The relationship between Epstein-Barr virus (EBV) and the germinal centre (GC) of the asymptomatic host remains an enigma. The occasional appearance of EBV-positive germinal centres in some patients, particularly those with a history of immunosuppression, suggests that EBV numbers in the GC are subject to immune control. The relationship, if any, between lymphoid hyperplasia with EBV-positive germinal centres and subsequent or concurrent lymphomagenesis remains to be clarified. As far as the development of EBV-associated Hodgkin's lymphoma is concerned, the suppression of virus replication, mediated by LMP1 on the one hand, and the loss of B-cell receptor signalling on the other, appears to be an important pathogenic mechanism. A further important emerging concept is that alterations in the microenvironment of the EBV-infected B-cell may be important for lymphomagenesis.

• MeSH
• B-lymfocyty imunologie   virologie   MeSH
• buněčná diferenciace imunologie   MeSH
• dospělí MeSH
• Hodgkinova nemoc imunologie   virologie   MeSH
• infekce virem Epsteina-Barrové virologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• proteiny virové matrix MeSH
• pseudolymfom virologie   MeSH
• receptory antigenů B-buněk imunologie   MeSH
• replikace viru imunologie   MeSH
• virus Epsteinův-Barrové imunologie   MeSH
• zárodečné centrum lymfatické uzliny imunologie   virologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• EBV-associated membrane antigen, Epstein-Barr virus MeSH Prohlížeč
• proteiny virové matrix MeSH
• receptory antigenů B-buněk MeSH

Epstein-Barr virus (EBV), defined as a group I carcinogen by the World Health Organization (WHO), is present in the tumour cells of patients with different forms of B-cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and, most recently, diffuse large B-cell lymphoma (DLBCL). Understanding how EBV contributes to the development of these different types of B-cell lymphoma has not only provided fundamental insights into the underlying mechanisms of viral oncogenesis, but has also highlighted potential new therapeutic opportunities. In this review, we describe the effects of EBV infection in normal B-cells and we address the germinal centre model of infection and how this can lead to lymphoma in some instances. We then explore the recent reclassification of EBV+ DLBCL as an established entity in the WHO fifth edition and ICC 2022 classifications, emphasising the unique nature of this entity. To that end, we also explore the unique genetic background of this entity and briefly discuss the potential role of the tumour microenvironment in lymphomagenesis and disease progression. Despite the recent progress in elucidating the mechanisms of this malignancy, much work remains to be done to improve patient stratification, treatment strategies, and outcomes.

• Klíčová slova
• Epstein–Barr virus, chronic inflammation, diffuse large B-cell lymphoma, tumour microenvironment,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The Epstein-Barr virus (EBV) is present in the tumour cells of a subset of patients with classic Hodgkin lymphoma (cHL), yet the contribution of the virus to the pathogenesis of these tumours remains only poorly understood. The EBV genome in virus-associated cHL expresses a limited subset of genes, restricted to the non-coding Epstein-Barr virus-encoded RNAs (EBERs) and viral miRNA, as well as only three virus proteins; the Epstein-Barr virus nuclear antigen-1 (EBNA1), and the two latent membrane proteins, known as LMP1 and LMP2, the latter of which has two isoforms, LMP2A and LMP2B. LMP1 and LMP2A are of particular interest because they are co-expressed in tumour cells and can activate cellular signalling pathways, driving aberrant cellular transcription in infected B cells to promote lymphomagenesis. This article seeks to bring together the results of recent studies of the latent membrane proteins in different B cell systems, including experiments in animal models as well as a re-analysis of our own transcriptional data. In doing so, we summarise the potentially co-operative and antagonistic effects of the LMPs that are relevant to B cell lymphomagenesis.

• Klíčová slova
• EBNA1, EBV, Hodgkin lymphoma, LMP1, LMP2A, germinal centre,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin's lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas.

• Publikační typ
• časopisecké články MeSH

The Epstein-Barr virus (EBV) is found almost exclusively in the activated B-cell (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), yet its contribution to this tumour remains poorly understood. We have focused on the EBV-encoded latent membrane protein-1 (LMP1), a constitutively activated CD40 homologue expressed in almost all EBV-positive DLBCLs and which can disrupt germinal centre (GC) formation and drive lymphomagenesis in mice. Comparison of the transcriptional changes that follow LMP1 expression with those that follow transient CD40 signalling in human GC B cells enabled us to define pathogenic targets of LMP1 aberrantly expressed in ABC-DLBCL. These included the down-regulation of S1PR2, a sphingosine-1-phosphate (S1P) receptor that is transcriptionally down-regulated in ABC-DLBCL, and when genetically ablated leads to DLBCL in mice. Consistent with this, we found that LMP1-expressing primary ABC-DLBCLs were significantly more likely to lack S1PR2 expression than were LMP1-negative tumours. Furthermore, we showed that the down-regulation of S1PR2 by LMP1 drives a signalling loop leading to constitutive activation of the phosphatidylinositol-3-kinase (PI3-K) pathway. Finally, core LMP1-PI3-K targets were enriched for lymphoma-related transcription factors and genes associated with shorter overall survival in patients with ABC-DLBCL. Our data identify a novel function for LMP1 in aggressive DLBCL. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Klíčová slova
• CD40, DLBCL, EBV, LMP1, S1P, S1PR2,
• MeSH
• 1-fosfatidylinositol-3-kinasa metabolismus   MeSH
• antigeny CD40 genetika   metabolismus   MeSH
• databáze genetické MeSH
• difúzní velkobuněčný B-lymfom genetika   metabolismus   mortalita   virologie   MeSH
• infekce virem Epsteina-Barrové mortalita   virologie   MeSH
• interakce hostitele a patogenu MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• prognóza MeSH
• proteiny virové matrix genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• receptory sfingosin-1-fosfátu genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce MeSH
• virová transformace buněk MeSH
• virus Epsteinův-Barrové genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa MeSH
• antigeny CD40 MeSH
• EBV-associated membrane antigen, Epstein-Barr virus MeSH Prohlížeč
• proteiny virové matrix MeSH
• protoonkogenní proteiny c-akt MeSH
• receptory sfingosin-1-fosfátu MeSH
• S1PR2 protein, human MeSH Prohlížeč