Quantitative cytokine level of TNF-α, IFN-γ, IL-10, TGF-β and circulating Epstein-Barr virus DNA load in individuals with acute Malaria due to P. falciparum or P. vivax or double infection in a Malaria endemic region in Indonesia

Plasmodium falciparum Malaria and Epstein-Barr Virus (EBV) infection are risk factors in the development of Burkitt’s lymphoma. In Indonesia, 100% of the population is persistently infected with EBV early in life and at risk of developing EBV-linked cancers. Currently, 10.7 million people in Indonesia are living in Malaria-endemic areas. This cross-sectional study was initiated to investigate how acute Malaria dysregulates immune control over latent EBV infection. Using blood and plasma samples of 68 patients with acute Malaria and 27 healthy controls, we measured the level of parasitemia for each plasmodium type (P. falciparum, P. vivax, and mixed) by microscopy and rapid test. The level of 4 regulatory cytokines was determined by quantitative ELISA and the level of circulating EBV genome by real-time PCR targeting the single copy EBNA-1 sequence. All Plasmodium-infected cases had high-level parasitemia (>1000 parasites/ul blood) except for one case. EBV-DNA levels were significantly more elevated in P. falciparum and P. vivax infections (P<0.05) compared to controls. EBV-DNA levels were not related to age, gender, Malaria symptoms, or plasmodium type. TNF-α and IL-10 levels were increased in Malaria cases versus controls, but IFN-γ and TGF- β levels were comparable between the groups. Only TNF-α levels in P. falciparum cases showed a clear correlation with elevated EBV DNA levels (R2 = 0.8915). This is the first study addressing the relation between EBV (re)activation and cytokine responses during acute Malaria, revealing a clear correlation between pro-inflammatory cytokine TNF-α and EBV-DNA levels, specifically in P. falciparum cases, suggesting this cytokine to be key in dysregulating EBV homeostasis during acute P. falciparum Malaria.

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Cytokine Gene Polymorphisms and Epstein-Barr Virus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.3125.3125 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3125-3125

Author(s):

Ren Lin ◽

Zhiping Fan ◽

Ke Zhao ◽

Qianli Jiang ◽

Jing Sun ◽

...

Keyword(s):

Epstein Barr Virus ◽

Post Transplant ◽

Barr Virus ◽

Ebv Infection ◽

Associated Diseases ◽

Tnf Α ◽

Cytokine Gene Polymorphisms ◽

Ifn Γ ◽

Epstein Barr ◽

Tgf Β1

Abstract Backgroud: Epstein-Barr virus (EBV) infection/reactivation and associated diseases remain common complications in recipients of HSCT, leading to severe end-organ diseases and malignance. Single nucleotide polymorphism (SNP) in cytokine genes is considered to be related with EBV-associated post-transplant lymphoproliferative disorders (PTLD) in solid-organ transplantation recipients. In this study, we analyzed the association between cytokine gene polymorphisms and EBV infection/reactivation or diseases in recipients undergoing allo-HSCT. Methods: A total of 233 patients who received allo-HSCT between March 2012 to December 2014 were enrolled in this study. Ten SNPs, including IL-1β -511 rs16944, IL-1RN +11100 rs315952, IL-2 -330 rs2069762, IL-4 -590 rs2243250, IL-10 -592 rs1800872, IL-12 +1188 rs3212227, TNF-α -308 rs1800629, TGF-β1-509 rs1800469, TGF-β1 +869 rs1800470, IFN-γ +874 rs2430561, were tested. The SNPs genotypes in patients with or without EBV infection/reactivation and associated diseases were compared. Besides, the risk factors for EBV infection/reactivation were studied. Results: Seventy-four patients developed EBV infection/reactivation. The patients with EBV infection/reactivation had higher frequencies of donor IL-1β -511 TT genotype, donor IL-4 -590 TT genotype and recipient TNF-α -308 GG genotype than those without (p=0.021, p=0.004, p=0.020, respectively) while the frequencies of donor IL-1β -511 CC genotype, donor IL-1RN +11100 TT genotype, donor IL-2 -330 TT genotype, donor IL-4 -590 CC genotype and recipient TNF-α-308 GA genotype in patients with EBV infection/reactivation were lower than those without (p=0.041, p=0.029, p=0.005, p=0.011, p=0.042, respectively). Multivariate analysis showed donor IL-4 -590TT genotype (p=0.016, HR=1.907, 95% CI =1.130-3.218) and recipient TNF-α -308GG genotype (p=0.002, HR=3.550, 95% CI=1.613-7.812) were risk factors for post-transplant EBV infection/reactivation while donor IL-1RN +11100TT genotype (p=0.001, HR=0.382, 95% CI=0.218-0.670) was protective factors for post-transplant EBV infection/reactivation. Twenty-one patients developed EBV-associated diseases. The patients who developed EBV-associated diseases had higher frequency of donor IFN-γ +874 AT genotype than those did not (p=0.027). On the contrary, the frequencies of donor IL-1β-511 CC genotype, donor IL-10 -592 AA genotype, donor IL-12 +1188 AA genotype and donor IFN-γ +874 AA genotype in patients with EBV-associated diseases were lower than those without (p=0.019, p=0.018, p=0.018, p=0.010, respectively). Conclusion: Several SNPs in cytokine genes might be associated with EBV infection/reactivation and the development of EBV-associated diseases in recipients of allo-HSCT. However, these association should be studied further. Disclosures No relevant conflicts of interest to declare.

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Epstein-Barr Virus BZLF1-Mediated Downregulation of Proinflammatory Factors Is Essential for Optimal Lytic Viral Replication

Journal of Virology ◽

10.1128/jvi.01921-15 ◽

2015 ◽

Vol 90 (2) ◽

pp. 887-903 ◽

Cited By ~ 6

Author(s):

Yuqing Li ◽

Xubing Long ◽

Lu Huang ◽

Mengtian Yang ◽

Yan Yuan ◽

...

Keyword(s):

Viral Replication ◽

Epstein Barr Virus ◽

Lytic Cycle ◽

Inflammatory Factors ◽

Barr Virus ◽

Ebv Infection ◽

Tnf Α ◽

Ifn Γ ◽

Epstein Barr ◽

Proinflammatory Factors

ABSTRACTElevated secretion of inflammatory factors is associated with latent Epstein-Barr virus (EBV) infection and the pathology of EBV-associated diseases; however, knowledge of the inflammatory response and its biological significance during the lytic EBV cycle remains elusive. Here, we demonstrate that the immediate early transcriptional activator BZLF1 suppresses the proinflammatory factor tumor necrosis factor alpha (TNF-α) by binding to the promoter of TNF-α and preventing NF-κB activation. A BZLF1Δ207-210 mutant with a deletion of 4 amino acids (aa) in the protein-protein binding domain was not able to inhibit the proinflammatory factors TNF-α and gamma interferon (IFN-γ) and reduced viral DNA replication with complete transcriptional activity during EBV lytic gene expression. TNF-α depletion restored the viral replication mediated by BZLF1Δ207-210. Furthermore, a combination of TNF-α- and IFN-γ-neutralizing antibodies recovered BZLF1Δ207-210-mediated viral replication, indicating that BZLF1 attenuates the antiviral response to aid optimal lytic replication primarily through the inhibition of TNF-α and IFN-γ secretion during the lytic cycle. These results suggest that EBV BZLF1 attenuates the proinflammatory responses to facilitate viral replication.IMPORTANCEThe proinflammatory response is an antiviral and anticancer strategy following the complex inflammatory phenotype. Latent Epstein-Barr virus (EBV) infection strongly correlates with an elevated secretion of inflammatory factors in a variety of severe diseases, while the inflammatory responses during the lytic EBV cycle have not been established. Here, we demonstrate that BZLF1 acts as a transcriptional suppressor of the inflammatory factors TNF-α and IFN-γ and confirm that BZLF1-facilitated escape from the TNF-α and IFN-γ response during the EBV lytic life cycle is required for optimal viral replication. This finding implies that the EBV lytic cycle employs a distinct strategy to evade the antiviral inflammatory response.

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Clinical Warning of Hemophagocytic Syndrome Caused by Epstein-barr Virus

10.21203/rs.3.rs-47979/v1 ◽

2020 ◽

Author(s):

Jinjin Shi ◽

Chu Chu ◽

Min Yu ◽

Dandan Zhang ◽

Yuqin Li ◽

...

