scholarly journals What Plasma Level of Interferon-γ Indicates in Systemic Chronic Active Epstein-Barr Virus Infection

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4529-4529
Author(s):  
Yu Uemura ◽  
Mayumi Yoshimori ◽  
Ayaka Ohashi ◽  
Tsuneaki Hirakawa ◽  
Naomi Wada ◽  
...  
Keyword(s):  
Nk Cells ◽  
Research Funding ◽  
Interferon Γ ◽  
Statistical Correlation ◽  
Epstein Barr Virus Infection ◽  
Mrna Levels ◽  
Barr Virus ◽  
Infected Cells ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Background and Aim Systemic chronic active Epstein-Barr virus infection (sCAEBV) is an intractable and progressive disease of which the symptoms include persistent or recurrent inflammation and harboring EBV-infected clonally proliferating T- or NK-cells. 24% of sCAEBV patients progress to hemophagocytic lymphohistiocytosis (HLH), a life-threatening condition. (Blood Adv. 2020;4:p2918) The presence of HLH at hematopoietic stem cell transplantation is associated with poor survival in sCAEBV (BMT. 2016;15;p879). Interferon-γ (IFN-γ) plays pivotal roles in developing HLH, and antagonistic anti-IFN-γ antibody is effective against HLH (N Engl J Med 2020;382:p1811). In this study, we examined the plasma level of IFN-γ to investigate its impact on disease conditions of sCAEBV and its possibility as a therapeutic target. Methods sCAEBV was diagnosed based on following criteria which confirm with the definition of CAEBV in the WHO 2017 classification: (1) elevated EBV-DNA load in peripheral blood (PB) (>10 2.5 copies/μg DNA) (2) EBV infection of T- or NK-cells (see below) in the affected tissues or PB (3) systemic inflammatory symptoms persisting for more than three months (4) exclusion of other possible diagnoses: primary infection of EBV, autoimmune disease, congenital immunodeficiency, HIV, and other immunodeficiencies or underlying diseases with potential immunosuppression Patients who fulfilled all criteria (1) to (4) were diagnosed as sCAEBV. (Blood Adv. 2020;4(13):2918-2926.) We defined a patient's condition as active disease when presenting any of following persistent inflammation: fever, liver dysfunction, progressive skin lesions, vasculitis, or uveitis. The plasma concentration of IFN-γ was measured by high sensitivity cytokine beads assay. mRNA was measured by real-time RT-PCR using TaqMan ® system. Results We examined 18 sCAEBV patients (CD4 type n = 7, CD8 type n = 1, and CD56 type n = 10). Their IFN-γ plasma levels were significantly higher than those of healthy donors. The levels in sCAEBV patients with active disease were higher than those with inactive disease. The mRNA expression of IFN-γ was detected in EBV-infected cells of all patients. A patient whose plasma IFN-γ was extremely high harbored HLH with markedly high expression of the mRNA of IFN-γ in EBV-infected cells, but there was no statistical correlation between the plasma IFN-γ levels and the mRNA levels of EBV-infected cells. Discussion Our findings infer IFN-γ's role in the inflammation of sCAEBV. The mRNA expression of IFN-γ was detected in EBV-infected cells of all patients. We discovered earlier that STAT3, a responsible transcriptional factor for IFN-γ expression, is constitutively activated in EBV-infected T- or NK-cells of CAEBV (Oncotarget.2018; 9;31077). Thus, we suspected that IFN-γ is produced by EBV-infected cells. Meanwhile, there was no statistical correlation between the plasma IFN-γ levels and the mRNA levels of EBV-infected cells as a whole. The proliferation of non-infected immunocompetent cells, such as NK cells, CD8-positive T cells, macrophages, and histiocytes, are often detected in the lesions of CAEBV. These cells also possibly produce IFN-γ. sCAEBV patients accompanied by hemophagocytic lymphohistiocytosis (HLH) had significantly higher IFN-γ levels in the serum compared to those without HLH. There was a report on emapalumab's effect on primary HLH. We expect emapalumab, a human anti-IFN-γ, is effective to sCAEBV patients, particularly who is harboring HLH． Conclusion Plasma IFN-γ in sCAEBV indicates disease activity and potentially be a therapeutic target. Disclosures Arai: Abbvie GK: Honoraria; BMS: Honoraria; Chugai Pharmaceutical Co Ltd: Honoraria, Research Funding; Eisai Co Ltd: Research Funding; Abbott Japan LLC: Honoraria; Kyowa Kirin Co ltd: Honoraria, Research Funding; Ono Pharmaceutical Co ltd: Honoraria, Research Funding; Nippon Shinyaku Co Ltd: Honoraria, Research Funding; Otsuka Pharmaceutical Co ltd: Research Funding; Novartis Pharma KK: Honoraria; Takeda Pharmaceuticals Co Ltd: Honoraria, Research Funding; Shionogi & Co ltd: Research Funding; Asahi Kasei Pharma Corporation: Research Funding; Sanofi KK: Honoraria; Pfizer Japan Inc: Honoraria; Astellas Pharma Inc: Honoraria.

