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Epstein Barr virus latent membrane protein 1 (LMP1) induces NK-[kappa]B activation through transformation effector sites (TES) 1 and 2, both of which are critical for B-lymphocyte transformation. TES2 principally activates canonical NK-[kappa]B, which we confirm is NK-[kappa]B essential modifier (NEMO)-dependent and requires an intact ubiquitin binding in A20 binding inhibitor of NK-[kappa]B and NEMO (UBAN) domain. LMP1 TES2 activated NK-[kappa]B in Jurkat cell lines harboring NEMO truncated at 372 (A45) or NEMO with an in-frame deletion of 133-224 (2C), whereas TNF[alpha], 12-O-Tetradecanoylphorbol-13-acetate, human T-cell leukemia virus 1 Tax, and CD40 did not. In both A45 and 2C Jurkat cell lines, LMP1 TES2-mediated NK-[kappa]B activation was blocked by siRNAs to TNF[alpha] receptor-associated factor 6 and NEMO, by I[kappa]B kinase inhibitors, and by the I[kappa]B[alpha] superrepressor, indicating that the NEMO mutants function to support canonical NK-[kappa]B activation. Expression of A45 or 2C mutants in NEMO-deficient murine embryonic fibroblasts reproduced the Jurkat phenotypes: LMP1 TES2 activated NF-[kappa]B in fibroblasts lacking NEMO amino acids 133-224 or 373-419, but TNF[alpha] and Tax did not. Further analysis indicated that TES2 did not activate NF-[kappa]B in cells expressing the double deletion mutant [DELTA]133-224/[DELTA]372-419. These data provide further evidence of the essential role for NEMO in LMP1 TES2 NF-[kappa]B activation and highlight the importance of unique domains within NEMO for sensing distinct NF-[kappa]B stimuli. I[kappa]B kinase [gamma] | tumor necrosis factor alpha | human T-cell leukemia virus | Tax | CD40 doi/ 10.1073/pnas.1011752107

A proportion of classical Hodgkin lymphoma (HL) is believed to be causally related to infection with the ubiquitous lymphotropic EBV. The determining factors for development of EBV-related HL remain poorly understood, but likely involve immunological control of the viral infection. Accordingly, markers of the HLA class I region have been associated with risk of EBV-related HL. To study the host genetic component of EBV-related HL further, we investigated the lymphoma's association with HLA-A*01 and HLA-A*02 simultaneously in the setting of infectious mononucleosis (IM), a risk factor for EBV-related HL, in a case-series analysis including 278 EBV-related and 656 EBV-unrelated cases of HL. By logistic regression, HLA-A*01 alleles [odds ratio (OR) per allele, 2.15; 95% CI, 1.60-2.88] were associated with increased and HLA-A*02 alleles (OR per allele, 0.70; 95% CI, 0.51-0.97) with decreased risk of EBV-related HL. These allele-specific associations corresponded to nearly 10-fold variation in risk of EBV-related HL between HLA-A*01 and HLA-A*02 homozygotes. History of IM was also associated with risk of EBV-related HL (OR, 3.40; 95% CI, 1.74-6.66). The association between history of IM and EBV-related HL was not seen in the presence of HLA-A*02 because this allele appeared to neutralize the effect of IM on EBV-related HL risk. Our findings suggest that HLA class I-restricted EBV-specific cytotoxic T-cell responses and events in the early immune response to EBV infection in IM play critical roles in the pathogenesis of EBV-related HL. case series | epidemiology doi/10.1073/pnas.0915054107

The protein levels of [beta]-catenin are tightly regulated by the ubiquitin/proteasome system. We provide evidence that two distinct ubiquitin-dependent degradation pathways for [beta]-catenin are active in the same Burkitt's lymphoma cells: Along with the classical glycogen-synthase kinase 3[beta]-dependent destruction machinery, degradation of [beta]-catenin through seven in absentia homolog 1 (Siah-1) ubiquitin ligase is functional in these cells. We show that inhibition of endogenous Siah-1 stabilizes and activates [beta]-catenin in B cells. The principal Epstein-Barr virus oncoprotein, latent membrane protein 1, is involved in [beta]-catenin up-regulation, and expression of latent membrane protein 1 in B lymphoma cells is associated with decreased Siah-1 RNA and protein levels. Thus, we demonstrate the significance of the endogenous Siah-1-dependent ubiquitin/proteasome pathway for [beta]-catenin degradation in malignant human cells and its regulation by a viral oncogene. B lymphoma | ubiquitin/proteasomal degradation | Epstein-Barr virus | latent membrane protein 1

