Epstein-Barr Virus Diseases Research Articles

EBNA-1 antibody and autoimmune rheumatic diseases: A Mendelian Randomization Study

BackgroundNumerous studies have investigated a possible correlation between Epstein-Barr virus (EBV) and autoimmune rheumatic diseases (ARDs). However, establishing a cause-and-effect relationship remains a challenging endeavor. This study employs Mendelian randomization to examine the impact of EBV nuclear antigen-1 antibody (EBNA-1) antibody levels on the susceptibility to nine distinct ARDs, including rheumatoid arthritis (RA), primary Sjogren's syndrome (PSS), systemic lupus erythematosus (SLE), undifferentiated reactive arthritis (UA), systemic sclerosis (SSc), adult-onset Still's disease (AOSD), psoriatic arthritis (PsA), dermatomyositis (DM), and ankylosing spondylitis (AS). MethodsThe researchers applied a two-sample Mendelian randomization approach, utilizing online data from separate cohorts of European descent. We drew upon data from GWAS related to EBNA-1 antibody levels and the nine autoimmune-related disorders. Our primary analyses predominantly relied on the Inverse Variance Weighted methodology, complemented by a range of sensitivity assessments. ResultsOur analysis revealed significant direct associations between EBNA-1 antibody levels and the risk of developing PSS (95 % CI: 0.44 to 0.85, p = 0.003), PsA (95 % CI: 0.36 to 0.99, p = 0.044), AS (95 % CI: 0.07 to 0.88, p = 0.031), and UA (95 % CI: 0.56 to 0.96, p = 0.025). These results remained consistent through comprehensive sensitivity analyses. However, no clear associations were found for the other specified conditions. ConclusionsOur findings provide compelling evidence that EBNA-1 antibody levels play a role in developing ARDs. These findings enhance our understanding of ARD pathogenesis and hold substantial promise for developing potential treatment strategies.

Inflammation and Epstein-Barr Virus at the Crossroads of Multiple Sclerosis and Post-Acute Sequelae of COVID-19 Infection.

Recent studies have strengthened the evidence for Epstein-Barr Virus (EBV) as an important contributing factor in the development of multiple sclerosis (MS). Chronic inflammation is a key feature of MS. EBV+ B cells can express cytokines and exosomes that promote inflammation, and EBV is known to be reactivated through the upregulation of cellular inflammasomes. Inflammation is a possible cause of the breakdown of the blood-brain barrier (BBB), which allows the infiltration of lymphocytes into the central nervous system. Once resident, EBV+ or EBV-specific B cells could both plausibly exacerbate MS plaques through continued inflammatory processes, EBV reactivation, T cell exhaustion, and/or molecular mimicry. Another virus, SARS-CoV-2, the cause of COVID-19, is known to elicit a strong inflammatory response in infected and immune cells. COVID-19 is also associated with EBV reactivation, particularly in severely ill patients. Following viral clearance, continued inflammation may be a contributor to post-acute sequelae of COVID-19 infection (PASC). Evidence of aberrant cytokine activation in patients with PASC supports this hypothesis. If unaddressed, long-term inflammation could put patients at risk for reactivation of EBV. Determining mechanisms by which viruses can cause inflammation and finding treatments for reducing that inflammation may help reduce the disease burden for patients suffering from PASC, MS, and EBV diseases.

Human genetic and immunological determinants of SARS-CoV-2 and Epstein-Barr virus diseases in childhood: Insightful contrasts.

There is growing evidence to suggest that severe disease in children infected with common viruses that are typically benign in other children can result from inborn errors of immunity or their phenocopies. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a cytolytic respiratory RNA virus, can lead to acute hypoxemic COVID-19 pneumonia in children with inborn errors of type I interferon (IFN) immunity or autoantibodies against IFNs. These patients do not appear to be prone to severe disease during infection with Epstein-Barr virus (EBV), a leukocyte-tropic DNA virus that can establish latency. By contrast, various forms of severe EBV disease, ranging from acute hemophagocytosis to chronic or long-term illnesses, such as agammaglobulinemia and lymphoma, can manifest in children with inborn errors disrupting specific molecular bridges involved in the control of EBV-infected B cells by cytotoxic T cells. The patients with these disorders do not seem to be prone to severe COVID-19 pneumonia. These experiments of nature reveal surprising levels of redundancy of two different arms of immunity, with type I IFN being essential for host defense against SARS-CoV-2 in respiratory epithelial cells, and certain surface molecules on cytotoxic T cells essential for host defense against EBV in B lymphocytes.