scholarly journals Tonsillar CD56brightNKG2A+ NK cells restrict primary Epstein-Barr virus infection in B cells via IFN-γ

Oncotarget ◽  
2016 ◽  
Vol 8 (4) ◽  
pp. 6130-6141 ◽  
Author(s):  
Aurelia Jud ◽  
Monika Kotur ◽  
Christoph Berger ◽  
Claudine Gysin ◽  
David Nadal ◽  
...  
Keyword(s):  
B Cells ◽  
Virus Infection ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr ◽  
Barr Virus Infection

Copies of Donor Killer Immunoglobulin-like Receptor Genes and Motifs Titrate Natural Killer (NK) Cells' Functional Response to Epstein - Barr Virus Infections and Influence the Risk of Developing Post-Transplant Lymphoproliferative Disease (PTLD) after Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 741-741
Author(s):  
Rehan Mujeeb Faridi ◽  
Taylor J Kemp ◽  
Poonam Dharmani ◽  
Victor A. Lewis ◽  
Noureddine Berka ◽  
...  
Keyword(s):  
Nk Cells ◽  
Functional Response ◽  
Epstein Barr Virus ◽  
Viral Infections ◽  
Nk Cell ◽  
Barr Virus ◽  
Infected Cells ◽  
Ifn Γ ◽  
Epstein Barr ◽  
Kir Gene

Abstract BACKGROUND: Recipientsof allogeneic HCT remain vulnerable to a heightened risk of reactivation of otherwise latent viral infections owing to a compromised immune system early after transplantation. Uncontrolled reactivation of Epstein-Barr virus (EBV) leading to post-transplant lymphoproliferative disorder (PTLD) is one of such major complications after T-cell depleted HCT. Recovering within weeks after transplantation and being first in line of defense against viral infections, natural killer (NK) cells are deemed important in the immunopathogenesis of EBV complications. Their role however remains elusive. NK cell responses are regulated by a series of activating and inhibitory cell surface receptors, central to which are the Killer Immunoglobulin-like Receptors (KIR). Through these receptors NK cells discriminate healthy cells from 'altered' self-cells by scaling the perturbations in HLA expression after viral transformation of the target cell. Here, we set out to determine whether and how KIR gene and motifs' content of HCT donors and/or recipients influences the development of PTLD after allo-HCT. STUDY DESIGN: Hypothesizing that diverse NK cell receptor repertoires can titrate NK cell functional responses to EBV infections/reactivation and can potentially modify the risk of developing PTLD, we determined the KIR gene repertoires of 356 HLA-matched donor-recipient pairs of first allo-HCT and 50 healthy donors through Next Generation Sequencing of the KIR locus on the Illumina MiSeq platform. Based on the presence/absence and number of copies of individual genes, the KIR genotypes were determined and classified into four common centromeric (cA01, cB01, cB02 and cB03) and two telomeric (tA01 and tB01) motifs along with their variants. PBMNCs from KIR typed healthy volunteers were stimulated with EBV-transformed target cells to enumerate NK cell response to EBV (degranulation and/or IFNγ production) as a function of KIR gene content and motifs' distribution using a multicolor flow cytometry-based assay. Effect of KIR gene profile on development of PTLD was analyzed using binomial competing risks regression statistics. Distribution of NK cell functional response across various KIR characterized groups was analyzed using Mann-Whitney U statistics. RESULTS: Donor telomeric A motifs (tA01, KIR3DL1+ve KIR2DS4+ve; KIR3DS1/2DS1+/-ve), strongly protected against PTLD (p=0.0001, SHR=0.17; Figure 1). An increased protection against PTLD with increasing number of tA01 was noted with at least one copy required for a significant protective effect (Figure 1B). Copy number analysis of tA01 gene contents yielded similar associations. Further, the number of EBV induced functional NK cell subsets were significantly higher in individuals with than without KIR genotypes containing tA01 motifs (Figure 2 A-C) and was found to be increasing with an increasing number of tA01 copies (Figure 2 A'-C'). There was no influence of recipients' KIR repertoire on the risk of developing PTLD CONCLUSIONS: NK cell responsiveness, a function of KIR gene repertoire has a profound effect on the development of PTLD. Appropriately characterized KIR gene profile based identification of HCT recipients at high risk of developing PTLD will enable closer monitoring of EBV DNAemia and facilitate prompt therapy. Figure 1. Donor KIR telomeric A motif (tA01) protects against the risk of developing PTLD (A). Presence of at least one copy of donor KIR tA01 motif confers significant protection from PTLD (B) Figure 1. Donor KIR telomeric A motif (tA01) protects against the risk of developing PTLD (A). Presence of at least one copy of donor KIR tA01 motif confers significant protection from PTLD (B) Figure 2. KIR telomeric A motifs (tA01) titrate NK cells' functional response to Epstein-Barr virus infected cells (A-C), with and increasing %functional NK cells and subsets (measures as expressing CD107a, IFN-γ, or both) are observed with increasing tA01 motifs' copies (A'-C') Figure 2. KIR telomeric A motifs (tA01) titrate NK cells' functional response to Epstein-Barr virus infected cells (A-C), with and increasing %functional NK cells and subsets (measures as expressing CD107a, IFN-γ, or both) are observed with increasing tA01 motifs' copies (A'-C') Disclosures No relevant conflicts of interest to declare.

