scholarly journals Differences in Epstein-Barr Virus Characteristics and Viral-Related Microenvironment Could Be Responsible for Lymphomagenesis in Children

Pathogens ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 68
Author(s):  
Aldana Vistarop ◽  
Oscar Jimenez ◽  
Melina Cohen ◽  
Elena De Matteo ◽  
Maria Victoria Preciado ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Immune Cell ◽  
Viral Latency ◽  
Barr Virus ◽  
Ebv Infection ◽  
Lmp1 Expression ◽  
The Mean ◽  
Epstein Barr

In Argentina, Epstein-Barr virus (EBV) presence is associated with Hodgkin lymphoma (HL) in patients younger than 10 years, suggesting a relationship between low age of EBV infection and HL. Given that HL is derived from germinal centers (GC), our aim was to compare EBV protein expression and microenvironment markers between pediatric HL patients and EBV+GC in children. Methods: EBV presence and immune cell markers were assessed by in situ hybridization and immunohistochemistry (IHC). Results: Viral latency II pattern was proved in all HL patients and in 81.8% of EBV+ tonsillar GCs. LMP1 and LMP2 co-expression were proved in 45.7% HL cases, but only in 7.7% EBV+ GC in pediatric tonsils. An increase in CD4+, IL10, and CD68+ cells was observed in EBV+ GC. In pediatric HL patients, only the mean of IL10+ cells was statistically higher in EBV+ HL. Conclusions: Our findings point us out to suggest that LMP1 expression may be sufficient to drive neoplastic transformation, that an immune regulatory milieu counteracts cytotoxic environment in EBV-associated Hodgkin lymphoma, and that CD4+ and CD68+ cells may be recruited to act in a local collaborative way to restrict, at least in part, viral-mediated lymphomagenesis in tonsillar GC.

scholarly journals Clinicopathologic Characteristics of Epstein–Barr Virus-Associated Gastric Cancer Over the Past Decade in Japan

2019 ◽  
Vol 7 (9) ◽  
pp. 305 ◽  
Author(s):  
Yanagi ◽  
Nishikawa ◽  
Shimokuri ◽  
Shuto ◽  
Takagi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epstein Barr Virus ◽  
Clinicopathologic Characteristics ◽  
Barr Virus ◽  
Ebv Infection ◽  
The Past ◽  
Lymphoid Stroma ◽  
Human Herpes Virus ◽  
Epstein Barr

: Epstein–Barr virus (EBV) is a ubiquitous human herpes virus, but related with several types of malignancies. Among EBV-related malignancies, EBV-associated gastric carcinoma (EBVaGC) has the largest patient’s number. We screened for EBV infection in 1067 GC lesions of 1132 patients who underwent surgical resection from 2007 to 2017 in Japan and examined clinicopathological features of EBVaGC. EBV infection was detected by in situ hybridization with EBV-encoded small RNA 1(EBER-1 ISH). EBV was infected in 80 GC lesions (7.1%). Mean age was significantly lower in patients with EBVaGC than with EBV-negative GC. EBVaGC was more frequent in men than in women. EBVaGC was found twice as frequent in the upper or middle stomach as in the lower stomach. Early EBVaGC was more frequent, and submucosally invaded cases were dominant. The presence of lymphatic vessel invasion was less in EBVaGC, but frequency of lymph node metastasis was similar. Carcinoma with lymphoid stroma (CLS) was found in 3.8% (43/1132) of all lesions with 60.5% of EBV positivity. The synchronous or metachronous multiple GC was frequent in EBVaGC. We clarified clinicopathologic characteristics of EBVaGC over the past decade in Japan. EBV infection should be examined in gastric cancer cases showing these characteristics.

scholarly journals Guidelines for Interpreting EBER In Situ Hybridization and LMP1 Immunohistochemical Tests for Detecting Epstein-Barr Virus in Hodgkin Lymphoma