Infectious mononucleosis is associated with an increased incidence of Crohn's disease: results from a cohort study of 31 862 outpatients in Germany.

The pathogenesis of inflammatory bowel disease (IBD) has not been fully uncovered to date. Epstein-Barr-Virus (EBV) infection has recently been associated with the pathogenesis of multiple sclerosis, suggesting a general link between EBV and autoimmune diseases. However, data on an association between EBV and IBD have remained inconclusive. This study aims at evaluating an association between EBV and the development of IBD. This retrospective cohort study included 15 931 patients with and 15 931 matched patients without infectious mononucleosis from the Disease Analyzer database (IQVIA) between 2000 and 2018. Incidences of Crohn's disease and ulcerative colitis were evaluated using Cox regression models. Within 5 years of the index date, the cumulative incidence of IBD was 124 and 90 cases per 100 000 person-years among patients with and without infectious mononucleosis, respectively (P = 0.040). In regression analyses, infectious mononucleosis was significantly associated with IBD [hazard ratios (HR), 1.35; 95% confidence interval (CI), 1.01-1.81]. Subgroup analyses revealed an association between infectious mononucleosis and Crohn's disease (HR, 1.93; 95% CI, 1.22-3.05) but not ulcerative colitis (HR, 1.03; 95% CI, 0.70-1.51). This association was strongest in patients between 14 and 20 years (HR, 4.50; 95% CI, 1.55-13.13) and was only observed in females (HR, 2.51; 95% CI, 1.39-4.53). Infectious mononucleosis is significantly associated with an increased incidence of Crohn's disease but not ulcerative colitis, especially in young female patients. Our data support the hypothesis of a pathophysiological involvement of EBV in the development of Crohn's disease and should trigger molecular research to further dissect the pathophysiology of IBD.

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

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.

Epstein-Barr virus reactivation after allogeneic hematopoietic stem cell transplantation: multifactorial impact on transplant outcomes.

Epstein-Barr virus (EBV) reactivation after allogeneic hematopoietic cell transplantation (allo-HCT) is one of the major concerns that may lead to fatal EBV diseases. However, updated data are needed because of the remarkable evolution of the HCT protocol and donor selection. We conducted a retrospective study that enrolled 890 allo-HCT recipients. Independent risk factors for EBV reactivation were use of antithymocyte globulin, haploidentical donor, and the presence of chronic graft-versus-host disease. The cumulative incidence of EBV reactivation was 2.9%, 11.7%, 27.3%, and 41.9% for patients with 0, 1, 2, and 3 risk factors, respectively (P < 0.001). Posttransplant lymphoproliferative disorders (PTLDs) occurred in seven patients. EBV reactivation was associated with inferior survival in recipients who survived more than 2 years post-HCT (P < 0.001) but might time-dependently benefit those patients with malignancies by decreasing relapse incidence (P = 0.046). A decreased relapse incidence was observed 1 year after HCT for recipients at first or second remission (P = 0.042) and in the first year post-HCT for recipients with advanced diseases (P = 0.032). We concluded that with current management, PTLDs were efficiently controlled, but EBV reactivation still had a multifactorial impact on transplant outcomes. Multicenter prospective studies are warranted to validate these findings.

A novel vaccine candidate based on chimeric virus-like particle displaying multiple conserved epitope peptides induced neutralizing antibodies against EBV infection.