scholarly journals Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection

2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Benjamin Fournier ◽  
David Boutboul ◽  
Julie Bruneau ◽  
Charline Miot ◽  
Cécile Boulanger ◽  
...  
Keyword(s):  
Native American ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Nk Cell ◽  
Rapid Identification ◽  
Effector Memory ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Infected Cells ◽  
Epstein Barr

Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.

Interferon-γ Prevents Apoptosis in Epstein-Barr Virus-Infected Natural Killer Cell Leukemia in an Autocrine Fashion

Blood ◽  
1999 ◽  
Vol 93 (10) ◽  
pp. 3494-3504 ◽  
Author(s):  
Shin-ichi Mizuno ◽  
Koichi Akashi ◽  
Koichi Ohshima ◽  
Hiromi Iwasaki ◽  
Toshihiro Miyamoto ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Cell Survival ◽  
Epstein Barr Virus ◽  
Killer Cell ◽  
Interferon Γ ◽  
Leukemia Cells ◽  
Cell Leukemia ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr

The significant function of cytokines includes maintenance of cell survival as well as induction of cell differentiation and/or proliferation. We demonstrate here that interferon-γ (IFN-γ) plays a role for progression of Epstein-Barr virus (EBV)-infected natural killer cell leukemia (NK leukemia) through maintaining cell survival. NK leukemia cells obtained from 7 patients had clonal episomal forms of EBV, indicating that the leukemic cells were of clonal origin. Although normal NK cells constitutively expressed Bcl-2, the EBV-infected NK leukemia cells lacked endogenous Bcl-2 expression and were hypersensitive to apoptosis in vitro. The addition of IFN-γ to the culture significantly inhibited their spontaneous apoptosis without inducing cell proliferation or upregulation of Bcl-2. The NK leukemia cells constitutively secreted IFN-γ, and the patients’ sera contained a high concentration of IFN-γ, levels that were high enough to prevent NK leukemia cells from apoptosis. Bcl-XL was not involved in the IFN-γ–induced NK leukemia cell survival. These data suggest that the acquisition of IFN-γ–mediated autocrine survival signals, other than Bcl-2 or BCL-XL, might be important for the development of EBV-infected NK leukemia.

scholarly journals CD137 Expression Is Induced by Epstein-Barr Virus Infection through LMP1 in T or NK Cells and Mediates Survival Promoting Signals

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e112564 ◽  
Author(s):  
Mayumi Yoshimori ◽  
Ken-Ichi Imadome ◽  
Honami Komatsu ◽  
Ludan Wang ◽  
Yasunori Saitoh ◽  
...  
Keyword(s):  
Virus Infection ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Epstein Barr ◽  
Barr Virus Infection

scholarly journals Tonsilar NK Cells Restrict B Cell Transformation by the Epstein-Barr Virus via IFN-γ

