scholarly journals Triple threat: pregnancy, SLE, EBV as potential triggers in secondary hemophagocytic lymphohistiocytosis

Author(s):  
Aiswarya Rajendran ◽  
Akil Adrian Sherif ◽  
Arun Divakar ◽  
Sandeep Surendran ◽  
Jyothi Visalakshy ◽  
...  

We present a case of hemophagocytic lymphocytosis (HLH) that occurred secondary to a combination of Epstein Barr virus (EBV) infection and systemic lupus erythematosus (SLE) in early pregnancy. A 29-years-old lady presented with complaints of fever, vomiting and loose stools. She underwent successful in-vitro fertilization (IVF) and embryo transfer 20 days prior to the onset of these symptoms. Her blood investigations revealed anemia, neutropenia, hyperferritinemia and hypertriglyceridemia, eventually resulting in a diagnosis of HLH further substantiated by bone marrow examination. Additional investigations revealed positive anti-dsDNA and EBV IgM antibodies amongst other findings, adding SLE and EBV to the diagnoses. They were considered potential triggers for HLH. However, the occurrence of these events following IVF poses the question of whether pregnancy played a role in the development of HLH. Our patient responded well to pulse steroid therapy and has had an uneventful course till date.

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
Author(s):  
Lisa Grossman ◽  
Chris Chang ◽  
Joanne Dai ◽  
Pavel A. Nikitin ◽  
Dereje D. Jima ◽  
...  

ABSTRACT Epstein-Barr virus (EBV) is a common human herpesvirus that establishes latency in B cells. While EBV infection is asymptomatic for most individuals, immune-suppressed individuals are at significantly higher risk of a form of EBV latent infection in which infected B cells are reactivated, grow unchecked, and generate lymphomas. This form of latency is modeled in the laboratory by infecting B cells from the blood of normal human donors in vitro. In this model, we identified a protein called CD226 that is induced by EBV but is not normally expressed on B cells. Rather, it is known to play a role in aggregation and survival signaling of non-B cells in the immune system. Cultures of EBV-infected cells adhere to one another in “clumps,” and while the proteins that are responsible for this cellular aggregation are not fully understood, we hypothesized that this form of cellular aggregation may provide a survival advantage. In this article, we characterize the mechanism by which EBV induces this protein and its expression on lymphoma tissue and cell lines and characterize EBV-infected cell lines in which CD226 has been knocked out. Epstein-Barr virus (EBV), an oncogenic herpesvirus, infects and transforms primary B cells into immortal lymphoblastoid cell lines (LCLs), providing a model for EBV-mediated tumorigenesis. EBV transformation stimulates robust homotypic aggregation, indicating that EBV induces molecules that mediate cell-cell adhesion. We report that EBV potently induced expression of the adhesion molecule CD226, which is not normally expressed on B cells. We found that early after infection of primary B cells, EBV promoted an increase in CD226 mRNA and protein expression. CD226 levels increased further from early proliferating EBV-positive B cells to LCLs. We found that CD226 expression on B cells was independent of B-cell activation as CpG DNA failed to induce CD226 to the extent of EBV infection. CD226 expression was high in EBV-infected B cells expressing the latency III growth program, but low in EBV-negative and EBV latency I-infected B-lymphoma cell lines. We validated this correlation by demonstrating that the latency III characteristic EBV NF-κB activator, latent membrane protein 1 (LMP1), was sufficient for CD226 upregulation and that CD226 was more highly expressed in lymphomas with increased NF-κB activity. Finally, we found that CD226 was not important for LCL steady-state growth, survival in response to apoptotic stress, homotypic aggregation, or adhesion to activated endothelial cells. These findings collectively suggest that EBV induces expression of a cell adhesion molecule on primary B cells that may play a role in the tumor microenvironment of EBV-associated B-cell malignancies or facilitate adhesion in the establishment of latency in vivo. IMPORTANCE Epstein-Barr virus (EBV) is a common human herpesvirus that establishes latency in B cells. While EBV infection is asymptomatic for most individuals, immune-suppressed individuals are at significantly higher risk of a form of EBV latent infection in which infected B cells are reactivated, grow unchecked, and generate lymphomas. This form of latency is modeled in the laboratory by infecting B cells from the blood of normal human donors in vitro. In this model, we identified a protein called CD226 that is induced by EBV but is not normally expressed on B cells. Rather, it is known to play a role in aggregation and survival signaling of non-B cells in the immune system. Cultures of EBV-infected cells adhere to one another in “clumps,” and while the proteins that are responsible for this cellular aggregation are not fully understood, we hypothesized that this form of cellular aggregation may provide a survival advantage. In this article, we characterize the mechanism by which EBV induces this protein and its expression on lymphoma tissue and cell lines and characterize EBV-infected cell lines in which CD226 has been knocked out.