Rationale: Epstein-Barr virus (EBV) is the causative pathogen for infectious mononucleosis and many kinds of malignancies including several lymphomas such as Hodgkin's lymphoma, Burkitt's lymphoma and NK/T cell lymphoma as well as carcinomas such as nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBV-GC). However, to date no available prophylactic vaccine was launched to the market for clinical use.Methods: To develop a novel vaccine candidate to prevent EBV infection and diseases, we designed chimeric virus-like particles (VLPs) based on the hepatitis B core antigen (HBc149). Various VLPs were engineered to present combinations of three peptides derived from the receptor binding domain of EBV gp350. All the chimeric virus-like particles were injected into Balb/C mice for immunogenicity evaluation. Neutralizing titer of mice sera were detected using an in vitro cell model.Results: All chimeric HBc149 proteins self-assembled into VLPs with gp350 epitopes displayed on the surface of spherical particles. Interestingly, the different orders of the three epitopes in the chimeric proteins induced different immune responses in mice. Two constructs (149-3A and 149-3B) induced high serum titer against the receptor-binding domain of gp350. Most importantly, these two VLPs elicited neutralizing antibodies in immunized mice, which efficiently blocked EBV infection in cell culture. Competition analysis showed that sera from these mice contained antibodies to a major neutralizing epitope recognized by the strong neutralizing mAb 72A1.Conclusion: Our data demonstrate that HBc149 chimeric VLPs provide a valuable platform to present EBV gp350 antigens and offer a robust basis for the development of peptide-based candidate vaccines against EBV.

Reactivation and dynamics of cytomegalovirus and Epstein-Barr virus after rabbit antithymocyte globulin and cyclosporine for aplastic anemia.

This study aimed to identify the natural course of cytomegalovirus (CMV)/Epstein-Barr virus (EBV) after rabbit antithymocyte globulin and cyclosporine (rATG-CsA) for aplastic anemia (AA). In 113 prospectively observed AA patients treated with rATG-CsA, the CMV/EBV cohort was classified into two groups by baseline viremic status: no viremia (CMV-G1, n=112; EBV-G1, n=98) and the presence of viremia (CMV-G2, n=1; EBV-G2, n=13). In CMV-G1, the mean CMV load increased up to 3months but was completely resolved from 6months. The mean EBV load of EBV-G1 showed a peak at 1month and then gradually decreased over time but remained detectable throughout the observation period. EBV-G2 showed fluctuating EBV dynamics. With reactivation rates of 38.4% in CMV-G1 and 62.2% in EBV-G1, a longer time to rATG-CsA from diagnosis and a lower absolute lymphocyte count at 1month from rATG-CsA were significantly associated with CMV and EBV reactivation, respectively. The mean peak CMV and EBV loads of patients with CMV-related (3.5%) and EBV-related (0.9%) diseases were evidently higher than those of the remaining patients without CMV and EBV diseases in the respective cohort. Considering frequent reactivation and distinct courses of CMV/EBV, virologic surveillance is recommended after rATG-CsA for AA.

Is Epstein-Barr Virus Infection Associated With Thyroid Tumorigenesis?-A Southern China Cohort Study.

Background: Epstein-Barr virus (EBV) is associated with many epithelial malignancies. A few reports on the association between EBV and thyroid tumorigenesis have been investigated. However, the conclusion is highly contradictory. We aimed to explore the role of EBV in thyroid nodule development and its clinical significance in a cohort from southern China.Method: We conducted a retrospective data abstraction study of patients who underwent thyroidectomy between December 2017 and June 2018. We retrospectively analyzed the clinicopathological parameters and EBV infection status (serological antibodies and in situ hybridization).Result: The cohort comprised 384 patients with newly diagnosed thyroid diseases, including 261 papillary thyroid carcinomas, 87 nodular goiters, 21 follicular adenomas, 12 follicular thyroid carcinomas, and 3 medullary thyroid carcinomas. Forty-two (10.9%) patients were identified as being serological antibody positive. However, there was no association between the clinicopathological parameters and serological antibody positivity. Additionally, none of the patients showed EBER expression in thyroid normal/cancer cell nuclei in in situ hybridization.Conclusion: In this study, no correlation between EBV and thyroid diseases was found in a cohort from southern China.

The Epstein Barr virus circRNAome.

