The interplay between local immune response and Epstein-Barr virus-infected tonsillar cells could lead to viral infection control.

Epstein Barr virus (EBV) gains access to the host through tonsillar crypts. Our aim was to characterize microenvironment composition around EBV+ cells in tonsils from pediatric carriers, to disclose its role on viral pathogenesis. LMP1 expression, assessed by immunohistochemistry (IHC), was used to discriminate EBV + and - zones in 41 tonsil biopsies. Three regions were defined: Subepithelial (SE), interfollicular (IF) and germinal center (GC). CD8, GrB, CD68, IL10, Foxp3, PD1, CD56 and CD4 markers were evaluated by IHC; positive cells/100 total cells were counted. CD8+, GrB+, CD68+ and IL10+ cells were prevalent in EBV+ zones at the SE region (p < 0.0001, p = 0.03, p = 0.002 and p = 0.002 respectively, Wilcoxon test). CD4+ and CD68+ cell count were higher in EBV + GC (p = 0.01 and p = 0.0002 respectively, Wilcoxon test). Increment of CD8, GrB and CD68 at the SE region could indicate a specific response that may be due to local homing at viral entry, which could be counterbalanced by IL10, an immunosuppressive cytokine. Additionally, it could be hypothesized that CD4 augment at the GC may be involved in the EBV-induced B-cell growth control at this region, in which macrophages could also participate.

Cytotoxic response against Epstein Barr virus coexists with diffuse large B-cell lymphoma tolerogenic microenvironment: clinical features and survival impact.

Epstein-Barr Virus (EBV) is present in neoplastic cells of 15% of Asian and Latin-American diffuse large B-cell lymphoma (DLBCL) patients. Even though a tolerogenic microenvironment was recently described in DLBCL, little is known concerning immunomodulatory features induced by EBV. As suggested in Hodgkin lymphoma, EBV-specific cytotoxic T-cells are increased but showing immune exhaustion features. Hence, host immunity suppression may play a critical role in tumor progression. This study aimed to investigate, whether an association between tumor microenvironment features and EBV presence is taking place, and its clinical correlate. The incidence of EBV+DLBCL NOS was 12.6% in this cohort. Cytokine and chemokine transcripts expression and immunophenotype analysis showed that EBV infection was associated with increased gene expression of immunosuppressive cytokine (IL-10) together with increased CD8+ T-cells and granzyme B+ cytotoxic effector cells. However, this specific response coexists with a tolerogenic milieu, by PD-1 expression, in EBV+ and EBV-DLBCL cases. High PD-1+ cell counts, EBV presence and low CCL22 expression were associated with worse survival, supporting our hypothesis that EBV-specific response is mounted locally and its inhibition by, for example PD-1+ cells, may negatively affect outcome. The better understanding of the interplay between lymphoma cells and microenvironment in a viral framework could thereby facilitate the discovery of new targets for innovative anti-lymphoma treatment strategies.

Analysis of Epstein-Barr virus infection models in a series of pediatric carriers from a developing country.

Epstein-Barr virus (EBV) is a B lymphotropic human herpesvirus. Two models, germinal center (GC) and direct infection, describe how EBV infects B-cells. Since in Argentina primary infection is mostly subclinical at young ages, children represent an interesting population where to analyze EBV infection, especially considering that most studies are usually performed in adults. Tonsil biopsies from pediatric carriers were studied to describe infection characteristics. EBV+ lymphocytes at the interfollicular region were mainly observed. Latency III pattern in subepithelial (SubEp) lymphocytes was observed at young ages, probably indicating a recent infection. In older patients EBV was mostly detected in epithelial cells, suggesting that they could have been infected some time ago. This finding was sustained by tonsillar viral load, which was higher in cases with LMP1+SubEp cells vs. LMP1+nonSubEp cells (p = 0.0237, Mann-Whiney test). Latency III was prevalent and related to the GC, while latency II was associated with non-GC (p = 0.0159, χ2 test). EBERs+/IgD+ cells were statistically prevalent over EBERs+/CD27+ cells (p = 0.0021, χ2 test). These findings indicated that both EBV infection models are not mutually exclusive and provide some basis for further understanding of EBV infection dynamics. Moreover, we provide a more accurate explanation of EBV infection in pediatric asymptomatic carriers from a developing country.