2002 ◽  
Vol 117 (2) ◽  
pp. 259-267 ◽  
Author(s):  
Margaret L. Gulley ◽  
Sally L. Glaser ◽  
Fiona E. Craig ◽  
Michael Borowitz ◽  
Risa B. Mann ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals A Positive Autoregulatory Loop of LMP1 Expression and STAT Activation in Epithelial Cells Latently Infected with Epstein-Barr Virus

2003 ◽  
Vol 77 (7) ◽  
pp. 4139-4148 ◽  
Author(s):  
Honglin Chen ◽  
Lindsey Hutt-Fletcher ◽  
Liang Cao ◽  
S. Diane Hayward
Keyword(s):  
Epithelial Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Ebv Infection ◽  
Lmp1 Expression ◽  
Cell Line Hela ◽  
Epstein Barr ◽  
Phosphorylated Stat3

ABSTRACT STAT3 and STAT5 are constitutively activated and nuclear in nasopharyngeal carcinoma (NPC) cells. In normal signaling, STATs are only transiently activated. To investigate whether Epstein-Barr virus (EBV), and in particular the protein LMP1, contributes to sustained STAT phosphorylation and activation in epithelial cells, we examined STAT activity in two sets of paired cell lines, HeLa, an EBV-converted HeLa cell line, HeLa-Bx1, the NPC-derived cell line CNE2-LNSX, and an LMP1-expressing derivative, CNE2-LMP1. EBV infection was associated with a significant increase in the tyrosine-phosphorylated forms of STAT3 and STAT5 in HeLa-Bx1 cells. This effect correlated with LMP1 expression, since phosphorylated STAT3 and STAT5 levels were also increased in CNE2-LMP1 cells relative to the control CNE2-LNSX cells. No change was observed in STAT1 or STAT6 phosphorylation in these cell lines, nor was there a significant change in the levels of total STAT3, STAT5, STAT1, or STAT6 protein. Tyrosine phosphorylation allows the normally cytoplasmic STAT proteins to enter the nucleus and bind to their recognition sequences in responsive promoters. The ability of LMP1 to activate STAT3 was further established by immunofluorescence assays in which coexpression of LMP1 in transfected cells was sufficient to mediate nuclear relocalization of Flag-STAT3 and by an electrophoretic mobility shift assay which showed that LMP1 expression in CNE2-LNSX cells was associated with increased endogenous STAT3 DNA binding activity. In addition, the activity of a downstream target of STAT3, c-Myc, was upregulated in HeLa-Bx1 and CNE2-LMP1 cells. A linkage was established between interleukin-6 (IL-6)- and LMP1-mediated STAT3 activation. Treatment with IL-6 increased phosphorylated STAT3 levels in CNE2-LNSX cells, and conversely, treatment of CNE2-LMP1 cells with IL-6 neutralizing antibody ablated STAT3 activation and c-Myc upregulation. The previous observation that STAT3 activated the LMP1 terminal repeat promoter in reporter assays was extended to show upregulated expression of endogenous LMP1 mRNA and protein in HeLa-Bx1 cells transfected with a constitutively activated STAT3. A model is proposed in which EBV infection of an epithelial cell containing activated STATs would permit LMP1 expression. This in turn would establish a positive feedback loop of IL-6-induced STAT activation, LMP1 and Qp-EBNA1 expression, and viral genome persistence.

Prognostic significance of Epstein–Barr virus (EBV) infection in Hodgkin lymphoma patients

2017 ◽  
Vol 23 (3) ◽  
pp. 121-130 ◽  
Author(s):  
Ben Dhiab Myriam ◽  
Ziadi Sonia ◽  
Saad Hanene ◽  
Louhichi Teheni ◽  
Trimeche Mounir
Keyword(s):  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Prognostic Significance ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

scholarly journals The characterization and frequency of diagnosis of EBV-positive variants with a lymphoid predominance in the structure of Hodgkin lymphoma

2021 ◽  
Vol 66 (4) ◽  
pp. 567-579
Author(s):  
I. A. Shupletsova ◽  
A. M. Kovrigina
Keyword(s):  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Classical Hodgkin Lymphoma ◽  
Biopsy Material ◽  
Barr Virus ◽  
Histological Variants ◽  
Epstein Barr ◽  
Old Men ◽  
Age Range