Keyword(s):

Laboratory Tests ◽

Epstein Barr Virus ◽

Hemophagocytic Syndrome ◽

Clinical Manifestations ◽

Prognostic Indicator ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Dna ◽

Epstein Barr ◽

D Dimer

Abstract Objectives This study aimed to compare the clinical features and laboratory tests of infectious mononucleosis (IM) and hemophagocytic syndrome (HLH) caused by Epstein-Barr virus (EBV) in 1-3-year-old children and to explore the risk factor of HLH caused by EBV (EBV-HLH). Methods The clinical data of 92 children with EBV infection admitted in our hospital from 2011 to 2019 were collected; 61 cases were diagnosed as EBV-IM, and 31 cases were diagnosed as EBV-HLH. The subjects’ clinical manifestations and laboratory tests were analyzed retrospectively. Results Compared with EBV-IM patients, EBV-HLH patients had longer durations of fever, both before hospitalization and overall, and a higher probability of hepatomegaly. The levels of ALT, AST, LDH, TG, SF, D-Dimer and the plasma EBV DNA load of EBV-HLH patients were significantly higher than those of EBV-IM patients. The absolute values of CD3+, CD4+, CD8+, NK, and CD3-CD19+ cells and IgA and IgM levels of EBV-HLH patients were significantly lower than those of EBV-IM patients. The plasma EBV DNA load was positively correlated with the PT, TT, α-HBDH, AST, LDH, CK, Scr, BUN, UA, TG, and CRP levels in EBV-HLH patients, and the plasma EBV DNA load was positively correlated with the D-Dimer level in the EBV-IM patients. Among the 10 different potential markers, at the cut-off point of 1721.500 µg/L, the sensitivity and specificity of D-Dimer was 88.90% and 90.20%, respectively. Conclusion The D-Dimer level may be a good prognostic indicator of EBV-HLH caused by EBV.

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Link of Nasopharyngeal Carcinoma and Epstein-Barr Virus

Biology Medicine & Natural Product Chemistry ◽

10.14421/biomedich.2018.72.51-55 ◽

2018 ◽

Vol 7 (2) ◽

pp. 51-55

Author(s):

Sugiyanto Sugiyanto ◽

Lina Aryati ◽

Fajar Adi Kusumo ◽

Mardiah Suci Hardianti

Keyword(s):

Nasopharyngeal Carcinoma ◽

Epstein Barr Virus ◽

Carcinoma Cells ◽

Lymphoid Cells ◽

Epithelial Tissue ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Dna ◽

Epstein Barr ◽

Basic Level

Nasopharyngeal Carcinoma (NPC) is a cancer that occurs in nasopharynx which is associated with Epstein-Barr Virus (EBV). Mutation agents in nasopharyngeal neoplasms occur because of EBV infection. Transformation of B-cells due to EBV causes hormone imbalance in lymphoid cells or nasopharyngeal epithelial tissue. Rates of EBV infection have been shown to be prognostic to NPC. The basic level of EBV DNA can be used for stratification prognosis, with higher titers showing greater disease severity and worse outcomes. With mathematical models, there is a correlation between the increase in Epstein-Barr Virus and the increase in Invasive Carcinoma Cells or increase in Nasopharyngeal Carcinoma Cells.

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Increasing Epstein-Barr virus infection in Chinese children: A single institutional based retrospective study.

F1000Research ◽

10.12688/f1000research.15544.1 ◽

2018 ◽

Vol 7 ◽

pp. 1211 ◽

Cited By ~ 1

Author(s):

Kiran Devkota ◽

Maio He ◽

Meng Yi Liu ◽

Yan Li ◽

You Wei Zhang

Keyword(s):