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in [SH2D1A.sup.-/-] mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens. Because germinal centers were absent in [SH2D1A.sup.-/-] mice upon primary immunization, and because SH2D1A was detectable in wt germinal center B cells, we examined whether [SH2D1A.sup.-/-] B cell functions were impaired. Using the adoptive cotransfer of B lymphocytes from hapten-primed [SH2D1A.sup.-/-] mice with CD[4.sup.+] T cells from primed wt mice into irradiated wt mice provided evidence that signal transduction events controlled by SH2DIA are essential for B cell activities resulting in antigen specific IgG production. Defects in naive [SH2D1A.sup.-/-] B cells became evident upon cotransfer with non-primed wt CD[4.sup.+] cells into Rag[2.sup.-/-] recipients. Thus, both defective T and B cells exist in the absence of SH2D1A, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients without involvement of Epstein-Barr virus. Epstein Barrvirus | germinal center | immunoglobulin | SLAM/CD150

The associaton of, children with multiple sclerosis (MS) is more likely to be seropositive for Epstein- Barr virus (EBV) or other common viruses than their healthy age-matched peers is studied. The results of the study suggest an association between EBV infection and pediatric MS.

Signalling lymphocyte-activation molecule (SLAM) is a glycosylated type-I transmembrane protein present on the surface of B and T cells. It is shown that a T-cell specific SLAM associated protein (SAP), containing an SH2 domain and a short tail, blocks recruitment of the SH2-domain containing signal transduction molecule SHP-2 to a SLAM cytoplasmic region docking site. Absence of the SAP inhibitor in XLP patients has an effect on T/B cell interactions, resulting in inability to control B-cell proliferation caused by Epstein-Barr viruses.

Despite progress in basic and clinical Epstein-Barr virus (EBV) research, the absence of a suitable animal model for EBV infection continues to impede studies of viral pathogenesis, vaccine development, and [...], Epstein-Barr virus (EBV) is a human lymphocryptovirus that causes infectious mononucleosis, persists asymptomatically for life in nearly all adults, and is associated with the development of B cell lymphomas and nasopharyngeal carcinomas. A highly similar rhesus lymphocryptovirus naturally endemic in rhesus monkeys was used to orally infect naive animals from a pathogen-free colony. This animal model reproduced key aspects of human EBV infection, including oral transmission, atypical lymphocytosis, lymphadenopathy, activation of [CD23.sup.+] peripheral blood B cells, sustained serologic responses to lytic and latent EBV antigens, latent infection in the peripheral blood, and virus persistence in oropharyngeal secretions. This system may be useful for studying the pathogenesis, prevention, and treatment of EBV infection and associated oncogenesis.

The immune response to the oncogenic manifestations of Epstein-Barr virus (EBV) infection may be curtailed by changes in processing and presentation of EBV antigens. Tumor cells are restricted to presenting only the EBNA1 antigen. They are also unable to process antigens that characterize latent EBV infection of B lymphocytes. This may be caused by dysfunction of antigen-processing genes. Strategies for producing an EBV vaccine are discussed.

The repetitive sequence, Gly-Ala, of the Epstein-Barr virus-encoded nuclear antigen (EBNA1) generates a cis-acting inhibitory signal that disturbs antigen processing and major histocompatibility complex (MHC) class I-restricted presentation. It acts as a mechanism to avoid cytotoxic T lymphocyte recognition without immunosuppression but rather immune evasion, possibly encouraging the long-term survival of virus-infected cells.

Recombinant phages barring sequences that encode beta-galactosidase fusion proteins (OBP), obtained from spliced cDNA of a gene family, are similar to Epstein-Barr virus antigen (EBVA-1) in their binding to certain regions of EBV. EBV modifies its life cycle according to cellular factor regulation.

Healthy Epstein-Barr virus (EBV) seropositive undergraduates (N = 57) completed a personality inventory, provided blood samples, and were randomly assigned to write or talk about stressful events, or to write about trivial events, during three weekly 20-min sessions, after which they provided a final blood sample. Individuals assigned to the verbal/stressful condition had significantly lower EBV antibody titers (suggesting better cellular immune control over the latent virus) after the intervention than those in the written/stressful group, who had significantly lower values than those in the written/trivial control group. Subjects assigned to the written/stressful condition expressed more negative emotional words than the verbal/stressful and control groups and more positive emotional words than the verbal/stressful group at each time point. The verbal/stressful group expressed more negative emotional words compared with the control group at baseline. Content analysis indicated that the verbal/stressful group achieved the greatest improvements in cognitive change, self-esteem, and adaptive coping strategies.

