scholarly journals Human immunity against EBV—lessons from the clinic

2017 ◽  
Vol 214 (2) ◽  
pp. 269-283 ◽  
Author(s):  
Stuart G. Tangye ◽  
Umaimainthan Palendira ◽  
Emily S.J. Edwards
Keyword(s):  
Immune Cell ◽  
Underlying Disease ◽  
Lymphoproliferative Disease ◽  
Barr Virus ◽  
Ebv Infection ◽  
Human Immunity ◽  
Critical Insight ◽  
Epstein Barr ◽  
Mammalian Immune System ◽  
Insight Into

The mammalian immune system has evolved over many millennia to be best equipped to protect the host from pathogen infection. In many cases, host and pathogen have coevolved, each acquiring sophisticated ways of inducing or protecting from disease. Epstein-Barr virus (EBV) is a human herpes virus that infects >90% of individuals. Despite its ubiquity, infection by EBV is often subclinical; this invariably reflects the necessity of the virus to preserve its host, balanced with sophisticated host immune mechanisms that maintain viral latency. However, EBV infection can result in various, and often fatal, clinical sequelae, including fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, organomegaly, and/or malignancy. Such clinical outcomes are typically observed in immunosuppressed individuals, with the most extreme cases being Mendelian primary immunodeficiencies (PIDs). Although these conditions are rare, they have provided critical insight into the cellular, biochemical, and molecular requirements for robust and long-lasting immunity against EBV infection. Here, we review the virology of EBV, mechanisms underlying disease pathogenesis in PIDs, and developments in immune cell–mediated therapy to treat disorders associated with or induced by EBV infection.

scholarly journals CAR-T Cells Targeting Epstein-Barr Virus gp350 Validated in a Humanized Mouse Model of EBV Infection and Lymphoproliferative Disease

2020 ◽  
Vol 18 ◽  
pp. 504-524
Author(s):  
Constanze Slabik ◽  
Maja Kalbarczyk ◽  
Simon Danisch ◽  
Reinhard Zeidler ◽  
Frank Klawonn ◽  
...  
Keyword(s):  
T Cells ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Barr Virus ◽  
Ebv Infection ◽  
Car T Cells ◽  
Car T ◽  
Epstein Barr

scholarly journals X-Linked Lymphoproliferative Disease Presenting as Pancytopenia in a 10-Month-Old Boy

2010 ◽  
Vol 2010 ◽  
pp. 1-3 ◽  
Author(s):  
S. Nicole Chadha ◽  
David Amrol
Keyword(s):  
Immune Responses ◽  
Fulminant Hepatitis ◽  
Epstein Barr Virus ◽  
Genetic Disorder ◽  
Signs And Symptoms ◽  
Lymphoproliferative Disease ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Patient Presentation

X-linked lymphoproliferative disease, also known as Duncan's syndrome, is a rare genetic disorder that causes exaggerated immune responses to Epstein-Barr virus (EBV) infection and often leads to death. Patient presentation varies but can include signs and symptoms typical of EBV, pancytopenia, and fulminant hepatitis.

SH2D1A mutations in Japanese males with severe Epstein-Barr virus–associated illnesses

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1268-1270 ◽  
Author(s):  
Ryo Sumazaki ◽  
Hirokazu Kanegane ◽  
Maki Osaki ◽  
Takashi Fukushima ◽  
Masahiro Tsuchida ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Infectious Mononucleosis ◽  
Epstein Barr Virus ◽  
Genetic Disorder ◽  
Lymphoproliferative Disease ◽  
Barr Virus ◽  
Ebv Infection ◽  
Sporadic Cases ◽  
Epstein Barr ◽  
Acute Infectious Mononucleosis

X-linked lymphoproliferative disease (XLP), a genetic disorder characterized by immunodeficiency to Epstein-Barr virus (EBV) infection, has been linked to mutations in the SH2D1A gene. To search for the occurrence of SH2D1A mutations in Japan, we performed genetic analysis of the SH2D1A gene in 40 males presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of these 40 patients. Five of these 10 cases were sporadic. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. By contrast, chronic active EBV infection was not associated with SH2D1Amutations. XLP survivors exhibited normal levels of circulating EBV-DNA during convalescence, suggesting that SH2D1A protein is not directly responsible for control of EBV replication. Thus, genetic analysis of the SH2D1A gene is particularly useful in the diagnosis of sporadic cases and carriers of XLP.

scholarly journals Comparative Study on Epstein-Barr Virus-Positive Mucocutaneous Ulcer and Methotrexate-Associated Lymphoproliferative Disorders Developed in the Oral Mucosa: A Case Series of 10 Patients and Literature Review