Retrospective Study ◽

High Risk ◽

Virus Infection ◽

Epstein Barr Virus ◽

Severe Illness ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Dna ◽

Epstein Barr

The Epstein-Barr virus (EBV) is a common virus in humans and the most common causative agent of Infectious Mononucleosis. EBV primary infection has recently risen in some countries and children below 2 years of age are highly susceptible. The clinical manifestations in children with EB virus infection involve multiple systems, causing severe illness, meaning attention should be paid during diagnosis and treatment. Objective: This single institution based retrospective study was carried out with the aim of estimating the overall prevalence of EBV infection and identifying high-risk age group among children. Methods: This study include total 253 patients under 15 years of age found to be positive for EBV DNA by PCR who were admitted to the Pediatrics Department of Renmin Hospital,(Shiyan, China) during a 4-year period from 2014 to 2017. Patients were divided into three groups; 0-<4years, 4-<6years and 6-<15years. We then calculated the percentage and prevalence of EBV DNA-positive cases. Results: The yearly EBV prevalence rate was 4.99 per 1000 admissions in 2014, 6.97 per 1000 admissions in 2015, 10.42 per 1000 admissions in 2016, and 12.16 per 1000 admissions in 2017. Out of 253 EBV-positive cases, those under 4 years had the highest rate of EBV infection (74.7%). The rate drops to 11.06% in the 4-6 years group, and was 14.22% in the 6-15 years group. Those between 6 months and 1 year are those at the highest risk. Conclusion: The rate of hospital admission of children due to EBV infection is increasing day by day. Children under 4 years of age are highly susceptible to infection and children of age between 6 months and 1 year are the high-risk group for EBV infection.

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Clinical warning of hemophagocytic syndrome caused by Epstein-Barr virus

10.21203/rs.3.rs-47979/v3 ◽

2020 ◽

Author(s):

Jinjin Shi ◽

Chu Chu ◽

Min Yu ◽

Dandan Zhang ◽

Yuqin Li ◽

...

Keyword(s):

Laboratory Tests ◽

Epstein Barr Virus ◽

Hemophagocytic Syndrome ◽

Clinical Manifestations ◽

Prognostic Indicator ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Dna ◽

Epstein Barr ◽

D Dimer

Abstract Objectives: This study aimed to compare the clinical features and laboratory tests of infectious mononucleosis (IM) and hemophagocytic syndrome (HLH) caused by Epstein-Barr virus (EBV) in 1-3-year-old children and to explore the risk factor of HLH caused by EBV (EBV-HLH). Methods: The clinical data of 92 children with EBV infection admitted in our hospital from 2011 to 2019 were collected; 61 cases were diagnosed as EBV-IM, and 31 cases were diagnosed as EBV-HLH. The subjects’ clinical manifestations and laboratory tests were analyzed retrospectively. Results: Compared with EBV-IM patients, EBV-HLH patients had longer durations of fever, both before hospitalization and overall, and a higher probability of hepatomegaly. The levels of ALT, AST, LDH, TG, SF, D-Dimer and the plasma EBV DNA load of EBV-HLH patients were significantly higher than those of EBV-IM patients. The absolute values of CD3 + , CD4 + , CD8 + , NK, and CD3-CD19 + cells and IgA and IgM levels of EBV-HLH patients were significantly lower than those of EBV-IM patients. The plasma EBV DNA load was positively correlated with the PT, TT, α-HBDH, AST, LDH, CK, Scr, BUN, UA, TG, and CRP levels in EBV-HLH patients, and the plasma EBV DNA load was positively correlated with the D-Dimer level in the EBV-IM patients. Among the 10 different potential markers, at the cut-off point of 1721.500 µg/L, the sensitivity and specificity of D-Dimer was 88.90% and 90.20%, respectively. Conclusion: The D-Dimer level may be a good prognostic indicator of EBV-HLH caused by EBV.

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Epstein–Barr virus infection is associated with clinical characteristics and poor prognosis of multiple myeloma

Bioscience Reports ◽

10.1042/bsr20190284 ◽

2019 ◽

Vol 39 (10) ◽

Author(s):

Bing Xia ◽

Xi Wang ◽

Ruifang Yang ◽

Li Mengzhen ◽

Kunpeng Yang ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Characteristics ◽

