article in English | MEDLINE | ID: mdl-10477739

ABSTRACT

Epstein-Barr virus (EBV) infection of humans has been associated with the development of lymphoid malignancies mainly of B-cell lineage, although occasionally T-cell lymphomas have been reported. We describe here the characterization of a novel EBV-like virus (HV(MNE)) isolated from a simian T-cell lymphotropic virus type I/II (STLV-I/II) seronegative pigtailed macaque (Macaca nemestrina) with a cutaneous T-cell lymphoma. Immunohistochemistry studies on the skin lesions demonstrated that the infiltrating cells were of the CD3(+)/CD8(+) phenotype. Two primary transformed CD8(+) T-cell lines were obtained from cultures of peripheral blood mononuclear cells (PBMC) and skin, and, with time, both cell lines became interleukin-2-independent and acquired the constitutive activation of STAT proteins. Polymerase chain reaction analysis of the DNA from the cell lines and tissues from the lymphomatous animal demonstrated the presence of a 536-bp DNA fragment that was 90% identical to EBV polymerase gene sequences, whereas the same DNA was consistently negative for STLV-I/II sequences. Electron microscopy performed on both cell lines, after sodium butyrate treatment, showed the presence of a herpes-like virus that was designated HV(MNE) according to the existing nomenclature. In situ hybridization studies using EBV Epstein-Barr viral-encoded RNA probes showed viral RNA expression in both CD8(+) T-cell lines as well as in the infiltrating CD8(+) T cells of skin-tissue biopsies. Phylogenetic analysis of a 465-bp fragment from the polymerase gene of HV(MNE) placed this virus within the Lymphocryptovirus genus and demonstrated that HV(MNE) is a distinct virus, clearly related to human EBV and other EBV-like herpesviruses found in nonhuman primates.


Subject(s)
Herpesvirus 4, Human/classification , Lymphocryptovirus/classification , Lymphocryptovirus/isolation & purification , Macaca nemestrina/virology , Mycosis Fungoides/veterinary , Phylogeny , Primate Diseases/virology , Skin Neoplasms/veterinary , T-Lymphocytes/immunology , Animals , Base Sequence , Cell Line, Transformed , DNA, Viral/chemistry , DNA, Viral/genetics , Herpesvirus 4, Human/genetics , Humans , Lymphocryptovirus/genetics , Molecular Sequence Data , Mycosis Fungoides/immunology , Mycosis Fungoides/pathology , Mycosis Fungoides/virology , Polymerase Chain Reaction , Primate Diseases/immunology , Primate Diseases/pathology , Sequence Alignment , Sequence Homology, Nucleic Acid , Skin/immunology , Skin/pathology , Skin/virology , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Skin Neoplasms/virology
16.
Semin Hematol ; 36(3): 260-9, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10462326

ABSTRACT

The epidemiologic and clinicopathologic features of Hodgkin's disease (HD) suggest that an infectious agent is involved in the etiology. Over the last 12 years, evidence has accumulated suggesting that Epstein-Barr virus (EBV) is associated with a proportion of cases: EBV genomes are present in Reed-Sternberg (HRS) cells and viral proteins including LMP1, which has oncogenic potential, are expressed. HD has a complex epidemiology and EBV-associated cases are not randomly distributed. Disease occurring in early childhood and older adult age groups is more likely to be EBV-associated than for young adult cases. Paradoxically, there is more evidence supporting an infectious etiology in the latter group of younger patients. Defective EBV genomes and "hit and run" mechanisms involving EBV cannot account for all cases, and the direct involvement of known viral agents, including other lymphotropic herpesviruses, has largely been excluded. Hitherto unknown virus may be responsible for the peak incidence in young adults, which is a feature of HD in developed countries.


Subject(s)
Herpesviridae Infections , Herpesvirus 4, Human , Hodgkin Disease/etiology , Tumor Virus Infections , Adolescent , Adult , Child , Female , Hodgkin Disease/virology , Humans , Male
17.
Int J Cancer ; 84(4): 442-8, 1999 Aug 20.
Article in English | MEDLINE | ID: mdl-10404101

ABSTRACT

DNA from malignant cells is present in the serum/plasma of cancer patients and DNA from this source is amenable to analysis by polymerase chain reaction (PCR). In the present study, we evaluated whether Epstein-Barr virus (EBV) DNA is present in the serum of patients with EBV-associated Hodgkin's disease (HD). Using conventional PCR, EBV DNA was detected in serum from 30/33 patients with EBV-associated HD but in only 6/26 patients with non-EBV-associated disease (p < 0.001). Samples from healthy individuals were negative and only 5/12 infectious mononucleosis samples were positive. Real-time quantitative PCR was subsequently employed to determine the concentration of EBV DNA present in serum; among positive samples the level ranged from 1 to 705 copies per 125 microliter of serum. Post-treatment samples from 5/14 cases with EBV-associated HD contained detectable EBV DNA; analysis of this small group of cases suggests that positivity in post-treatment samples correlates with risk factors indicative of a poor prognosis. Overall, our results are consistent with the notion that DNA from Reed-Sternberg cells is present in the serum of HD patients, and further suggest that serum EBV should be evaluated as a prognostic marker. Int. J. Cancer (Pred. Oncol.) 84:442-448, 1999.


