Epstein-Barr virus and its role in the pathogenesis of Burkitt's lymphoma: An unresolved issue.

For several reasons Burkitt's lymphoma (BL) has become a paradigm in cancer research: for its particular geographical distribution, the presence of Epstein-Barr virus (EBV) in the cases in high incidence areas, and for the activation of the proto-oncogene c-myc by chromosomal translocation in one of the immunoglobulin gene loci. As c-MYC activates both, proliferation and apoptosis, at least two events have to cooperate in lymphomagenesis: Activation of c-MYC and a shift in the balance from apoptosis towards survival. Antigenic and/or polyclonal stimulation of the B cell receptor, genetic instability imposed by activation induced deaminase (AID), as well as the viral gene products EBNA1 and several small non-coding non-polyadenylated RNAs are the main factors suspected to play an important role in the pathogenesis of BL Despite intensive research, the role of the virus has remained largely elusive in the past decades, but the discovery of two viral microRNA clusters that are expressed in EBV associated tumors including BL has raised new hopes and expectations that EBV is going to reveal its mystery. This review focuses on the interplay between cellular and viral factors and puts special emphasis on mouse models and experimental cell culture systems that address these points

Epstein-Barr virus and the pathogenesis of Burkitt's lymphoma: More questions than answers.

Burkitt's lymphoma (BL) wits first described as a clinical entity in children in Central Africa by Denis Burkitt in 1958. The particular epidemiological features (if this tumor initiated the search for it virus as the causative agent and led to the discovery of Epstein-Barr virus (EBV) by Epstein and coworkers in 1964. It became apparent in the seventies and eighties that the tumor is not restricted to Central Africa, but occurs with lesser incidence all over the world (sporadic BL) and is also particularly frequent in HIV infected individuals, and that not all Ill. cases are associated with EBV: about 95% of the cases in Central Africa, 40 to 50% of the cases in HIV-infected individuals and 10 to 20% of the sporadic cases harbour the viral information and express at least one viral antigen (EBNA1) and a number of non-coding viral RNAs. In contrast, all BL. cases regardless of their geographical origin exhibit one of three c-myc/Ig chromosomal translocations leading to (lie activation of the c-myc gene as a crucial event in the development of this disease. Although epidemiological evidence clearly points to a role of the virus in the African cases, the role of EBV in the pathogenesis of BL, has remained largely elusive. This review summarizes current concepts and ideas how ERV might contribute to the development of BL in the light of the progress made in the last decade and discusses the problems of the experimental systems available to test such hypotheses

The role of virus-specific CD4+ T cells in the control of Epstein-Barr virus infection.

Epstein-Barr virus (EBV) establishes lifelong persistent infections in humans and has been implicated in the pathogenesis of several human malignancies. Protective immunity against EBV is mediated by T cells, as indicated by an increased incidence of EBV-associated malignancies in immunocompromised patients, and by the successful treatment of EBV-associated post-transplant lymphoproliferative disease (PTLD) in transplant recipients by the infusion of polyclonal EBV-specific T cell lines. To implement this treatment modality as a conventional therapeutic option, and to extend this protocol to other EBV-associated diseases, generic and more direct approaches for the generation of EBV-specific T cell lines enriched in disease-relevant specificities need to be developed. To this aim, we studied the poorly defined EBV-specific CD4+ T cell response during acute and chronic infection

Burkitt lymphoma: The role of Epstein-Barr virus revisited.

The particular epidemiological features of Burkitt lymphoma (BL) in Tropical Africa, first described by Denis Burkitt in 1958, initiated the search for a virus that induces malignant B cell lymphomas in humans and is transmitted by arthropods. The herpes virus (Epstein-Barr virus, EBV) discovered by Epstein and collaborators in cell lines established from BL biopsies fulfilled some of these predictions. It drives primary B cells into unlimited proliferation, induces malignant B cell lymphomas in immunocompromised individuals (post-transplant lymphoproliferative disease, PTLD) in vivo, and footprints of the virus are generally detected in African BL biopsies supporting a causative role of the virus in the pathogenesis of BL. The virus is, however, not transmitted by arthropods and is spread ubiquitously amongst the human population through saliva. Furthermore, BL and EBV-induced PTLD are now recognized as pathogenetically distinct entities: BL involves MYC-immunoglobulin translocations in contrast to PTLD, and different patterns of viral genes are expressed in both diseases. Viral gene products expressed in BL are assumed to contribute to inhibition of apoptosis, although their precise mechanism of action is not fully understood. In the future, next generation sequencing is expected to shed more light on the contribution of EBV to the pathogenesis of BL

Mitochondrial and cytosolic thioredoxin reductase knockout mice.

To address the role of the thioredoxin system in redox regulation of apoptosis and proliferation, mice with targeted deletions of both the cytosolic (Txnrd1) and the mitochondrial (Txnrd2) thioredoxin reductases were generated. These two selenoproteins are key enzymes governing the activities of cytosolic and mitochondrial thioredoxins, respectively, which are, in turn, implicated in a variety of cellular functions, such as cell-cell communication, proliferation and apoptosis. Ubiquitous and heart-specific inactivation revealed widely non-redundant functions of Txnrd1 and Txnrd2. A significant drop in cell proliferation rates throughout the embryo (except in the heart), but not increased apoptosis, was the underlying cause of embryonic death of Txnrd1 knockout embryos at E10.5. Perturbed cardiac development and increased apoptosis of fetal blood cells in the liver caused severe anemia, growth retardation and embryonic death (E13.5) in Txnrd2 knockout embryos. Cardiac-tissue restricted inactivation of Txnrd2 led to biventricular dilated cardiomyopathy and postnatal death; in contrast heart-specific inactivation of Txnrd1 had no apparent effect on the viability of the knockout mice. In conclusion, Txnrd1 contributes to cell proliferation, whereas Txnrd2 is rather involved in apoptosis regulation