Byline: Marc B. Lande (1), Jeanne A. Mowry (1), Donald C. Houghton (2), Clifton R. White (1), Michael S. Borzy (4) Keywords: Key words: Epstein-Barr virus; Infectious mononucleosis; Acute glomerulonephritis; Immune complex; Leukocytoclastic vasculitis; Acute renal failure Abstract: We describe a patient with immune complex-mediated glomerulonephritis and leukocytoclastic vasculitis associated with Epstein-Barr virus (EBV) infectious mononucleosis. The patient required hemodialysis and has residual hypertension. This case implicates acute EBV infection as a cause of immune complex-mediated glomerulonephitis. Author Affiliation: (1) Division of Pediatric Nephrology, Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health Sciences University, Portland, Oregon 97201, USA, US (2) Department of Pathology, Oregon Health Sciences University, Portland, Oregon 97201, USA, US (3) Department of Dermatology, Oregon Health Sciences University, Portland, Oregon 97201, USA, US (4) Division of Immunology and Rheumatology, Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health Sciences University, Portland, Oregon 97201, USA, US Article note: Received October 10, 1997 received in revised form January 20, 1998 accepted January 27, 1998

The major target tissues for Epstein-Barr virus (EBV) infection are B lymphocytes and epithelial cells of the oropharyngeal zone. The product of the EBV BZLF1 early gene, EB1, a member of the basic leucine-zipper family of transcription factors, interacts with both viral and cellular promoters and transcription factors, modulating the reactivation of latent EBV infection. Here, we characterize a novel cellular protein interacting with the basic domains of EB1 and c-Jun, and competing of their binding to the AP1 consensus site. The transcript is present in a wide variety of human adult, fetal, and tumor tissues, and the protein is detected in the nuclei throughout the human epidermis and as either grainy or punctuate nuclear staining in the cultured keratinocytes. The overexpression of tagged cDNA constructs in keratinocytes revealed that the [NH.sub.2] terminus is essential for the nuclear localization, while the central domain is responsible for the interaction with EB1 and for the phenotype of transfected keratinocytes similar to terminal differentiation. The gene was identified in tail-to-tail orientation with the periplakin gene (PPL) in human chromosome 16p13.3 and in a syntenic region in mouse chromosome 16. We designated this novel ubiquitously expressed nuclear protein as ubinuclein and the corresponding gene as UBN1. Key words: Epstein-Barr virus * epidermis * protein-protein interaction * keratinocyte differentiation * chromosome 16

The Epstein-Barr virus (EBV) affects approximately 95% of the world's population with the majority of infections coming within the first three years of life. The EBV is classified as a [...]

Byline: Chan Jong Kim (1,2), Young Jong Woo (1), Hoon Kook (1), Young Youn Choi (1), Jae Sook Ma (1), Tai Ju Hwang (1) Keywords: Henoch-Schonlein purpura; Henoch-Schonlein purpura nephritis; Epstein-Barr virus; Identical twins Author Affiliation: (1) Department of Pediatrics, Chonnam National University Medical School, Gwangju, Korea (2) Department of Pediatrics, Chonnam National University Medical School, 8 Hak-Dong, Dong-Gu, Gwangju 501--757, Korea Article History: Online Date: 16/12/2003

Byline: Ken Johkura (1), Takayuki Momoo (2), Yoshiyuki Kuroiwa (3) Author Affiliation: (1) Department of Neurology, Hiratsuka 254-8502, Japan. johkura-k@kkr.hiratsuka.kanagawa.jp, JP (2) Department of Neurology, Medical Center, Yokohama City University, Yokohama, Japan, JP (3) Department of Neurology, Yokohama City University School of Medicine, Yokohama, Japan, JP Article note: Received: 7 May 2002, Received in revised form: 13 September 2002, Accepted: 25 September 2002 Correspondence to K. Johkura

Byline: Toru Watanabe (1) Keywords: Hemolytic uremic syndrome; Epstein-Barr virus Author Affiliation: (1) Department of Pediatrics, Niigata City General Hospital, 2--6-1 Shichikuyama, Niigata 950--8739, Japan Article History: Registration Date: 22/01/2004 Online Date: 03/03/2004