Author(s):  
O. Abrahamovych ◽  
U. Abrahamovych ◽  
S. Guta ◽  
M. Farmaha ◽  
L. Kobak

Introduction. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by various manifestations and clinical course, many aspects of the etiology and pathogenesis of which remain unclear. Recently, the interest of researchers in studying the role of cytomegalovirus (CMV) and Epstein - Barr virus (EBV) has been growing in the occurrence and course of a number of human diseases due to their ability to affect almost all organs and systems of the body, causing the formation of latent, active or chronic infection, which can often cause temporary disability, disability or even death, however, for the patients with SLE, despite the possibility of approaching the difficult problem of diagnosis and treatment of this disease, this issue is given insufficient attention, as evidenced by isolated studies.The aim of the study. Detect cytomegalovirus and Epstein - Barr infection in patients with systemic lupus erythematosus and its dependence on gender and age of patients. Materials and methods of research. The study involved 120 patients (15 men (12.50%) and 105 women (87.50%) aged 18 to 69 years with SLE, who were in the rheumatology department of the Communal Non-Commercial Enterprise of the Lviv Regional Council "Lviv Regional Clinical Hospital" in 2014-2019. To diagnose CMV and EBV infection by enzyme-linked immunosorbent assay, antibodies of IgM and IgG to viruses were detected in blood serum, and viruses were detected by polymerase chain reaction. According to the results of virus detection, formed groups of the patients, namely: patients with active CMV infection, active EBV, active CMV and EBV, without active CMV and EBV. All patients with SLE included in the study were subsequently stratified by age according to the classification of the World Health Organization (2015), according to which the following age limits were determined: young age, middle-aged, elderly, senile. Statistical analysis was performed on a personal computer in MS Excel and Statistica 6.0 using descriptive statistics. The frequency of cases of active CMV and EBV infection was calculated mathematically by the binomial coefficient of I. Newton. Research results and their discussion. We found in the vast majority of patients with SLE (117 patients, 97.50%) increase in the titer of specific antibodies to CMV. Only in 3 patients (2.50%) the titer of antibodies to this virus was within normal limits. Analyzing the frequency of EBV infection in patients with SLE, we recorded an increase in the titer of specific antibodies to the virus in 119 patients (99.17%). Among the examined patients with SLE in all (100.00%) found an increase in the titer of antibodies to CMV and / or EBV, of which 97.50% - infected with CMV and 97.17% - infected with EBV. The active phase of CMV and / or EBV infection was detected in 54.17%, of which 23.33% - active CMV infection, 17.50% - active EBV infection and 12.50% - a combination of active CMV and EBV infection simultaneously, which indicates a high frequency of CMV and EBV infection in patients with SLE and reflects the urgency of the problem of diagnosing herpesvirus infection in them. We found that activeCMV, EBV infections and their combinations are present only in women (64 patients, which is 60.96% of the total number of women with SLE), of which 28 patients (26.67%) there was only active CMV infection, in 21 patients (20.00%) - only active EBV infection and in 15 patients (14.29%) – combination of active CMV and EBV infection. 41 women (39.05%) and all (100.00%) men were not found to have active CMV and EBV infection, which indicates that men at the time of the survey were significantly more likely to have this infection in the integration phase. The most frequently active EBV infection was detected in patients with SLE of young age (17 cases, 24.64%), and in middle-aged patients 3 cases (6.52%) were recorded, which indicates a significant (p <0.05) difference in the frequency of cases of active EBV infection in patients of both groups. Only 1 case (20.00%) of active EBV infection was detected in elderly patients. Conclusions. All patients with systemic lupus erythematosus are infected - 97.50% with cytomegalovirus and 97.17% with Epstein-Barr virus infection, that was confirmed by the increased titer of antibodies to them. Among the mentioned patients 53.33% of them had the active phase of infection (23.33% - cytomegalovirus infection in the replication phase, 17.50% - the Epstein- Barr virus infection in the replication phase and 12.50% - their combination). The prevalence of active viral infection in patients with systemic lupus erythematosus depends on gender (active cytomegalovirus, active Epstein-Barr virus infection and their combination are significantly more common in women) and age - they are probably more common in young patients.  