Epstein Barr Virus ◽

High Expression ◽

Epstein Barr Virus Infection ◽

Dna Concentration ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Dna ◽

Epstein Barr

Abstract The aim of the present study was to evaluate the relationship of Epstein–Barr virus (EBV) infection and multiple myeloma (MM) and its impact on clinical characteristics and prognosis. Fresh peripheral blood mononuclear cells (PBMCs) from 139 MM patients who had been diagnosed and treated from January 2010 to May 2018 and 50 PBMC samples from healthy donors were obtained. PCR was carried out for detection of EBV-DNA. The results indicated a significantly higher EBV-DNA concentration among 139 MM patients compared with healthy controls (P<0.05). Correlation analysis showed that the expression of EBV-DNA was positively correlated with the serum free light chain ratio (sFLCR) and progressive disease (PD)/relapse (P<0.05). Especially, in EBV-DNA high-expression MM patients, EBV-DNA concentration for patients with sFLCR ≥100 was higher than that of patients with sFLCR <100. EBV-DNA concentration was higher in patients with disease PD/relapse than those without disease PD/relapse. In univariate analysis, the progress free survival (PFS) was inferior in MM patients with high expression of EBV-DNA, high lactate dehydrogenase (LDH), and high-risk according to mSMART and International Myeloma Working Group (IMWG), stage III according to R-ISS staging, extramedullary lesions, and genetic changes (P<0.05). However, in multivariate analysis, LDH, poor karyotype, R-ISS staging, and mSMART were independent prognostic factors for PFS. Taken together, our studies suggest that an association exists between EBV infection and clinical characteristics of MM patients, and EBV infection appears to have a slight impact on the prognosis of MM. However, the results require further validation in other independent prospective MM cohorts.

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Clinical and Biological Factors Associated With Early Epstein-Barr Virus Infection in Human Immunodeficiency Virus–Exposed Uninfected Infants in Eastern Uganda

Clinical Infectious Diseases ◽

10.1093/cid/ciaa161 ◽

2020 ◽

Author(s):

Ana Montoya-Ferrer ◽

Armen Sanosyan ◽

Alexis Fayd’herbe de Maudave ◽

Amandine Pisoni ◽

Karine Bollore ◽

...

Keyword(s):

Breast Milk ◽

Epstein Barr Virus ◽

First Year ◽

Maternal Factors ◽

Factors Associated ◽

Barr Virus ◽

Ebv Infection ◽

Ebv Dna ◽

Epstein Barr ◽

Exposed Uninfected

Abstract Background Immune control of Epstein-Barr virus (EBV) infection is impaired in individuals with HIV. We explored maternal factors associated with EBV acquisition in HIV-exposed uninfected (HEU) infants and the relationship between EBV infection and serious adverse events (SAEs) during the first year of life. Methods 201 HEU infants from Uganda enrolled in the ANRS 12174 trial were tested for antiviral capsid antigen (anti-VCA) antibodies at week 50. Date of infection was estimated by testing EBV DNA at weeks 1, 6, 14, 26, 38, and 50 postpartum on dried blood spots. Results Eighty-seven (43%) infants tested positive for anti-VCA IgG at week 50. Among the 59 infants positive for EBV DNA, 25% were infected within the first 26 weeks. Almost half (12%) were infected before week 14. Shedding of EBV in breast milk was associated with EBV DNA in maternal plasma (P = .009), HIV RNA detection (P = .039), and lower CD4 count (P = .001) and correlated with plasma EBV DNA levels (P = .002). EBV infant infection at week 50 was associated with shedding of EBV in breast milk (P = .009) and young maternal age (P = .029). Occurrence of a clinical SAE, including malaria and pneumonia, was associated with higher levels of EBV DNA in infants (P = .010). Conclusions By assessing EBV infection in HEU infants we observed that infection during the first year is determined by HIV and EBV maternal factors and that EBV DNA levels were higher among infants with clinical SAEs.

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Epstein-Barr Virus Infection In Recipient Of Allogeneic Hematopoietic Stem Cell Transplantation: The Role Of Cytomegalovirus

Blood ◽

10.1182/blood.v122.21.4555.4555 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4555-4555

Author(s):