Diagnostics ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1375
Author(s):  
Kyoichi Obata ◽  
Tatsuo Okui ◽  
Sawako Ono ◽  
Koki Umemori ◽  
Shoji Ryumon ◽  
...  
Keyword(s):  
Oral Mucosa ◽  
Lymphoproliferative Disorder ◽  
Epstein Barr Virus ◽  
Case Series ◽  
Underlying Disease ◽  
Immunosuppressive Drugs ◽  
Barr Virus ◽  
Ebv Infection ◽  
Number Of Patients ◽  
Epstein Barr

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is an iatrogenic immunodeficiency-associated lymphoproliferative disorder that occurs mainly with MTX use. This disorder has been associated with Epstein-Barr virus (EBV) infection. In 2017, the WHO newly defined the disease concept of EBV-positive mucocutaneous ulcer (EBV-MCU) as a good-prognosis EBV-related disease. Here, we report 10 cases of MTX-LPD or EBV-MCU in the oral mucosa. This retrospective, observational study was conducted with MTX-LPD or EBV-MCU in the oral mucosa patients who visited us during the nine year period from 2012 to 2021. We gathered the basic information, underlying disease, histopathological evaluation, treatment and prognosis for the subjects. All were being treated with MTX for rheumatoid arthritis. EBV infection was positive in all cases by immunohistochemistry. A complete or partial response was obtained in all cases with the withdrawal of MTX. Our results suggests that the most common risk factor for developing EBV-MCU is the use of immunosuppressive drugs. The most common site of onset is the oral mucosa, which may be attributed to the mode of EBV infection and the high incidence of chronic irritation of the oral mucosa. A small number of patients had been diagnosed with MTX-LPD, but we consider that these cases were EBV-MCU based on our study.

Human plasmacytoid dendritic cells regulate immune responses to Epstein-Barr virus (EBV) infection and delay EBV-related mortality in humanized NOD-SCID mice

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1043-1050 ◽  
Author(s):  
Wai Hon Lim ◽  
Svjetlana Kireta ◽  
Graeme Randolph Russ ◽  
Patrick Toby Hewlett Coates
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Median Survival ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Scid Mice ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV) is associated with posttransplant lymphoproliferative disease (PTLD), which is a leading cause of cancer death in recipients of transplants. We investigated the role of plasmacytoid dendritic cells (PDCs) in the development of EBV infection and the onset of lymphoproliferative disease (LPD) in humanized NOD-SCID mice and studied the effect of EBV on PDC function. NOD-SCID mice reconstituted with PDC-depleted peripheral blood mononuclear cells (PBMCs) from EBV IgG+ human donors had significantly enhanced mortality from disseminated EBV infection (median survival, 43 days) compared to PBMC-only mice (median survival, 72 days; log-rank P < .05). Mice reconstituted with PDC-enriched PBMCs challenged with EBV exhibited delayed mortality from EBV-LPD (median survival, 80 days) compared to PBMC-only mice challenged with EBV (median survival, 50 days; log-rank P < .05). EBV-stimulated pDCs produced interferon α (IFN-α) and promoted the activation of natural killer cells and IFN-γ–producing CD3+T cells. PDC activation of CD3+T cells in response to EBV stimulation was dependent on cell-to-cell contact, in part mediated by toll-like receptor 9 (TLR-9) signaling that was inhibited by chloroquine and TLR-9 inhibitory CpG. Thus, PDCs play an important role in anti-EBV cellular immune responses that may be targets for manipulation in novel strategies for the treatment of PTLD.

scholarly journals Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection

Blood ◽  
2020 ◽  
Vol 135 (9) ◽  
pp. 644-655 ◽  
Author(s):  
Stuart G. Tangye ◽  
Sylvain Latour
Keyword(s):  
Host Defense ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disease ◽  
Primary Immunodeficiencies ◽  
Inborn Errors ◽  
Barr Virus ◽  
Ebv Infection ◽  
Different Types ◽  
Epstein Barr ◽  
Global Population

Abstract Epstein-Barr virus (EBV) is an enigma; on one hand, it infects and persists in latent form in the vast majority of the global population, causing relatively benign disease in otherwise healthy individuals. On the other hand, EBV represents the first identified oncogenic virus, capable of causing ≥7 different types of malignancies, usually in immunocompromised individuals. Furthermore, some individuals with defined inborn errors of immunity exhibit extreme susceptibility to EBV-induced disease, developing severe and often fatal infectious mononucleosis, hemophagocytic lymphohistiocytosis, lymphoproliferative disease, and/or EBV+ B-cell lymphoma. Thus, host and pathogen have coevolved to enable viral persistence and survival with minimal collateral damage to the healthy host. However, acquired or genetic disruptions to host defense that tip the balance in favor of EBV can have catastrophic effects. The study of primary immunodeficiencies has provided opportunities to define nonredundant requirements for host defense against EBV infection. This has not only revealed mechanisms underlying EBV-induced disease in these primary immunodeficiencies but also identified molecules and pathways that could be targeted to enhance the efficacy of an EBV-specific vaccine or treat severe EBV infection and pathological consequences in immunodeficient hosts.

Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host

Blood ◽  
2004 ◽  
Vol 104 (5) ◽  
pp. 1482-1489 ◽  
Author(s):  
Pierre Rivailler ◽  
Angela Carville ◽  
Amitinder Kaur ◽  
Pasupuleti Rao ◽  
Carol Quink ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Rhesus Macaques ◽  
Humoral Response ◽  
Lymphoproliferative Disease ◽  
Barr Virus ◽  
Ebv Infection ◽  
Oral Inoculation ◽  
Epstein Barr ◽  
Intravenous Inoculation ◽  
Specific Humoral Response

Abstract To develop a model for Epstein-Barr virus (EBV) pathogenesis in immunosuppressed hosts, we studied experimental infections of immunocompetent versus SHIV 89.6P–infected, immunosuppressed rhesus macaques with the EBV-related rhesus lymphocryptovirus (LCV). Primary LCV infection after oral inoculation of 4 immunocompetent animals was characterized by an acute viremia and seroconversion followed by asymptomatic LCV persistence. Four immunosuppressed macaques infected orally with LCV failed to develop an LCV-specific humoral response and viremia was more pronounced, but there was no evidence of LCV-induced lymphoproliferative disease. A more aggressive primary challenge was administered by intravenous inoculation of 108 autologous, LCV-immortalized B cells in 4 additional immunosuppressed animals. Two animals with modest immunosuppression remained asymptomatic, and 1 of 2 severely immunosuppressed animals developed an aggressive, monoclonal LCV-positive lymphoma. These studies demonstrate the potential for lymphomagenesis in an experimental model system for EBV infection and underscore the strength and depth of immune control in limiting LCV-induced lymphoproliferative disease.

scholarly journals Lytic Induction Therapy for Epstein-Barr Virus-Positive B-Cell Lymphomas

2004 ◽  
Vol 78 (4) ◽  
pp. 1893-1902 ◽  
Author(s):  
Wen-hai Feng ◽  
Gregory Hong ◽  
Henri-Jacques Delecluse ◽  
Shannon C. Kenney
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Immediate Early ◽  
B Cell Lymphomas ◽  
Lymphoblastoid Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT A novel therapy for Epstein-Barr virus (EBV)-positive tumors involves the intentional induction of the lytic form of EBV infection combined with ganciclovir (GCV) treatment. Virally encoded kinases (thymidine kinase and BGLF4) which are expressed only during the lytic form of infection convert GCV (a nucleoside analogue) into its active, cytotoxic form. However, tightly latent EBV infection in B cells has made it difficult to identify drugs that can be used clinically to induce lytic viral infection in B-cell lymphomas. Here we demonstrate that gemcitabine and doxorubicin (but not 5-azacytidine, cis-platinum, or 5-fluorouracil) induce lytic EBV infection in EBV-transformed B cells in vitro and in vivo. Gemcitabine and doxorubicin both activated transcription from the promoters of the two viral immediate-early genes, BZLF1 and BRLF1, in EBV-negative B cells. This effect required the EGR-1 motif in the BRLF1 promoter and the CRE (ZII) and MEF-2D (ZI) binding sites in the BZLF1 promoter. GCV enhanced cell killing by gemcitabine or doxorubicin in lymphoblastoid cells transformed with wild-type EBV, but not in lymphoblastoid cells transformed by a mutant virus (with a deletion in the BZLF1 immediate-early gene) that is unable to enter the lytic form of infection. Most importantly, the combination of gemcitabine or doxorubicin and GCV was significantly more effective for the inhibition of EBV-driven lymphoproliferative disease in SCID mice than chemotherapy alone. In contrast, the combination of zidovudine and gemcitabine was no more effective than gemcitabine alone. These results suggest that the addition of GCV to either gemcitabine- or doxorubicin-containing chemotherapy regimens may enhance the therapeutic efficacy of these drugs for EBV-driven lymphoproliferative disease in patients.

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