Subject(s)
DNA, Viral/blood , Genome, Viral , Herpesvirus 4, Human/isolation & purification , Hodgkin Disease/virology , Adult , Antibodies, Viral/blood , Female , Herpesvirus 4, Human/genetics , Hodgkin Disease/blood , Hodgkin Disease/immunology , Hodgkin Disease/pathology , Humans , Immunoglobulin M/blood , Infectious Mononucleosis/blood , Infectious Mononucleosis/immunology , Infectious Mononucleosis/virology , Male , Middle Aged , Polymerase Chain Reaction/methods , Predictive Value of Tests , Reed-Sternberg Cells/virology , Reference Values , Reproducibility of Results
18.
Oncogene ; 18(20): 3063-70, 1999 May 20.
Article in English | MEDLINE | ID: mdl-10340377

ABSTRACT

The NF-kappaB/Rel family of transcription factors regulates a wide variety of genes whose products play a fundamental role in inflammatory and immune responses. The implication of NF-kappaB/Rel proteins and their IkappaB regulatory subunits in the control of cellular growth and oncogenesis, was suggested by the induction of fatal lymphomas in birds by the v-rel oncoprotein, and the rearrangement and amplification of several genes encoding the NF-kappaB/Rel/IkappaB signal transduction factors in human malignancies, primarily of lymphoid origin. Hodgkin's disease (HD) is a lymphoma characterized by a low frequency of malignant Hodgkin and Reed-Sternberg (H/RS) cells in a reactive background of non-neoplastic cells. The peculiar activated phenotype of Hodgkin and Reed-Sternberg cells and their pattern of cytokine secretion are believed to be a consequence of constitutive activation of the NF-kappaB transcription factor. Here, we report the detection of mutations of the IkBa gene, in two HD-derived cell lines and in two out of eight biopsy samples from patients with relapsed Hodgkin's disease. The presence of defective IkappaBalpha is thus likely to explain the constitutive activation of NF-kappaB in these cells and suggests that IkappaBalpha is a tumour suppressor controlling the oncogenic activation of NF-kappaB in Hodgkin and Reed-Sternberg cells.


Subject(s)
DNA-Binding Proteins/genetics , Genes, Tumor Suppressor , Hodgkin Disease/genetics , I-kappa B Proteins , Mutation , Alleles , Base Sequence , Biopsy , DNA Primers , Hodgkin Disease/pathology , Humans , NF-KappaB Inhibitor alpha , RNA, Messenger/genetics , Sequence Deletion
19.
Blood ; 92(7): 2252-9, 1998 Oct 01.
Article in English | MEDLINE | ID: mdl-9746762

ABSTRACT

Hodgkin's disease is a common malignancy of the lymphoid system. Although the scarce Hodgkin and Reed-Sternberg (HRS) tumor cells in involved tissue synthesize major histocompatibility complex (MHC) class II and costimulatory molecules such as CD40 or CD86, it is unclear whether these tumor cells are operational antigen-presenting cells (APC). We developed an immunofluorescence-based assay to determine the number of MHC class II molecules present on the surface of single living HRS cells. We found that in fresh Hodgkin's disease lymph node biopsies, a subset of HRS cells express a substantial number of surface MHC class II molecules that are occupied by MHC class II-associated invariant chain peptides (CLIP), indicating deficient loading of MHC class II molecules with antigenic peptides. Cultured Hodgkin's disease-derived (HD) cell lines, however, were found to express few MHC class II molecules carrying CLIP peptides on the cell surface and were shown to generate sodium dodecyl sulphate (SDS)-stable MHC class II alphabeta dimers. In addition to showing deficient MHC class II antigen presentation in a subset of HRS cells, our results show that the widely used HD-cell lines are not ideal in vitro models for the disease. The disruption of MHC class II-restricted antigen presentation in HRS cells could represent a key mechanism by which these tumor cells escape immune surveillance.


Subject(s)
Antigen Presentation , Antigens, Neoplasm/immunology , HLA-D Antigens/immunology , Hodgkin Disease/immunology , Adult , Antigens, Differentiation, B-Lymphocyte/metabolism , B-Lymphocytes/immunology , Biological Transport , Blotting, Western , Burkitt Lymphoma/pathology , Female , Flow Cytometry , Histocompatibility Antigens Class II/metabolism , Hodgkin Disease/pathology , Humans , Lymph Nodes/pathology , Male , Microscopy, Fluorescence , Peptide Fragments/immunology , Peptide Fragments/metabolism , Tumor Cells, Cultured
20.
Leukemia ; 12(8): 1272-6, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9697883

ABSTRACT

The epidemiology of Hodgkin's disease suggests that it is a heterogeneous condition comprising more than one disease entity. The Epstein-Barr virus (EBV) is present in the Reed-Sternberg cells of a proportion of cases and is likely to play a role in the pathogenesis of these cases. In this study we show that EBV association rates vary with age at diagnosis. We suggest that Hodgkin's disease can be divided into three disease entities on the basis of EBV association and age, thereby providing biological support for the multiple aetiology hypothesis proposed by MacMahon (Cancer Res 1966; 26: 1189-1290).


Subject(s)
Burkitt Lymphoma/epidemiology , Herpesvirus 4, Human , Hodgkin Disease/virology , Adolescent , Adult , Age Factors , Age of Onset , Aged , Child , Child, Preschool , Hodgkin Disease/epidemiology , Humans , Infant , Infant, Newborn , Middle Aged
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