The Expression Pattern of Epstein-Barr Virus Latent Genes In Vivo Is Dependent upon the Differentiation Stage of the Infected B Cell

Babcock, Gregory J.; Hochberg, Donna; Thorley‐Lawson, David A.

doi:10.1016/s1074-7613(00)00049-2

Cited by 405 publications

(408 citation statements)

References 31 publications

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“…In addition, transformation of EBV latency‐II‐expressing benign B cells may represent an initiating event in the pathogenesis of EBV + cHL. EBV‐infected germinal centre B cells have been shown to express the EBV latency‐II pattern 61, 62, identical to that seen in the HRS cells of EBV + cHL, which are known to have an atypical germinal centre derivation 63. In this situation, differential EBV latency‐II‐specific effector CD8 + T cell immune surveillance might contribute to the pathogenesis of EBV + cHL by attenuating immune‐mediated destruction of premalignant B cells.…”

Section: Discussionmentioning

confidence: 92%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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SummaryIn 40% of cases of classical Hodgkin lymphoma (cHL), Epstein–Barr virus (EBV) latency‐II antigens [EBV nuclear antigen 1 (EBNA1)/latent membrane protein (LMP)1/LMP2A] are present (EBV+cHL) in the malignant cells and antigen presentation is intact. Previous studies have shown consistently that HLA‐A*02 is protective in EBV+cHL, yet its role in disease pathogenesis is unknown. To explore the basis for this observation, gene expression was assessed in 33 cHL nodes. Interestingly, CD8 and LMP2A expression were correlated strongly and, for a given LMP2A level, CD8 was elevated markedly in HLA‐A*02– versus HLA‐A*02+ EBV+cHL patients, suggesting that LMP2A‐specific CD8+ T cell anti‐tumoral immunity may be relatively ineffective in HLA‐A*02– EBV+cHL. To ascertain the impact of HLA class I on EBV latency antigen‐specific immunodominance, we used a stepwise functional T cell approach. In newly diagnosed EBV+cHL, the magnitude of ex‐vivo LMP1/2A‐specific CD8+ T cell responses was elevated in HLA‐A*02+ patients. Furthermore, in a controlled in‐vitro assay, LMP2A‐specific CD8+ T cells from healthy HLA‐A*02 heterozygotes expanded to a greater extent with HLA‐A*02‐restricted compared to non‐HLA‐A*02‐restricted cell lines. In an extensive analysis of HLA class I‐restricted immunity, immunodominant EBNA3A/3B/3C‐specific CD8+ T cell responses were stimulated by numerous HLA class I molecules, whereas the subdominant LMP1/2A‐specific responses were confined largely to HLA‐A*02. Our results demonstrate that HLA‐A*02 mediates a modest, but none the less stronger, EBV‐specific CD8+ T cell response than non‐HLA‐A*02 alleles, an effect confined to EBV latency‐II antigens. Thus, the protective effect of HLA‐A*02 against EBV+cHL is not a surrogate association, but reflects the impact of HLA class I on EBV latency‐II antigen‐specific CD8+ T cell hierarchies.

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Section: Discussionmentioning

confidence: 92%

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Jones

Wockner

Brennan

et al. 2015

Clinical and Experimental Immunology

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“…1 h 6 h 12 h 24 h 48 h 72 h Increased levels of the Pyst2-L transcript were detected in TPA-treated cells already 1 h following the onset of the experiment Pyst2-L is highly expressed in malignancy, differentiating, and activated cells O Levy-Nissenbaum et al involve MAPK signaling pathways (Steinitz et al, 1977;Chu et al, 1996;Babcock et al, 2000). It should be noted that the expression levels of Pyst2-L were higher in untreated cells cultured for 72 h than in untreated cells cultured for shorter periods.…”

Section: Mapk Activation Signals Upregulate Pyst2-l Expression In ML mentioning

confidence: 99%

Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells

et al. 2003

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Northern blotting confirmed previous results indicating that the mitogen-activated protein kinase (MAPK) phosphatase Pyst2-L was highly expressed in leukocytes obtained from acute myeloid leukemia (AML) patients. High levels of Pyst2-L mRNA were expressed in bone marrow (BM) and peripheral leukocytes from nine AML and acute lymphoblastic leukemia (ALL) patients. BM from healthy individuals expressed very low levels of Pyst2-L. Whereas high levels of Pyst2-L mRNA and protein were detected in several leukemia cell lines, Pyst2-L mRNA was detected neither in 33/34 samples of normal peripheral blood mononuclear cells (PBMC) nor in leukocyte fractions enriched with CD34 þ cells. Certain solid tumor and lymphoblastoid cell lines expressed high levels of Pyst2-L mRNA. In view of the association of Pyst2-L to MAPK signaling cascades, we tested if cell activation, a process involving MAPK signaling, influences Pyst2-L expression. Indeed, activation of T cells and endothelial cells increased Pyst2-L in these cells. Furthermore, TPA, a known MAPK activator, induces the expression of both Pyst2-L mRNA as well as the Pyst2-L protein in leukemia cells. This induction was partially inhibited by PD098059, an Mek1/2-specific inhibitor. Based on the results of this and previous studies, we hypothesize that the high levels of Pyst2-L detected in the active state of AML and ALL diseases and in other types of cancer reflect an altered MAPK signaling pathway in such malignant processes. This alteration may be the result of a failed attempt to counter the constitutive activation of MAPK in transformed cells or alternatively, may represent the activated state of such cells.

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“…EBV infection in humans has lytic and latent infection stages. Lytic infection produces infectious virus for transmission to other susceptible host cells within the infected individual, mainly epithelial and B cells, or to uninfected individuals during transmission via saliva exchange (Young and Rickinson, 2004 (Babcock et al, 1998;Babcock et al, 2000;Hochberg et al, 2004). Infected plasma B cell differentiation reactivates EBV into lytic replication 6 (Laichalk and Thorley-Lawson, 2005).…”

Section: Programs Of Ebv Infection In His Micementioning

confidence: 99%

Animal models of Epstein Barr virus infection

Gujer

Chatterjee

Landtwing

et al. 2015

Current Opinion in Virology

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Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. AbstractEpstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50 years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. Chatterjee et al. 3

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The Expression Pattern of Epstein-Barr Virus Latent Genes In Vivo Is Dependent upon the Differentiation Stage of the Infected B Cell

Cited by 405 publications

References 31 publications

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

The impact of HLA class I and EBV latency-II antigen-specific CD8+ T cells on the pathogenesis of EBV+ Hodgkin lymphoma

Dual-specificity phosphatase Pyst2-L is constitutively highly expressed in myeloid leukemia and other malignant cells

Animal models of Epstein Barr virus infection

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