Introduction. Epstein — Barr virus (EBV) plays an important role in the pathogenesis of lymphoid tumors, in particular Hodgkin lymphoma. The frequency of expression of the EBV varies in different histological variants of classical Hodgkin lymphoma and is rarely observed in nodular lymphocyte predominant Hodgkin lymphoma.Aim — to study the pathomorphological features of the histological variants of Hodgkin lymphoma with lymphoid predominance associated with the EBV, as well as the frequency of their diagnosis in the structure of Hodgkin lymphoma.Materials and methods. The retrospective study included 794 patients with a verified diagnosis of Hodgkin lymphoma using histological and immunohistochemical methods on biopsy material for the period 2018–2019 (age range — 18–91 years old; median — 34 years old; men : women — 1.1 : 1). The presence of EBV in biopsies was assessed by immunohistochemical reaction with antibodies to EBV (clone LMP1), or by chromogenic in situ hybridization with probes for EBV-encoded small RNAs.Results. Classical Hodgkin lymphoma was diagnosed in 91 % (725/794) cases, nodular lymphocyte predominant Hodgkin lymphoma — in 9 % (69/794) cases. EBV-positive Hodgkin lymphoma accounted for 11 % (82/725) of all cases of classical Hodgkin lymphoma, (age range — 18–81 years old, median — 45 years old; men : women — 2.5 : 1). All cases of nodular lymphocyte predominant Hodgkin lymphoma were EBV-negative. Lymphocyte-rich classical Hodgkin lymphoma was found in 14 patients (14/725, 2 %), 4 patients showed intermediate morphoimmunohistochemical features with nodular lymphocyte predominant Hodgkin lymphoma, which were statistically significantly different from classical Hodgkin lymphoma by the presence of B-zones in the form of large nodules (p = 0.0157) and expression CD20 by tumor cells (p = 0.0404).Conclusion. Nodular lymphocyte predominant Hodgkin lymphoma is not characterized by a connection with EBV infection, unlike classical variant — lymphocyte-rich classical Hodgkin lymphoma. The obtained data support the concept of the existence of a transient form of Hodgkin lymphoma, which has the features of nodular lymphocyte predominant Hodgkin lymphoma and classical Hodgkin lymphoma, in the pathogenesis of which the Epstein — Barr virus likely plays a role. 

scholarly journals Epstein-Barr Virus Immediate-Early Proteins BZLF1 and BRLF1 Activate the ATF2 Transcription Factor by Increasing the Levels of Phosphorylated p38 and c-Jun N-Terminal Kinases

2000 ◽  
Vol 74 (3) ◽  
pp. 1224-1233 ◽  
Author(s):  
Amy L. Adamson ◽  
Dayle Darr ◽  
Elizabeth Holley-Guthrie ◽  
Robert A. Johnson ◽  
Amy Mauser ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Epstein Barr Virus ◽  
Viral Latency ◽  
Immediate Early ◽  
Expression Vectors ◽  
Protein Z ◽  
Barr Virus ◽  
Ebv Infection ◽  
Early Protein ◽  
Epstein Barr

