Epstein-Barr-virus-carrying lymphoma in a patient with ataxia-telangiectasia.

Saemundsen, Ari K.; Berkel, A.I. van; Henle, Werner; Henle, Gertrude; Anvret, Maria; Sanal, Özden; Ersoy, F; Çağlar, Meltem; Klein, George

doi:10.1136/bmj.282.6262.425

Cited by 103 publications

(19 citation statements)

References 22 publications

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“…ATMdeficient hosts, whether humans or mice, are selectively susceptible to severe chronic, but not acute, viral infections. Specifically, A-T patients display elevated EBV and HHV-6 loads, have prolonged and exacerbated primary varicella-zoster virus infection, and display more robust and persistent skin lesions associated with human papillomavirus (HPV) infection (11)(12)(13)(14)(15)(16)(17). These observations contradict the well-established proviral phenotypes in tissue culture systems, where ATM facilitates infection and replication of diverse herpesviruses and HPV.…”

Section: Discussioncontrasting

confidence: 53%

“…Intriguingly, in contrast to the proviral activity of ATM manifested in tissue culture, A-T patients are selectively susceptible to severe herpesvirus infections, including frequent complications of primary varicella-zoster virus infection (11)(12)(13)(14)(15)(16)(17). Further, EBV (and human herpesvirus 6 [HHV-6], when present) loads are significantly elevated in A-T patients, and abnormal EBV-driven lymphoproliferation observed early in life has been suggested as a possible diagnostic trigger for A-T (12).…”

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confidence: 99%

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B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

Darrah

Kulinski

Mboko

et al. 2017

J Virol

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Manipulation of host cellular pathways is a strategy employed by gammaherpesviruses, including mouse gammaherpesvirus 68 (MHV68), in order to negotiate a chronic infection. Ataxia-telangiectasia mutated (ATM) plays a unique yet incompletely understood role in gammaherpesvirus infection, as it has both proviral and antiviral effects. Chronic gammaherpesvirus infection is poorly controlled in a host with global ATM insufficiency, whether the host is a mouse or a human. In contrast, ATM facilitates replication, reactivation, and latency establishment of several gammaherpesviruses in vitro, suggesting that ATM is proviral in the context of infected cell cultures. The proviral role of ATM is also evident in vivo, as myeloidspecific ATM expression facilitates MHV68 reactivation during the establishment of viral latency. In order to better understand the complex relationship between host ATM and gammaherpesvirus infection, we depleted ATM specifically in B cells, a cell type critical for chronic gammaherpesvirus infection. B cell-specific ATM deficiency attenuated the establishment of viral latency due to compromised differentiation of ATM-deficient B cells. Further, we found that during long-term infection, peritoneal B-1b, but not related B-1a, B cells display the highest frequency of gammaherpesvirus infection. While ATM expression did not affect gammaherpesvirus tropism for B-1 B cells, B cell-specific ATM expression was necessary to support viral reactivation from peritoneal cells during long-term infection. Thus, our study reveals a role of ATM as a host factor that promotes chronic gammaherpesvirus infection of B cells.IMPORTANCE Gammaherpesviruses infect a majority of the human population and are associated with cancer, including B cell lymphomas. ATM is a unique host kinase that has both proviral and antiviral roles in the context of gammaherpesvirus infection. Further, there is insufficient understanding of the interplay of these roles in vivo during chronic infection. In this study, we show that ATM expression by splenic B cells is required for efficient establishment of gammaherpesvirus latency. We also show that ATM expression by peritoneal B cells is required to facilitate viral reactivation during long-term infection. Thus, our study defines a proviral role of B cellspecific ATM expression during chronic gammaherpesvirus infection.KEYWORDS ATM, gammaherpesvirus, B cell, T cell response, reactivation, chronic infection A taxia-telangiectasia (A-T) mutated (ATM) kinase is a multifunctional kinase, insufficiency of which in humans manifests as A-T (1, 2). The function of ATM was originally defined in the context of response to double-stranded DNA breaks. However,

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Section: Discussioncontrasting

confidence: 53%

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confidence: 99%

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

Darrah

Kulinski

Mboko

et al. 2017

J Virol

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“…It is seen with immunodeficiency states, including post solid organ transplant, 1 and with immune-deficient syndromes including HIV/AIDS infection, 2 Wiskott-Aldrich syndrome, 3,4 and ataxia-telangiectasia. 5 It has also been noted to occur in approximately 1% of adult patients after allogeneic bone marrow transplantation. 6 A variety of risk factors for EBV-LPD post allogeneic bone marrow transplantation have been recognized, many of which are linked to the depth of immune suppression.…”

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confidence: 99%

An unexpectedly high incidence of Epstein–Barr virus lymphoproliferative disease after CD34+ selected autologous peripheral blood stem cell transplant in neuroblastoma

Powell

Bunin

Callahan

et al. 2004

Bone Marrow Transplant

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Summary:The risk of Epstein-Barr virus lymphoproliferative disease (EBV-LPD) increases with the use of highly immunosuppressive therapies. Allogeneic BMT, especially supported by T-cell-depleted stem cell products, is a risk factor for EBV-LPD. Although the risk of EBV-LPD after autologous transplantation is low, case reports of this complication in the autologous setting exist. We report a higher incidence than previously described of EBV-LPD in children undergoing sequential high-dose chemotherapy supported with CD34 selected peripheral blood stem cells (CD34 þ PBSC). The median time to LPD after tandem transplant was 3 months (range 1-5 months). Five patients out of 156 (3.5%) developed EBV-LPD while enrolled on two trials of tandem autologous SCT in high-risk pediatric malignancies. Both studies employed five cycles of induction therapy, followed by tandem autologous PBSC transplants. In all, 108 out of 156 patients received CD34 þ PBSC; 48 received unselected PBSC. All patients contracting LPD were from the CD34 selected group. Treatment of EBV-LPD included rituximab in four out of five patients, IVIg in two out of five patients, and gancyclovir in two out of five patients. EBV-LPD resolved in four out of five patients. We conclude that the combination of tandem SCT and CD34 selection may have increased immunosuppression in these patients to a point where there is an elevated risk of EBV-LPD.

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“…'. 2 In the current study, EBV DNA was found in a lymphoma arising in the primary immunodeficiency, Wiskott-Aldrich syndrome (WAS). WAS patients are known to have high EBV titres to VCA and EA antigens, accompanied by low EBNA tit re^.^,^ The relative risk of malignancy in WAS is about 126-fold, with non-Hodgkin lymphoma being the overwhelmingly predominant type of tumour enco~ntered.~ The histologic characteristics of WAS lymphomas6 are similar to those encountered in AIDS and transplant patients where EBV is also implicated in lymphomagenesis.…”

Section: Introductionmentioning

confidence: 95%

Epstein‐barr virus‐related lymphomagenesis in a child with wiskott‐aldrich syndrome

Gulley¹,

Chen

Raab‐Traub

1993

Hematological Oncology

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Epstein-Barr virus (EBV) DNA was detected in immunoblastic lymphoma arising in a child with the primary immunodeficiency, Wiskott-Aldrich syndrome. Southern blot analysis of the structure of the EBV genome revealed that the lymphoma was monoclonal and contained episomal EBV DNA. The EBV latent genes, latent membrane protein 1 (LMP1) and the EBV nuclear antigen 2 (EBNA2), were detected by immunohistochemistry in the Wiskott-Aldrich lymphoma but not in an EBV-positive Burkitt's lymphoma, implying that host immune factors could influence EBV gene expression. Hybridization in situ demonstrated expression of EBV-encoded RNA (EBER), the cellular c-fgr protooncogene, and CD23 B-cell activation transcripts in the Wiskott-Aldrich lymphoma whereas EBER and c-fgr but not CD23 were expressed in the Burkitt's lymphoma. These data suggest that in primary immunodeficiency-related lymphoma, LMP1 and EBNA2 are expressed and that this expression correlates with expression of CD23. This supports previous in vitro studies showing that CD23 is specifically induced by LMP1 or EBNA2 genes. In contrast, expression of c-fgr may be independent of expression of these EBV latent genes.

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Epstein-Barr-virus-carrying lymphoma in a patient with ataxia-telangiectasia.

Abstract: An undifferentiated lymphocytic lymphoma of mesenteric lymph nodes occurred in a young boy with ataxiatelangiectasia. Two immunodeficiencies.

Cited by 103 publications

References 22 publications

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection

An unexpectedly high incidence of Epstein–Barr virus lymphoproliferative disease after CD34+ selected autologous peripheral blood stem cell transplant in neuroblastoma

Epstein‐barr virus‐related lymphomagenesis in a child with wiskott‐aldrich syndrome

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