2008 ◽  
Vol 4 (2) ◽  
pp. e27 ◽  
Author(s):  
Till Strowig ◽  
Fabienne Brilot ◽  
Frida Arrey ◽  
Gwenola Bougras ◽  
Dolca Thomas ◽  
...  
Keyword(s):  
B Cell ◽  
Nk Cells ◽  
Epstein Barr Virus ◽  
Cell Transformation ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr

scholarly journals A Nationwide Survey on Chronic Active Epstein-Barr Virus Infection in Japan Based on New Diagnostic Criteria: Clinical Features and Treatment Strategies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1631-1631
Author(s):  
Ayako Arai ◽  
Ichiro Yonese ◽  
Chizuko Sakashita ◽  
Ken-Ichi Imadome ◽  
Tohru Kobayashi ◽  
...  
Keyword(s):  
Disease Activity ◽  
Nationwide Survey ◽  
Skin Lesions ◽  
Epstein Barr Virus Infection ◽  
Barr Virus ◽  
Infected Cells ◽  
Ebv Dna ◽  
Epstein Barr ◽  
Barr Virus Infection ◽  
Definition Of

Abstract Background and aims Chronic active Epstein-Barr virus infection (CAEBV) is classified into T- or NK-cell neoplasms in the new WHO classification revised in 2017. Allogeneic stem cell transplantation (allo-HSCT) has recently been reported to be an effective treatment for this disorder. Conversely, effects of chemotherapies on CAEBV have not yet been examined in a large number of patients. To clarify clinical features and the current state of chemotherapies for CAEBV under the new definition of the disease, we performed a nationwide survey in Japan. Methods Questionnaires were sent to all educational hospitals certified by the Japanese Society of Hematology and the Japanese Pediatric Society. Subjects were patients newly diagnosed with CAEBV between January 2003 and March 2016. CAEBV was diagnosed according to criteria suggested by the Research group of Measures against Intractable Diseases by Ministry of Health, Labour and Welfare of Japan in 2016: (1) elevated EBV DNA load in peripheral blood (PB) (>102.5 copies/μg DNA); (2) detection of EBV infection in T or NK cells from the affected tissues or PB; (3) systemic inflammatory symptoms (such as fever, lymphadenopathy, liver dysfunction, progressive skin lesions, vasculitis, and uveitis) persisting for >3 months; and (4) exclusion of other possible diagnoses, such as primary EBV infection, autoimmune disease, immunodeficiencies, and lymphomas. Patients who fulfilled (1)-(4) were diagnosed with CAEBV. These criteria were established based on those proposed by Okano et al.(Am J Hematol. 2005;80,p64) and Kimura et al.(Blood. 2012;119,p673) and were compatible with the definition of CAEBV described by WHO in 2017. The disease activity was defined according to the previous reports (Blood. 2012;119,p673 and BMT. 2016;51,p879) as follows: positive for fever, ALT level elevation, vasculitis, progressive skin lesions, or uveitis. Effects of treatments were evaluated as follows: partial response (PR), partial resolution of disease activity; complete response (CR), complete resolution of disease activity with EBV load in PB remaining high (>102.5 copies/μg DNA, which is the upper limit for healthy people); virological CR (vCR), CR with a significant decrease in the EBV DNA load in PB (<102.5 copies/μg DNA). Results Completed questionnaires were returned by 29 institutes and 100 patients were evaluated. They were 53 males and 47 females aged 1-78 (median, 21) years. Types of EBV-infected cells were as follows: CD4 (n = 25), CD8 (n = 13), and CD56 (n = 28). The 3-year overall survival (OS) from diagnosis was 58%. Because different outcomes have been reported between children and adults with CAEBV, we divided patients into three groups according to their onset ages: childhood onset (CO) with patients aged <9 years, adolescent- and adult-onset (AAO), and advanced age-onset (AO) with patients aged >45 years. Seventy-eight percent patients in the CO group were males. Conversely, 85% patients in the AO group were females. The 3-year OS from diagnosis in the CO, AAO, and AO groups were 83%, 57%, and 31%, respectively. The prognosis of CO of CAEBV was significantly better than that of AAO (p = 0.0151) and AO (p = 0.0034) of CAEBV. Spontaneous regression was not observed in patients with active disease. Main chemotherapies employed were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 patients and CHOP in 45 patients. The rate of CR + PR was as follows: cooling therapy, 57% and CHOP, 39%. Viral CR was not observed. Three-year OS from the start of treatment was 0% in patients treated with only chemotherapy (n = 20) and 69% in those who received allo-HSCT (n = 59). Conclusions Based on the difference in OS and increased prevalence of males in the CO group, it can be concluded that CO of CAEBV may be independent from AO and AAO of CAEBV. Chemotherapy alone is currently insufficient for eradicating infected cells and resolving CAEBV. The development of an effective treatment reagent is an urgent issue. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cytokine induction after Epstein-Barr virus infection of peripheral T-lymphocytes in vitro

2010 ◽  
Vol 4 (1) ◽  
pp. 69-77
Author(s):  
Putrada Ninla-aesong ◽  
Jintana Pradutkanchana ◽  
Kusumarn Noipha ◽  
Winyou Mitarnun
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Γ ◽  
Cell Infection ◽  
Barr Virus ◽  
Cytokine Induction ◽  
Tnf Α ◽  
Ifn Γ ◽  
Epstein Barr

Abstract Background: Although the presence of Epstein-Barr virus (EBV) in different T-cell malignancies has been widely reported, there is very few data available for EBV infection of normal T cells. This leads to the lack of knowledge on the early events after T cell infection. Objective: Investigate the early events occurring after normal human peripheral T-cells are infected with EBV in vitro. Methods: T-cells were treated with EBV in vitro. The expression of tumor necrosis factor- α (TNF-α) mRNA were determined using reverse-transcription (RT)-PCR, and the level of TNF-α and interferon- γ (IFN-γ) in the culture supernatant were measured using ELISA. The effect of virus inactivation on cytokine induction from T-cells was also determined. Results: At the beginning of T cell infection by EBV, the expression of several lytic EBV transcripts (BALF5, BcLF1, and BLLF1) were observed using RT-PCR. This indicated the susceptibility of in vitro EBV infection and the entering lytic cycle of EBV-infected T-cells. The interactions of EBV with T-cells lead to induction of inflammatory cytokines, tumour necrosis factor- α (TNF-α) and interferon- γ (IFN-γ), production from the T-cells. Inactivation of the virus by UV irradiation eliminated the TNF-α and IFN-γ induction by EBV, suggesting the involvement in the expression of viral gene(s). Conclusion: This in vitro analysis demonstrated the cytokine induction by EBV after primary infection of T-cells.

scholarly journals Regulation of IL-27 p28 gene expression in macrophages through MyD88- and interferon-γ–mediated pathways

2007 ◽  
Vol 204 (1) ◽  
pp. 141-152 ◽  
Author(s):  
Jianguo Liu ◽  
Xiuqin Guan ◽  
Xiaojing Ma
Keyword(s):  
Transcription Initiation ◽  
Gene Promoter ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Barr Virus ◽  
Ifn Γ ◽  
Epstein Barr ◽  
Activated Monocytes ◽  
Myeloid Differentiation Factor

Interleukin (IL)-27 is the newest member of the IL-12 family of heterodimeric cytokines composed of the Epstein-Barr virus–induced gene 3 and p28 chains. IL-27 not only plays an important role in the regulation of differentiation of naive T helper cells but also possesses antiinflammatory properties. IL-27 is an early product of activated monocytes/macrophages and dendritic cells. However, the mechanisms whereby inflammatory signals stimulate IL-27 production have not been explored. In this study, we investigated the transcriptional regulation of the mouse IL-27 p28 gene in macrophages in response to lipopolysaccharide (LPS) and interferon (IFN)-γ. We found that LPS-stimulated p28 production was completely dependent on the Toll-like receptor 4/myeloid differentiation factor 88 (MyD88)–mediated pathway but only partially dependent on nuclear factor κB c-Rel. IFN-γ–induced p28 production/secretion was also partially dependent on MyD88 but independent of c-Rel. We then cloned the mouse p28 gene promoter and mapped its multiple transcription initiation sites. Furthermore, we identified critical promoter elements that mediate the inductive effects of LPS and IFN-γ, separately and synergistically, on p28 gene transcription in a c-Rel– and interferon regulatory factor 1–dependent manner, respectively.

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