ABSTRACT Expression of either Epstein-Barr virus (EBV) immediate-early protein BZLF1 (Z) or BRLF1 (R) is sufficient to convert EBV infection from the latent to lytic form. Disruption of viral latency requires transcriptional activation of the Z and R promoters. The Z and R proteins are transcriptional activators, and each immediate-early protein activates expression of the other immediate-early protein. Z activates the R promoter through a direct binding mechanism. However, R does not bind directly to the Z promoter. In this study, we demonstrate that the ZII element (a cyclic AMP response element site) in the Z promoter is required for efficient activation by R. The ZII element has been shown to be important for induction of lytic EBV infection by tetradecanoyl phorbol acetate and surface immunoglobulin cross-linking and is activated by Z through an indirect mechanism. We demonstrate that both R and Z activate the cellular stress mitogen-activated protein (MAP) kinases, p38 and JNK, resulting in phosphorylation (and activation) of the cellular transcription factor ATF2. Furthermore, we show that the ability of R to induce lytic EBV infection in latently infected cells is significantly reduced by inhibition of either the p38 kinase or JNK pathways. In contrast, inhibition of stress MAP kinase pathways does not impair the ability of Z expression vectors to disrupt viral latency, presumably because expression of Z under the control of a strong heterologous promoter bypasses the need to activate Z transcription. Thus, both R and Z can activate the Z promoter indirectly by inducing ATF2 phosphorylation, and this activity appears to be important for R-induced disruption of viral latency.

scholarly journals Epstein Barr Virus in childhood and adolescent classical Hodgkin lymphoma in a French cohort of 301 patients

2021 ◽  
Author(s):  
Victor Pereira ◽  
Sabah Boudjemaa ◽  
Caroline Besson ◽  
Thierry Leblanc ◽  
Charlotte Rigaud ◽  
...  
Keyword(s):  
Viral Load ◽  
Hodgkin Lymphoma ◽  
Epstein Barr Virus ◽  
Male Gender ◽  
Barr Virus ◽  
Classic Hodgkin Lymphoma ◽  
Male Patients ◽  
Epstein Barr

To analyze the role of Epstein-Barr virus (EBV) in the biological and clinical characteristics of patients treated for classic Hodgkin lymphoma (cHL) in France. Bio-pathological data of 301 patients treated for a cHL in or according to the protocol of the EuroNet PHL-C1 trial between November 2008 and February 2013 were centrally reviewed. Median age at diagnosis was 14 [3-18] years and the F/M ratio 0.86, 0.47 before 10 years and 0.9 from 11 to 18. CHL subtypes were nodular sclerosis for 266/301 (88%) patients, mixed cellularity for 22/301 (7%), lymphocyte rich for 2/301 (1%), and 11/301 were unclassified. EBV expression in situ (EBV cHL) was observed for 68/301 (23%) patients, significantly associated with MC subtype and male gender, and there was a trend with age <10 years, it was particularly overrepresented in boys below 10 years: 15/23 (65%) vs 28/139 among other male patients (20%). Event-free and overall survival were equivalent between EBV and non-EBV cHL patients. EBV viral load was tested for 108/301 patients and detectable in 22/108 (22%) cases. A positive viral load was overrepresented in EBV cHL versus non-EBV cHL patients: 13/28 (46%) vs 9/80 (11%). Detailed semi-quantitative histological analysis showed a high number of B-cell residual follicles in EBV cHL and no significant association with CD 20 or PAX 5 immunostaining in tumoral cells relative to EBV-negative HL. Distribution of EBV cHL in children and adolescents is associated with young age and male gender, suggesting a specific physiopathology and may require a differential therapeutic approach.

Epstein–Barr virus plays little role in cervical carcinogenesis in Korean women

2005 ◽  
Vol 15 (2) ◽  
pp. 312-318
Author(s):  
S. S. Seo ◽  
W. H. Kim ◽  
Y. S. Song ◽  
S. H. Kim ◽  
J. W. Kim ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Epstein Barr Virus ◽  
Intraepithelial Neoplasia ◽  
Cervical Carcinogenesis ◽  
Korean Women ◽  
Barr Virus ◽  
Ebv Infection ◽  
Ebv Dna ◽  
Epstein Barr

We examined whether Epstein–Barr virus (EBV) infection plays a role in cervical carcinogenesis in Korean women. EBV infection was examined using polymerase chain reaction (PCR) with two different primer pairs flanking the BamHI “W” fragment of EBV and by EBV-encoded small RNAs (EBER) in situ hybridization in various histologic types of cervical cancer, including 17 cases of squamous cell carcinoma, 36 cases of adenocarcinoma, and 3 cases of small-cell carcinoma. We also evaluated 20 cases of cervical intraepithelial neoplasia and 20 cases of normal uterine cervix. One case of squamous cell carcinoma and three cases of cervical intraepithelial neoplasia were positive for EBV DNA using PCR, but EBER in situ hybridization analysis showed that none of the PCR-positive cases expressed EBER. EBV DNA was not found using PCR in any of the 20 normal uterine cervices. From our results, EBV infection does not seem to play a role in cervical carcinogenesis in Korean women.

