Epstein–Barr virus infection negatively impacts the CXCR4‐dependent migration of tonsillar B cells

Ehlin‐Henriksson, Barbro; Mowafi, Frida; Klein, George; Nilsson, Anna

doi:10.1111/j.1365-2567.2005.02311.x

Cited by 21 publications

(22 citation statements)

References 35 publications

(86 reference statements)

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“…by guest www.bloodjournal.org From Importantly, these data indicated that in CLL the mechanism of IL-4 is both receptor-and cell type-dependent. The IL-4-mediated downregulation of CXCR4 expression and function by CLL cells mirrors the effect of BCR stimulation on this receptor, 61,62 suggesting that these influences may be acting together to locate cells to extrafollicular sites 63 where enhanced IgM expression then increases antigen engagement and subsequent downstream signalling events.…”

Section: Discussionmentioning

confidence: 99%

IL-4 enhances expression and function of surface IgM in CLL cells

Aguilar-Hernández

Blunt

Dobson

et al. 2016

Blood

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Key Points• IL-4 treatment augments sIgM expression and subsequent downstream signalling in a JAK3/STAT6 dependent manner within CLL samples.• IL-4 exposure partially opposes the activity of Bruton tyrosine kinase or PI3K inhibitors on sIgM-mediated signalling.Kinase inhibitors targeting the B-cell receptor (BCR) are now prominent in the treatment of chronic lymphocytic leukemia (CLL). We have focused here on interleukin 4 (IL-4), a cytokine that protects normal and malignant B cells from apoptosis and increases surface immunoglobulin M (sIgM) expression on murine splenic B cells. First, we have demonstrated that IL-4 treatment increased sIgM expression in vitro on peripheral blood B cells obtained from healthy individuals. In CLL, IL-4 target genes are overexpressed in cells purified from the lymph nodes of patients compared with cells derived from matched blood and bone marrow samples. As for normal B cells, IL-4 increased sIgM expression on CLL cells in vitro, especially in samples expressing unmutated V-genes. IL-4-induced sIgM expression was associated with increased receptor signalling activity, measured by anti-IgM-induced calcium mobilization, and with increased expression of CD79B messenger RNA and protein, and the "mature" glycoform of sIgM. Importantly, the ability of the BCR-associated kinase inhibitors idelalisib and ibrutinib, approved for treatment of CLL and other B-cell malignancies, to inhibit anti-IgM-induced signalling was reduced following IL-4 pretreatment in samples from the majority of patients. In contrast to stimulatory effects on sIgM, IL-4 decreased CXCR4 and CXCR5 expression; therefore, CLL cells, particularly within the progressive unmutated V-gene subset, may harness the ability of IL-4 to promote BCR signalling and B-cell retention within lymph nodes. Effects of IL-4 were mediated via JAK3/STAT6 and we propose a potential role for JAK inhibitors in combination with BCR kinase inhibitors for the treatment of CLL. (Blood. 2016;127(24):3015-3025)

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Section: Discussionmentioning

confidence: 99%

IL-4 enhances expression and function of surface IgM in CLL cells

Aguilar-Hernández

Blunt

Dobson

et al. 2016

Blood

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“…Regulation of CXCR4 expression appears to be a common feature of herpesvirus infection, as EBV, human herpesvirus 6, and human herpesvirus 7 have all been shown to downmodulate CXCR4 expression in infected B and T cells, respectively (36,53). In addition, EBV infection of primary tonsillar B cells results in downregulation of CXCR4 expression within 48 h, with a corresponding decrease in the ability of infected cells to respond to CXCL12 (7). Although the precise mechanism of EBNA-3B-mediated CXCR4 regulation remains to be defined, our preliminary studies suggest that EBNA-3B alone cannot repress CXCR4 expression in T-cell lines and that either the presence of other EBV genes or the context of an LCL background may be required for EBNA-3B-mediated modulation of CXCR4 expression.…”

Section: Discussionmentioning

confidence: 99%

EBNA-3B- and EBNA-3C-Regulated Cellular Genes in Epstein-Barr Virus-Immortalized Lymphoblastoid Cell Lines