Qifa Liu ◽

Ren Lin ◽

Can Liu ◽

Meiqing Wu ◽

Li Xuan ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Research Funding ◽

Epstein Barr Virus ◽

Hematopoietic Stem ◽

Barr Virus ◽

Ebv Infection ◽

Associated Diseases ◽

Ebv Dna ◽

Epstein Barr

Background Epstein-Barr virus (EBV) infection is a common complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), leading to fatal post-transplant lymphoproliferative disorders (PTLD) and other EBV-associated diseases. A few studies suggested that cytomegalovirus (CMV) might play a role in PTLD. In this study, the effect of CMV on EBV DNA-emia and EBV-associated diseases was evaluated in the recipients of allo-HSCT. Methods Three hundred and fifty-two patients undergoing allo-HSCT were enrolled in this prospective study between July 2008 and June 2013. The EBV-DNA and CMV-DNA levels in blood and secretion were monitored by quantitative real-time polymerase chain reaction (RQ-PCR) before and in different time points after transplantation. EBV and CMV DNA-emia were diagnosed when EBV-DNA or CMV-DNA in the blood was positive twice consecutively. Results During the follow-up period, 99 patients (28.1%) developed EBV DNA-emia and 41 (11.6%) developed EBV-associated diseases including 27 EBV-associated PTLD and 14 other EBV-associated diseases. One hundred and fifty-nine patients (45.2%) developed CMV DNA-emia and 10 (2.8%) developed CMV-associated diseases. Of the 99 patients who developed EBV DNA-emia, 56 had CMV DNA-emia before EBV DNA-emia, and the median time from occurrence of CMV DNA-emia to EBV DNA-emia and EBV-associated diseases were 15 (range, 0-269) days and 26 (range, 0-255) days, respectively. Six patients developed co-existing CMV DNA-emia at the time of EBV-associated diseases diagnosed. DNA-emia before EBV infection had positive correlation with EBV DNA-emia (r=0.14, p=0.007) and EBV-associated diseases (r=0.15, p=0.005), but both correlation coefficients were weak. There was a strong positive correlation between EBV DNA-emia and EBV-associated diseases (r=0.56, p<0.001). The patients with CMV DNA-emia had a higher risk for developing EBV infection than those without (OR 2.279, 95% conﬁdence interval [CI] 1.420-3.657, p=0.001). After EBV infection occurred, 15 patients developed CMV DNA-emia, including 4 developed CMV-associated diseases, at a median time of 33 days (range, 12-50 days). EBV infection was not related to CMV DNA-emia (p=0.87) or CMV associated diseases (p=0.27) occurring after EBV infection. Conclusion The results suggest that CMV may play a contributory role in the development of EBV DNA-emia and EBV-associated diseases. Disclosures: Liu: This work was supported by the National High Technology Research and Development Program of China (863 Program) (No. 2011AA020105), the National Public Health Grand Research Foundation (Grant No. 201202017).: Research Funding; This work was also supported by National Natural Science Foundation of China (Grant No.81000231, No.30971300, No.81270647), the Science and Technology Project of Guangdong Province of China (Grant No.2009A030200007).: Research Funding; This work was also supported by the Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding.

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Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome

Blood ◽

10.1182/blood-2005-04-1406 ◽

2005 ◽

Vol 106 (9) ◽

pp. 3090-3096 ◽

Cited By ~ 64

Author(s):

Huai-Chia Chuang ◽

Jong-Ding Lay ◽

Wen-Chuan Hsieh ◽

Hui-Ching Wang ◽

Yao Chang ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Epstein Barr Virus ◽

Cell Activation ◽

Hemophagocytic Syndrome ◽

Barr Virus ◽

Ebv Infection ◽

Ifn Γ ◽

Epstein Barr ◽

Th1 Cytokines

AbstractThe primary infection of Epstein-Barr virus (EBV) may result in fatal infectious mononucleosis or hemophagocytic syndrome (HPS) in 2 diseases; that is, X-linked lymphoproliferative disorder (XLP) and hemophagocytic lymphohistiocytosis (HLH). XLP is linked to mutations of the SAP/SH2D1A gene with dysregulated T-cell activation in response to EBV infection. Patients with sporadic HLH, however, usually have no mutation of the SAP/SH2D1A gene, and EBV latent membrane protein-1 (LMP1) can up-regulate Th1 cytokines in EBV-infected T cells. Since both diseases share common manifestations of HPS, it is important to clarify whether a cross-talk exists between signaling lymphocyte activation molecule (SLAM)–associated protein (SAP) and LMP1-mediated pathways to explain the common pathogenesis of HPS. In this study, no mutation of the SAP/SH2D1A gene at exon 2/3 was detected in 7 HLH cases. Interestingly, EBV LMP1 could transcriptionally inhibit the expression of SAP/SH2D1A and activate downstream molecules ERK and interferon-γ (IFN-γ). LMP1-mediated SAP/ERK/IFN-γ signals appear to act via the TNF receptor–associated factor (TRAF)2,5/nuclear factor κB (NF-κB) pathway, since dominantnegative TRAF2/5 and NF-κB inhibitor could rescue SAP expression and downregulate IFN-γ. Although HLH is genetically distinct from XLP, our data suggest that both diseases share a common signal pathway, through either the mutation or LMP1-mediated suppression of the SAP gene, leading to overt T-cell activation and enhanced Th1 cytokine secretion in response to EBV infection.

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