Our appreciation for the extent of Epstein Barr virus (EBV) transcriptome complexity continues to grow through findings of EBV encoded microRNAs, new long non-coding RNAs as well as the more recent discovery of over a hundred new polyadenylated lytic transcripts. Here we report an additional layer to the EBV transcriptome through the identification of a repertoire of latent and lytic viral circular RNAs. Utilizing RNase R-sequencing with cell models representing latency types I, II, and III, we identified EBV encoded circular RNAs expressed from the latency Cp promoter involving backsplicing from the W1 and W2 exons to the C1 exon, from the EBNA BamHI U fragment exon, and from the latency long non-coding RPMS1 locus. In addition, we identified circular RNAs expressed during reactivation including backsplicing from exon 8 to exon 2 of the LMP2 gene and a highly expressed circular RNA derived from intra-exonic backsplicing within the BHLF1 gene. While expression of most of these circular RNAs was found to depend on the EBV transcriptional program utilized and the transcription levels of the associated loci, expression of LMP2 exon 8 to exon 2 circular RNA was found to be cell model specific. Altogether we identified over 30 unique EBV circRNAs candidates and we validated and determined the structural features, expression profiles and nuclear/cytoplasmic distributions of several predominant and notable viral circRNAs. Further, we show that two of the EBV circular RNAs derived from the RPMS1 locus are detected in EBV positive clinical stomach cancer specimens. This study increases the known EBV latency and lytic transcriptome repertoires to include viral circular RNAs and it provides an essential foundation and resource for investigations into the functions and roles of this new class of EBV transcripts in EBV biology and diseases.

NK Cell Recognition of Peptides Encoded by EBV Latent Cycle Proteins

Introduction Epstein–Barr virus (EBV) infects more than 90% of adults worldwide and is associated with several malignancies, including post-transplant lymphoproliferative disorder (PTLD). Although EBV infection is typically asymptomatic in immune-competent individuals, transplant recipients, especially children, are highly susceptible to EBV-associated PTLD due to the immunosuppression treatment required to prevent graft rejection. Innate immune responses, including Natural Killer (NK) cells, are considered vital early in the infection process. Our group has recently demonstrated that a specific NK cell subset can recognize and respond to autologous B cells latently infected with EBV. This NK subset expresses NKG2A/CD94, an inhibitory receptor that recognizes HLA-E. Since EBV-infected cells induced NK cell activation despite the expression of HLA-E, we hypothesize that EBV encoded peptides play a pivotal role in the recognition and response of NKG2A+ NK cells towards latently infected EBV+ cells. Methods and Results Using in silico analysis (NetMHCpan 4.0) a peptide library derived from EBV latent cycle proteins (LMPs and EBNAs) was generated. Initial assessment resulted in a library of 61 peptides which could potentially bind to HLA-E. Then, using target cells, we performed a peptide stabilization assay in vitro to test the ability of individual peptides to be presented by HLA-E. We identified 37 peptides, expressed during the latency III stage of EBV infection that bound and induced HLA-E expression at the surface of the target cells. Functional assays, using CD107a as a readout for NK cell activity, demonstrated HLA-E bound EBV-derived peptides were able to inhibit NK cell activation (15 peptides), or prevent NK cell inhibition via the NKG2A receptor, resulting in NK cell activation (12 peptides). We determined that, in general, peptides encoded by LMPs tended to favor NK cell degranulation (NK cell killing) while peptides encoded by EBNAs were mostly inhibitory. Conclusions Our results demonstrate that EBV latent cycle proteins can encode for peptides that bind to HLA-E which have the ability to promote NK cell degranulation and therefore may be involved in the elimination of EBV latently infected B cells. As NK cells are less susceptible to immunosuppression, understanding NK cell interactions with EBV-infected cells will lead to improvements in therapeutic strategies to control EBV diseases post-transplant. Stanford Transplantation and Tissue engineering center of Excellence (TTE) Fellowship.

Immunization With Fc-Based Recombinant Epstein-Barr Virus gp350 Elicits Potent Neutralizing Humoral Immune Response in a BALB/c Mice Model.

Epstein–Barr virus (EBV) was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B-lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers; however, the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe, and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here, we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared with wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody (nAb) and binding to its receptor by enzyme-linked immunosorbent assay and surface plasmon resonance. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared with gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent nAbs against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications.