Chen

Zhao

Kieff

et al. 2006

J Virol

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The cellular pathways that Epstein-Barr virus (EBV) manipulates in order to effect its lifelong persistence within hosts and facilitate its transmission between hosts are not well understood. The EBV nuclear antigen 3 (EBNA-3) family of latent infection proteins consists of transcriptional regulators that influence viral and cellular gene expression in EBV-infected cells. To identify EBNA-3B-and EBNA-3C-regulated cellular genes potentially important for virus infection in vivo, we studied a lymphoblastoid cell line (LCL) infected with an unusual EBV mutant, where a genetic manipulation to delete EBNA-3B also resulted in a significant decrease in EBNA-3C expression and slower than normal growth (3B ؊ /3C low ). Transcriptional profiling was performed on the 3B ؊ /3C low LCLs, and comparison of mutant and wild-type LCL profiles resulted in a group of 21 probe sets representing 16 individual genes showing statistically significant differences in expression. Further quantitative reverse transcription-PCR analyses comparing 3B ؊ /3C low LCLs to a previously described EBNA-3B mutant (3B ؊ ) where EBNA-3C expression was normal revealed three potential EBNA-3B-repressed genes, three potential EBNA-3C-repressed genes, and two potential EBNA-3C-activated genes. The most highly EBNA-3C-repressed gene was Jagged1, a cell surface ligand and inducer of the Notch receptor signaling pathway that is usurped by EBV genes essential for B-cell immortalization. 3B ؊ /3C low LCLs expressed increased levels of Jagged1 protein and were able to more efficiently induce functional Notch signaling, and this signaling was dependent on Notch cleavage by ␥-secretase. However, inhibiting ␥-secretase-mediated Notch cleavage did not rescue 3B ؊ /3C low LCL growth, suggesting that EBNA-3C-mediated repression of this signaling pathway did not contribute to LCL growth in tissue culture. Similarly, expression of the chemokine receptor CXCR4 was reproducibly upregulated in EBNA-3B-null LCLs. Since deletion of EBNA-3B has no significant impact on B-cell immortalization in tissue culture, this finding suggested that EBNA-3B-mediated regulation of CXCR4 may be an important viral strategy for alteration of B-cell homing in the infected host. These studies identify two cellular genes that do not contribute to EBV-induced B-cell growth but whose expression levels are strongly EBNA-3 regulated in EBV-infected primary B cells. These EBV-manipulated cellular pathways may be important for virus survival or transmission in humans, and their independence from EBV-induced B-cell growth makes them potential targets for testing in vivo with the rhesus lymphocryptovirus animal model for EBV infection.

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“…However, the lack of EBV-infected CD19 ϩ cells in HL strongly suggests that the role of B lymphocytes in EBV spreading to oral epithelium is limited at best. Furthermore, it has been shown that EBV infection in B lymphocytes inhibits CXCR4 expression on the B-lymphocyte surface (9,27), leading to reduced migration of EBV-infected B lymphocytes toward stromal cell-derived factor 1 in vitro (9).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus (EBV)-Infected Monocytes Facilitate Dissemination of EBV within the Oral Mucosal Epithelium

Tugizov

Herrera²,

Veluppillai

et al. 2007

J Virol

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Epstein-Barr virus (EBV) causes hairy leukoplakia (HL), a benign lesion of oral epithelium that occurs primarily in the setting of human immunodeficiency virus (HIV)-associated immunodeficiency. However, the mechanisms of EBV infection of oral epithelium are poorly understood. Analysis of HL tissues shows a small number of EBV-positive intraepithelial macrophages and dendritic/Langerhans cells. To investigate a role for these cells in spreading EBV to epithelial cells, we used tongue and buccal explants infected ex vivo with EBV. We showed that EBV first infects submucosal CD14 ؉ monocytes, which then migrate into the epithelium and spread virus to oral epithelial cells, initiating productive viral infection within the terminally differentiated spinosum and granulosum layers. Incubation of EBV-infected monocytes and oral explants with antibodies to CCR2 receptor and monocyte chemotactic protein 1 prevented entry of monocytes into the epithelium and inhibited EBV infection of keratinocytes. B lymphocytes played little part in the spread of EBV to keratinocytes in our explant model. However, cocultivation of EBV-infected B lymphocytes with uninfected monocytes in vitro showed that EBV may spread from B lymphocytes to monocytes. Circulating EBV-positive monocytes were detected in most HIV-infected individuals, consistent with a model in which EBV may be spread from B lymphocytes to monocytes, which then enter the epithelium and initiate productive viral infection of keratinocytes.Epstein-Barr virus (EBV) is a human herpesvirus with oncogenic potential, contributing to the development of lymphoproliferative diseases of B lymphocytes and nasopharyngeal carcinoma (18). EBV infects about 90% of the human population, but in most immunocompetent individuals EBV persists in latent form and does not cause any significant disease. During human immunodeficiency virus (HIV)-associated immunosuppression, however, EBV may reactivate and may be associated with development of a benign lesion of oral mucosal epithelium known as hairy leukoplakia (HL) (12-14). The histopathology of HL includes acanthosis, irregular hyperparakeratosis, and balloon cell formation within the spinosum and granulosum layers of the epithelium, which may result from high-level EBV replication (14).HL is a common lesion in HIV-positive patients with low CD4 ϩ counts, suggesting that immunosuppression is an important factor in its development. The source of the EBV in HL is not known. Several lines of evidence support hematogenous spread from circulating white blood cells (WBC) (11,29). The main reservoir of latent EBV infection in the body is memory B lymphocytes, but mechanisms of spread from cells in the blood compartment to the mucosal epithelium are not known. Furthermore, HL epithelium may support both latent and lytic replication of EBV (43), with lytic EBV replication and cellto-cell spread of virions restricted exclusively to the terminally differentiated stratum spinosum and granulosum layers (28,31,44). Neither the mechanisms by which EBV enters ...

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Epstein–Barr virus infection negatively impacts the CXCR4‐dependent migration of tonsillar B cells

Cited by 21 publications

References 35 publications

IL-4 enhances expression and function of surface IgM in CLL cells

IL-4 enhances expression and function of surface IgM in CLL cells

EBNA-3B- and EBNA-3C-Regulated Cellular Genes in Epstein-Barr Virus-Immortalized Lymphoblastoid Cell Lines

Epstein-Barr Virus (EBV)-Infected Monocytes Facilitate Dissemination of EBV within the Oral Mucosal Epithelium

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