Epstein-Barr Virus Related Classical Hodgkin Lymphoma Reveals a Pro-Inflammatory RNA Expression Profile at Diagnosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5292-5292
Author(s):  
Priscilla Brito Silva ◽  
Juliana Monte Real ◽  
Ludmila Rodrigues Pinto Ferreira ◽  
Adriana M. Damasco Penna ◽  
Gustavo Henrique Esteves ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hodgkin Lymphoma ◽  
Expression Profile ◽  
Epstein Barr Virus ◽  
Immune Gene ◽  
Classical Hodgkin Lymphoma ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Inflammatory Profile

Abstract Introduction: Epstein-Barr virus (EBV) is associated with a variety of human diseases including classical Hodgkin lymphoma. EBV recruit mainly cells with anti-inflammatory properties, providing an immunosuppressive environment and the immune escape of Reed-Sternberg (RS) cells. Studies have shown that patients with cHL EBV-related is associated with increased gene expression of IL-6, IL-10 and CD25. However, the molecular mechanism by which EBV orchestrates the cytokines secretion profile that promotes microenvironment propitious to survival and growth to neoplastic RS cells remains unclear. Objectives: In this study we aimed evaluate the immune gene expression profile and association in EBV-related cHL patients. Methods: This is an open multicenter study and, so far, we included 51 patients consecutively from February 2011 to November 2015. Twenty consecutively diagnosed cHL patients, with whole blood RNA extracted at diagnosis and after treatment (1 to 4 months), were recruited for this study and prospectively evaluated. The general expression of 96 messengers RNAs present in the peripheral blood and involved in immune response was performed by a customized quantitative real-time PCR array (TaqMan¨Low Density Array). We also included 7 healthy controls. The data was normalized with B2M mRNAs levels and relative gene expression was calculated by the 2^DDCt method, considering Wilcoxon test and Benjamini-Hochberg adjustment to correct p-values. In this study, only cHL patients whose histology could be confirmed were studied. The EBV status was evaluated in paraffin-embedded tissue by immunohistochemical analysis. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. Results: From the 20 patients recruited for this study, 12 (60%) were male, 18 (90%) patients presented with B symptoms and 19 (95%) patients had advanced diseases at diagnosis (stage IIBx, II and IV). Interestingly, 5 (31%) had Epstein-Barr virus related cHL. The EBV infection reflected in increased amounts of IL-2 (8 fold, p=0.040), IL-23A (2.4 fold, p=0.040) and IL-7 (3.4 fold, p=0.053) mRNAs in blood circulation at the time of diagnosis (summarized in following table). After treatment, no mRNA immune gene was different expressed, suggesting that it returned to normal levels in both groups. We not found any correlation with clinical and epidemiological features and EBV. Conclusions: In this study, we showed that, EBV infection in patients with cHL is related with pro-inflammatory profile gene expression. Although IL-2 and IL-7 are related with a pro-inflammatory profile, these cytokines are co-stimulators of a standard immune suppression as their receptors are markers of regulatory T cells (IL7-R= CD127 and IL-2Ra= CD25). IL-2/IL-2Ra and IL-7/IL-7R constitutes an additional signaling pathway between H-RS cells and their reactive cellular background, thereby affecting proliferation and survival of tumor cells, acting as a cofactor for Tregs expansion and EBV infection. Certainly our results need to be validated in larger cohorts. Nevertheless, given the incidence of EBV-related cHL, disease presentation and severity are different in developing countries than in developed ones, we emphasize the importance of our results. Table Table. Disclosures No relevant conflicts of interest to declare.

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