THE ASSOCIATION OF EPSTEIN-BARR VIRUS ANTIBODIES WITH RHEUMATOID ARTHRITIS AMONG YEMENI PATIENTS IN SANA’A CITY

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with progressive disability, systemic complications and early death. Etiology of RA is unknown. It is assumed that environmental factors initiate RA development in genetically susceptible individuals. Epstein- Barr Virus (EBV) stimulates polyclonal B cell activation and has been suggested to play a role in RA pathogenesis. Current study aimed to study the association between EBV and RA. Methods: One hundred and sixty subjects were enrolled in the study. Eighty individuals were clinically diagnosed to have RA and confirmed by anti-CCP3 test. The remaining 80 individuals were healthy controls matched for age and sex. Serum IgG and IgM antibodies against EBV viral capsid antigen (VCA) were tested by an enzyme-linked immunosorbent assay (ELISA). Results: The crude prevalence rate of EBV-VCA IgM antibodies among patients was (21.2%) while in healthy individuals was (8.7%) with significant OR equals to 2.8 times for RA patient's. The female prevalence rate of EBV-VCA IgM antibodies was (21.8%) higher than of male (18.7%). The female prevalence rate of EBV-VCA IgG antibodies was (95.3%) higher than of male (75%). EBV-VCA IgG and IgM antibodies titers were elevated in RA patients than in healthy controls. However, the causative relationship between EBV and RA is complex and involves different mechanisms. Conclusion: In conclusion, high titers of EBV antibodies are associated with RA. However, the causative relationship between EBV and autoimmune diseases is complex and involves different mechanisms. Peer Review History: Received 16 August; Revised 28 August; Accepted 5 September, Available online 15 September 2017 Academic Editor: Dr. Amany Mohamed Alboghdadly, Princess Nourah bint abdulrahman university, Riyadh, amalbgadley@pnu.edu.sa UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.5/10 Average Peer review marks at publication stage: 8.0/10 Reviewer(s) detail: Dr. Mujde Eryilmaz, Ankara University,Turkey, meryilmaz@ankara.edu.tr Dr. Tamer Elhabibi, Suez Canal University, Egypt, tamer_hassan@pharm.suez.edu.eg Similar Articles: SEROPREVALENCE OF ANTI-MANNOSE BINDING LECTIN AUTOANTIBODIES IN PATIENTS WITH RHEUMATOID ARTHRITIS IN SANA'A CITY- YEMEN

Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers.

Most patients infected with Epstein-Barr virus (EBV) are asymptomatic, have nonspecific symptoms, or have self-limiting infectious mononucleosis. EBV, however, may result in severe primary disease or cancer. We report EBV diseases associated with GATA2 deficiency at one institution and describe the hematology, virology, and cytokine findings. Seven patients with GATA2 deficiency developed severe EBV disease. Three presented with EBV infectious mononucleosis requiring hospitalization, 1 had chronic active EBV disease (B-cell type), 1 had EBV-associated hydroa vacciniforme-like lymphoma with hemophagocytic lymphohistiocytosis, and 2 had EBV-positive smooth muscle tumors. Four of the 7 patients had severe warts and 3 had disseminated nontuberculous mycobacterial infections. All of the patients had low numbers of monocytes, B cells, CD4 T cells, and natural killer cells. All had elevated levels of EBV in the blood; 2 of 3 patients tested had expression of the EBV major immediate-early gene in the blood indicative of active EBV lytic infection. Mean plasma levels of tumor necrosis factor α, interferon γ, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls. GATA2 is the first gene associated with EBV hydroa vacciniforme-like lymphoma. GATA2 deficiency should be considered in patients with severe primary EBV infection or EBV-associated cancer, especially in those with disseminated nontuberculous mycobacterial disease and warts.

THE MODERN CONCEPTIONS ABOUT IMMUNOPATHOGENESIS OF INFECTION CAUSED BY THE EPSTEIN–BARR VIRUS

Abstract. The current review summarizes modern data about structural and functional organization of the Epstein–Barr virus (EBV) and stages of its reproduction. The information concerning immune pathogenesis and clinical features of infection caused by EBV and EBV-associated diseases is presented in the article.

