Lack of evidence for an association of Epstein–Barr virus infection with breast carcinoma

BACKGROUND: Epstein–Barr virus (EBV) is a ubiquitous human γ-herpes virus infecting more than 90% of the population worldwide. EBV is associated with certain malignancies (e.g. Burkitt lymphoma, Hodgkin lymphoma and nasopharyngeal carcinoma). Recent studies have raised the possibility that EBV may also be involved in the pathogenesis of breast carcinoma, the most common carcinoma of females. If substantiated, this finding would have major implications regarding prevention and therapy of the disease. The studies published so far have employed diverse methods, however, and the results have been controversial. METHODS: Using the EBV DNA PCR, EBV DNA in situ hybridisation and in situ hybridisation for the detection of the EBV-encoded RNAs, and using immunohistochemistry for the demonstration of the EBV-encoded nuclear antigen 1, we have studied a series of 59 invasive breast carcinomas for evidence of EBV infection. RESULTS: EBV-encoded RNA-specific in situ hybridisation and EBV-encoded nuclear antigen 1 immunohistochemistry were negative in all cases. Using the PCR, EBV DNA was detected in four out of 59 cases. These cases were further studied by EBV DNA in situ hybridisation, showing an absence of viral DNA from the tumour cells. CONCLUSION: These results indicate that breast carcinoma is not an EBV-associated tumour

Epstein–Barr virus in the multiple sclerosis brain: a controversial issue—report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria

Recent epidemiological and immunological studies provide evidence for an association between Epstein–Barr virus infection and multiple sclerosis, suggesting a role of Epstein–Barr virus infection in disease induction and pathogenesis. A key question in this context is whether Epstein–Barr virus-infected B lymphocytes are present within the central nervous system and the lesions of patients with multiple sclerosis. Previous studies on this topic provided highly controversial results, showing Epstein–Barr virus reactivity in B cells in the vast majority of multiple sclerosis cases and lesions, or only exceptional Epstein–Barr virus-positive B cells in rare cases. In an attempt to explain the reasons for these divergent results, a workshop was organized under the umbrella of the European Union FP6 NeuroproMiSe project, the outcome of which is presented here. This report summarizes the current knowledge of Epstein–Barr virus biology and shows that Epstein–Barr virus infection is highly complex. There are still major controversies, how to unequivocally identify Epstein–Barr virus infection in pathological tissues, particularly in situations other than Epstein–Barr virus-driven lymphomas or acute Epstein–Barr virus infections. It further highlights that unequivocal proof of Epstein–Barr virus infection in multiple sclerosis lesions is still lacking, due to issues related to the sensitivity and specificity of the detection methods

EBV-associated post-transplantation B-cell lymphoproliferative disorder following allogenic stem cell transplantation for acute lymphoblastic leukaemia: tumor regression after reduction of immunosuppression - a case report

Epstein-Barr virus (EBV)-associated B-cell post-transplantation lymphoproliferative disorder (PTLD) is a severe complication following stem cell transplantation. This is believed to occur as a result of iatrogenic immunosuppression leading to a relaxation of T-cell control of EBV infection and thus allowing viral reactivation and proliferation of EBV-infected B-lymphocytes. In support of this notion, reduction of immunosuppressive therapy may lead to regression of PTLD

Revisiting the Tissue Microenvironment of Infectious Mononucleosis: Identification of EBV Infection in T Cells and Deep Characterization of Immune Profiles