PEDIATRICS ◽  
1983 ◽  
Vol 71 (6) ◽  
pp. 964-967
Author(s):  
THOMAS J. BOWEN ◽  
RALPH J. WEDGWOOD ◽  
HANS D. OCHS ◽  
WERNER HENLE

In vivo and in vitro humoral and cellular immune responses were studied in a 2½-year-old girl immediately before, during, and after an asymptomatic infection with Epstein-Barr virus. During the acute EBV infection, the patient's peripheral blood mononuclear cells were deficient in immunoglobulin synthesis and suppressed the in vitro immunoglobulin synthesis of normal allogeneic cells. In vitro mitogen transformation of lymphocytes was reduced. In vivo antibody responses to the T cell-dependent antigens bacteriophage φX 174 and Keyhole limpet hemocyanin were markedly depressed. These studies suggest that suppressor cells induced during acute EBV infection not only suppress immunoglobulin synthesis in vitro, but also interfere with in vivo antibody synthesis.


1994 ◽  
Vol 180 (5) ◽  
pp. 1995-1998 ◽  
Author(s):  
K Ritter ◽  
R J Kühl ◽  
F Semrau ◽  
H Eiffert ◽  
H D Kratzin ◽  
...  

Antibodies directed against the autoantigen p26 were detected in sera from 32 patients with acute Epstein-Barr virus (EBV) infection and clinical symptoms of infectious mononucleosis. P26 has now been identified as the enzyme manganese superoxide dismutase (MnSOD) by comparison of the NH2-terminal amino acid sequence. Antibodies against MnSOD belong to the immunoglobulin class M. They are not detectable in sera of patients with other herpesvirus infections. In the 32 patients investigated, the rise and fall of the autoantibodies coincides with the clinical symptoms. In vitro, the autoantibodies were shown to inhibit the dismutation of superoxide radicals by blocking MnSOD. As presented in the discussion this effect may contribute to the pathogenesis of acute EBV infection.


2021 ◽  
Vol 17 (3) ◽  
pp. e1009419
Author(s):  
Makoto Ohashi ◽  
Mitchell Hayes ◽  
Kyle McChesney ◽  
Eric Johannsen

Epstein-Barr virus (EBV) infection is associated with the development of specific types of lymphoma and some epithelial cancers. EBV infection of resting B-lymphocytes in vitro drives them to proliferate as lymphoblastoid cell lines (LCLs) and serves as a model for studying EBV lymphomagenesis. EBV nuclear antigen 3C (EBNA3C) is one of the genes required for LCL growth and previous work has suggested that suppression of the CDKN2A encoded tumor suppressor p16INK4A and possibly p14ARF is central to EBNA3C’s role in this growth transformation. To directly assess whether loss of p16 and/or p14 was sufficient to explain EBNA3C growth effects, we used CRISPR/Cas9 to disrupt specific CDKN2A exons in EBV transformed LCLs. Disruption of p16 specific exon 1α and the p16/p14 shared exon 2 were each sufficient to restore growth in the absence of EBNA3C. Using EBNA3C conditional LCLs knocked out for either exon 1α or 2, we identified EBNA3C induced and repressed genes. By trans-complementing with EBNA3C mutants, we determined specific genes that require EBNA3C interaction with RBPJ or CtBP for their regulation. Unexpectedly, interaction with the CtBP repressor was required not only for repression, but also for EBNA3C induction of many host genes. Contrary to previously proposed models, we found that EBNA3C does not recruit CtBP to the promoters of these genes. Instead, our results suggest that CtBP is bound to these promoters in the absence of EBNA3C and that EBNA3C interaction with CtBP interferes with the repressive function of CtBP, leading to EBNA3C mediated upregulation.


1998 ◽  
Vol 72 (5) ◽  
pp. 4352-4363 ◽  
Author(s):  
Q. Y. Yao ◽  
D. S. G. Croom-Carter ◽  
R. J. Tierney ◽  
G. Habeshaw ◽  
J. T. Wilde ◽  
...  

ABSTRACT In apparent contrast to earlier work on Epstein-Barr virus (EBV) carriage in the general Caucasian population, in vitro virus isolations from human immunodeficiency virus (HIV)-positive male homosexual cohorts have shown frequent examples of multiple EBV infection and an overall prevalence of type 2 EBV strains exceeding 30%. Here we ask to what extent these findings might hold true in another T-cell-immunocompromised cohort, HIV-positive hemophilic patients. Resident EBV strains were rescued within lymphoblastoid cell lines derived from the blood and throat washings of 39 such individuals, using the same in vitro protocols of virus isolation as for the homosexual cohort. A mean of 19 independent cell lines was made per patient, and in each case the resident virus was characterized by PCR-based viral genomic analysis and by immunoblotting to reveal the viral “EBNAprint.” By these criteria a significant proportion (14 of 39) of the hemophilic cohort carried more than one EBV strain, suggesting that T-cell impairment does indeed sensitize virus carriers to reinfection with new strains of exogenously transmitted virus. However, the overall incidence of type 2 EBV infection was 10%, which is close to that observed in the earlier work with healthy carriers and substantially lower than that seen in HIV-positive homosexuals. We infer that type 2 EBV is relatively rare in the general Caucasian population but has become endemic in the homosexual community.


1977 ◽  
Vol 146 (2) ◽  
pp. 495-508 ◽  
Author(s):  
D A Thorley-Lawson ◽  
L Chess ◽  
J L Strominger

Studies have been performed on in vitro infection by Epstein-Barr virus (EBV) of subpopulations of human lymphocytes. B cells of adult peripheral or fetal cord blood transform with equal efficiency, whether assayed by DNA synthesis induction or by outgrowth of transformed lymphocytes. In contrast, unfractionated adult lymphocytes transform much less efficiently than those from fetal cord. Reconstitution experiments of different cell preparations indicated that this difference was due to a suppression of B-cell proliferation by adult Ig-negative lymphocytes which fetal Ig-negative lymphocytes were unable to perform. Separation of Ig-negative lymphocytes into various subpopulations revealed that the suppression was performed by T cells. Macrophages and null cells play little or no role in suppression. The relevance of this phenomenon to infection and recovery from EBV infection during and after infectious mononucleosis is discussed.


Blood ◽  
2000 ◽  
Vol 96 (2) ◽  
pp. 625-634 ◽  
Author(s):  
David H. Dreyfus ◽  
Masayuki Nagasawa ◽  
Colm A. Kelleher ◽  
Erwin W. Gelfand

Interaction between viral proteins and tumor suppressor p53 is a common mechanism of viral pathogenesis. The Epstein-Barr virus (EBV) BZLF-1 ORF-encoded ZEBRA protein (also denoted EB1, Z, Zta) binds to p53 in vitro and has been associated with the altered transcription of p53-regulated genes in B lymphocytes and epithelial cells. In this work, Jurkat T-lymphoblastoid cells that express ZEBRA were characterized by the use of transiently transfected p53 and p53 reporter genes. Stable expression of ZEBRA was associated with the activation of p53-dependent transcription and increased p53 dependent apoptotic cell death. In Jurkat cell lines, stably expressed ZEBRA protein was apparently localized to the cell cytoplasm, in contrast to the typical nuclear localization of this protein in other cell types. Previous studies have suggested that EBV infection of T lymphocytes may contribute to the malignant transformation of T cells and the increased replication of human immunodeficiency virus. Our observations suggest a mechanism through which ZEBRA protein expressed in human T lymphocytes could alter T-cell proliferation and apoptosis during EBV infection.


1998 ◽  
Vol 72 (11) ◽  
pp. 9150-9156 ◽  
Author(s):  
Jun Komano ◽  
Makoto Sugiura ◽  
Kenzo Takada

ABSTRACT In the present study, we established an in vitro system representing the Burkitt’s lymphoma (BL)-type Epstein-Barr virus (EBV) infection which is characterized by expression of EBV-determined nuclear antigen 1 (EBNA-1) and absence of EBNA-2 and latent membrane protein 1 (LMP1) expression. EBV-negative cell clones isolated from the EBV-positive BL line Akata were infected with an EBV recombinant carrying a selectable marker, and the following selection culture easily yielded EBV-infected clones. EBV-reinfected clones showed BL-type EBV expression and restored the capacity for growth on soft agar and tumorigenicity in SCID mice that were originally retained in parental EBV-positive Akata cells and lost in EBV-negative subclones. Moreover, it was found that EBV-positive cells were more resistant to apoptosis than were EBV-negative cells. EBV-infected cells expressed the bcl-2 protein, through which cells might become resistant to apoptosis, at a higher level than did uninfected cells. This is the first report that BL-type EBV infection confers apoptosis resistance even in the absence of expression of LMP1 and BHRF1, both of which are known to have an antiapoptotic function. Surprisingly, transfection of the EBNA-1 gene into EBV-negative Akata clones could not restore malignant phenotypes and apoptosis resistance, thus suggesting that EBNA-1 alone was not sufficient for conferring them. Our results suggest that the persistence of EBV in BL cells is required for the cells to be more malignant and apoptosis resistant, which underlines the oncogenic role of EBV in BL genesis.


Author(s):  
O. Abrahamovych ◽  
U. Abrahamovych ◽  
S. Guta ◽  
O. Synenkyi ◽  
V. Chemes

Actuality. The infection with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in the patients with systemic lupus erythematosus (SLE) is of particular interest to researchers. SLE is a chronic autoimmune disease of unknown etiology that is characterized by multisystemic lesions and is potentially life-threatening [1, 2, 3]. The severity of the problem is caused by the fact that active viral infection can change the manifestations of SLE, but these changes are not always specific, so primary care physicians have no reason to suspect active virus infection at the first stage of examination of SLE patients and prescribe expensive direct virological tests accordingly. It has not been definitively established yet which complaints are the most meaningful regarding the presence of active viral infection in patients with SLE.The purpose of the research was to study complaints in SLE patients with active cytomegalovirus and Epstein-Barr virus infection and determine their diagnostic value. Materials and methods. We randomly enrolled 120 SLE patients – 15 men (12.50%) and 105 women (87.50%) aged 18 to 69 years. All patients received treatment at the Rheumatology Department of Lviv Regional Clinical Hospital in 2014-2019. The diagnosis of SLE was established based on the diagnostic criteria of the American College of Rheumatologists (ACR, 1997). In addition, IgM and IgG antibodies to serum viruses were detected for the diagnosis of CMV and EBV infection. To confirm the presence of active viral infection, viruses were detected in media (CMV - urine, blood; EBV - oral mucosa, blood) by polymerase chain reaction, resulting in 28 patients with SLE (23.33%) detected active CMV infection, in 21 patients with SLE (17.50%) - active EBV infection and in 15 patients with SLE (12.5%) - a combination of active CMV and EBV infection. To achieve the purpose of the study, we identified three steps: the first step was to analyze complaints in patients with SLE with active CMV infection and determine their diagnostic value, the second - in the analysis of complaints in patients with SLE with active EBV infection and clarify their diagnostic values and the third - in the analysis of complaints in patients with SLE with a combination of active CMV and EBV infection and clarification of their diagnostic value. We identified three steps: the first step was to analyze complaints in patients with SLE with active CMV infection and determine their diagnostic value, the second - in the analysis of complaints in patients with SLE with active EBV infection and clarify their diagnostic values and the third - in the analysis of complaints in patients with SLE with a combination of active CMV and EBV infection and clarification of their diagnostic value.Statistical analysis was performed by calculating the chances of establishing the phase of CMV and EBV infection in patients with SLE, using a separate feature - a marker that can be detected during the initial examination of the patient. The probable probability of active infection was determined using indicators of sensitivity, specificity and accuracy [4]. The actual material was processed on a personal computer in MS Excel and SPSS on the basis of conjugation tables with calculation of diagnostic value indicators. The association between active infection and a particular patient complaint was considered to be confirmed when the coefficient of association exceeded 0.5 (or 0.3 for the coefficient of contingency). Research results. It was found that in patients with SLE the presence of active cytomegalovirus infection among the main complaints significantly more often indicate the presence of myalgias (coefficient of association 0.79) or fever (0.51), or chills of the extremities (0.51), or arthralgia (coefficient of contingent 0.31). The presence of active virus Epstein - Barr infections are significantly more often evidenced by the presence of myalgias (coefficient of contingent 0.31) or sleep disorders (coefficient of association 0.84), or mood swings (0.74), or fever (0.61), or the appearance of new rashes (0.53). On the presence of a combination of active cytomegalovirus and virus Epstein - Barr infections significantly more often indicate complaints of sleep disturbances (coefficient of association 0.97) or mood swings (0.83), or a feeling of dryness in the eyes (0.51), or fever (0.50). Conclusions. The presence of active cytomegalovirus infection in patients with systemic lupus erythematosus among the main complaints often indicates the presence of myalgias or fever, or chills of the extremities, or arthralgia, the presence of active virus Epstein - Barr infection - myalgia or sleep disturbances, or mood swings, or fever, or the appearance of new rashes, the presence of their combination - sleep disturbances or mood swings, or a feeling of dryness in the eyes, or fever, which can be used in the diagnostic algorithm. The established patterns of complaints allow us to reasonably suspect in patients with systemic lupus erythematosus the presence of active cytomegalovirus and Epstein-Barr virus infection, the final verification of which requires the use of direct serological tests.


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