Epstein-Barr Virus (EBV) Infection in Chinese Children: A Retrospective Study of Age-Specific Prevalence

BackgroundEpstein-Barr Virus (EBV) is a globally prevalent herpesvirus associated with infectious mononucleosis and many malignancies. The survey on EBV prevalence appears to be important to study EBV-related diseases and determine when to administer prophylactic vaccine. The purpose of this retrospective study was to collect baseline information about the prevalence of EBV infection in Chinese children.Methodology/Principal FindingWe collected 1778 serum samples from healthy children aged 0 to 10, who were enrolled in conventional health and nutrition examinations without any EBV-related symptom in 2012 and 2013 in North China (n = 973) and South China (n = 805). We detected four EBV-specific antibodies, i.e., anti-VCA-IgG and IgM, anti-EBNA-IgG and anti-EA-IgG, by ELISA, representing all of the phases of EBV infection. The overall EBV seroprevalence in samples from North and South China were 80.78% and 79.38% respectively. The EBV seropositivity rates dropped slightly at age 2, and then increased gradually with age. The seroprevalence became stabilized at over 90% after age 8. In this study, the seroprevalence trends between North and South China showed no difference (P>0.05), and the trends of average antibody concentrations were similar as well (P>0.05).Conclusions/SignificanceEBV seroprevalence became more than 50% before age 3 in Chinese children, and exceed 90% after age 8. This study can be helpful to study the relationship between EBV and EBV-associated diseases, and supportive to EBV vaccine development and implementation.

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Epstein-Barr Virus in Systemic Lupus Erythematosus, Rheumatoid Arthritis and Multiple Sclerosis—Association and Causation

Epidemiological data suggest that the Epstein-Barr virus (EBV) is associated with several autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis. However, it is not clear whether EBV plays a role in the pathogenesis of these diseases, and if so, by which mechanisms the virus may contribute. In this review, we discuss possible viral and immunological mechanisms that might explain associations between EBV and autoimmune diseases and whether these associations represent causes or effects of inflammation and autoimmunity.

Opportunistic infections in myasthenia gravis treated with mycophenolate mofetil

Mycophenolate mofetil (MMF) is used for immunosuppression in myasthenia gravis (MG). Although there are numerous data on associated infection and prophylaxis in transplant patients who are on MMF, data in MG remains lacking. We report two elderly seropositive MG patients who developed cytomegalovirus (CMV) enteritis and Epstein–Barr virus (EBV) encephalitis while on MMF for 5months and 1year, respectively. Chronic MMF therapy in MG patients may trigger life-threatening infections including CMV and EBV diseases, especially in the elderly. Similar to the practice in transplant patients, viral serology testing and appropriate prophylactic regimen with antiviral agents should be considered, particularly in older MG patients.

A method for evaluating antiviral drug susceptibility of Epstein-Barr virus

correspondence: henry h Balfour Jr MMc 437, University of Minnesota Medical school, Minneapolis, Mn 55455-0392 UsA Tel 1 612 625 3998 Fax 1 612 626 1923 email balfo001@umn.edu Abstract: We developed an in vitro Epstein-Barr virus (EBV) drug susceptibility assay using P3HR1 cells or lymphoblastoid cells from subjects with infectious mononucleosis, which were grown in the presence of various concentrations of acyclovir (ACV), ganciclovir (GCV) or R-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) and 12-O-tetradecanoyl-phorbol-13acetate (TPA). On day 7, total cellular DNA was extracted and EBV DNA was detected using an in-house quantitative real-time polymerase chain reaction (PCR) method. All three drugs had in vitro activity against EBV in both the laboratory standard producer cell line P3HR1 and in subject-derived lymphoblastoid cell lines. The median 50% inhibitory concentrations (IC 50 s) in P3HR1 cells were: ACV, 3.4 μM; GCV, 2.6 μM; and H2G, 2.7 μM and in 3 subject-derived cells were: ACV, 2.5 μM; GCV, 1.7 μM; and H2G, 1.9 μM. Our assay can be used to screen candidate anti-EBV drugs. Because we can measure the IC 50 of patients’ strains of EBV, this assay may also be useful for monitoring viral resistance especially in immunocompomised hosts receiving antiviral drugs for prevention or treatment of EBV diseases.