To aid understanding of primary EBV infection, we have performed an in depth analysis of EBV-infected cells and of local immune cells in tonsils from infectious mononucleosis (IM) patients. We show that EBV is present in approximately 50% of B-cells showing heterogeneous patterns of latent viral gene expression probably reflecting different stages of infection. While the vast majority of EBV+ cells are B-cells, around 9% express T-cell antigens, with a predominance of CD8+ over CD4+ cells. PD-L1 was expressed by a median of 14% of EBV+ cells. The numbers of EBER+PD-L1+ cells were directly correlated with the numbers of EBER+CD3+ and EBER+CD8+ cells suggesting a possible role for PD-L1 in EBV infection of T-cells. The microenvironment of IM tonsils was characterized by a predominance of M1-polarized macrophages over M2-polarized cells. However, at the T-cell level, a heterogeneous picture emerged with numerous Th1/cytotoxic cells accompanied and sometimes outnumbered by Th2/regulatory T-cells. Further, we observed a direct correlation between the numbers of Th2-like cells and EBV– B-cells. Also, a prevalence of cytotoxic T-cells over Th2-like cells was associated with an increased viral load. These observations point to contribution of B- and Th2-like cells to the control of primary EBV infection. 35% of CD8+ cells were differentiated CD8+TBET+ cells, frequently detected in post-capillary venules. An inverse correlation was observed between the numbers of CD8+TBET+ cells and viral load suggesting a pivotal role for these cells in the control of primary EBV infection. Our results provide the basis for a better understanding of immune reactions in EBV-associated tumors

Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling

Background and Objectives. In early and polymorphic post-transplant lymphoprolifera- tive disorders (PTLD) Epstein-Barr virus (EBV), through its latency proteins, drives the proliferation of B lymphocytes, a process which in immunocompetent individuals leads to the establishment of latently infected memory B cells. Design and Methods. We analyzed 11 cases, which included early and polymorphic PTLD, and 12 controls for latency of EBV infection and their antigenic profile. Results. We identified a minority of terminally differentiated EBER+ IRTA1+ memory B cells and EBER+ CD138+ PRDM1+ plasma cells in these samples. These elements were identified both in PTLD and in tumor-free tonsils from post-transplant patients but not in EBV– control tonsils. The expression of EBV latency proteins is heterogeneous, and is associated with activation of the NF-κB pathway. EBV signaling (through EBNA2, LMP1 and LMP2A) and NF-κB activation correlated with upregulation of target proteins: cMYC, JunB, CCL22, TRAF1 and IRF4. EBV-infected lymphocytes in early and polymor- phic PTLDs represent a mixture of latencies II, III and, in at least 1/3 of infected cells, of latency 0. Interpretation and conclusions. EBV infection correlates with NF-κB activation, with EBV-dependent cell signaling, and lastly, with the presence of EBV-infected plasma cells and memory cells. Key words: post-transplant lymphoproliferative disorder, Epstein-Barr virus, viral latency, NF-κB signaling, plasma cell, memory B cell

M1-like macrophage polarization prevails in young children with classic Hodgkin Lymphoma from Argentina

The microenvironment in classical Hodgkin lymphoma (cHL) comprises a mixture of different types of cells, which are responsible for lymphoma pathogenesis and progression. Even though microenvironment composition in adult cHL has been largely studied, only few groups studied pediatric cHL, in which both Epstein Barr virus (EBV) infection and age may display a role in their pathogenesis. Furthermore, our group described that EBV is significantly associated with cHL in Argentina in patients under the age of 10 years old. For that reason, our aim was to describe the microenvironment composition in 46 pediatric cHL patients. M1-like polarization status prevailed in the whole series independently of EBV association. On the other hand, in children older than 10 years, a tolerogenic environment illustrated by higher FOXP3 expression was proved, accompanied by a macrophage polarization status towards M2. In contrast, in children younger than 10 years, M1-like was prevalent, along with an increase in cytotoxic GrB+ cells. This study supports the notion that pediatric cHL exhibits a particular tumor microenvironment composition.Fil: Jimenez, Oscar Eduardo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Barros, M. H.. Unfallkrankenhaus Berlin; AlemaniaFil: de Matteo, Elena Noemí. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Garcia Lombardi, M.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Preciado, María Victoria. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; ArgentinaFil: Niedobitek, G.. Unfallkrankenhaus Berlin; AlemaniaFil: Chabay, Paola Andrea. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentin