Differences in Epstein-Barr Virus Characteristics and Viral-Related Microenvironment Could Be Responsible for Lymphomagenesis in Children

Abstract

In Argentina, Epstein-Barr virus (EBV) presence is associated with Hodgkin lymphoma (HL) in patients younger than 10 years, suggesting a relationship between low age of EBV infection and HL. Given that HL is derived from germinal centers (GC), our aim was to compare EBV protein expression and microenvironment markers between pediatric HL patients and EBV+GC in children. Methods: EBV presence and immune cell markers were assessed by in situ hybridization and immunohistochemistry (IHC). Results: Viral latency II pattern was proved in all HL patients and in 81.8% of EBV+ tonsillar GCs. LMP1 and LMP2 co-expression were proved in 45.7% HL cases, but only in 7.7% EBV+ GC in pediatric tonsils. An increase in CD4+, IL10, and CD68+ cells was observed in EBV+ GC. In pediatric HL patients, only the mean of IL10+ cells was statistically higher in EBV+ HL. Conclusions: Our findings point us out to suggest that LMP1 expression may be sufficient to drive neoplastic transformation, that an immune regulatory milieu counteracts cytotoxic environment in EBV-associated Hodgkin lymphoma, and that CD4+ and CD68+ cells may be recruited to act in a local collaborative way to restrict, at least in part, viral-mediated lymphomagenesis in tonsillar GC.

The circuitry of the tumor microenvironment in adult and pediatric Hodgkin lymphoma: cellular composition, cytokine profile, EBV, and exosomes

“…Interestingly, EBV+ cases with Th1 reaction did not show a better prognosis. In contrast, EBV+ pediatric patients exhibited a cytotoxic profile characterized by increased infiltration of CD8 + T cells and showed a better therapeutic response 8,73‐75 . However, a subset of EBV+ patients showed worse outcome with a high number of FOXP3+ cells, suggesting EBV modulates the immune escape strategies by enrichment of the TME with T reg cells and associated, immunosuppressive cytokines 76 .…”

“…In contrast, EBV+ pediatric patients exhibited a cytotoxic profile characterized by increased infiltration of CD8 + T cells and showed a better therapeutic response. 8 , 73 , 74 , 75 However, a subset of EBV+ patients showed worse outcome with a high number of FOXP3+ cells, suggesting EBV modulates the immune escape strategies by enrichment of the TME with T reg cells and associated, immunosuppressive cytokines. 76 This outcome could be attributed to an insufficient intratumoral immune response against EBV in adult HL that fails to remove tumor cells.…”

Pediatric inborn errors of immunity causing hemophagocytic lymphohistiocytosis: Case report and review of the literature

“…17,18 In developing countries, such as Argentina, EBV primary infection occurs at early ages and it has been published that about 89% of the population has a positive serology for EBV at 3 years old, thus representing a major problem in patients with IEI, which predispose them to develop HLH. 19,20 Both primary and acquired HLH may have common overlapping clinical features and/or laboratory findings, highlighting the importance to distinguish between them to timely administer targeted therapies. Although several IEI affecting T cells and inflammasome proteins among others, may lead to HLH, in this review, we will focus on primary forms of HLH affecting cytotoxicity and therefore, in which HLH is the predominant manifestation.…”

“…Moreover, mortality rates varies widely among studies, ranging from more than 40 to 75% depending on several underlying conditions 17,18 . In developing countries, such as Argentina, EBV primary infection occurs at early ages and it has been published that about 89% of the population has a positive serology for EBV at 3 years old, thus representing a major problem in patients with IEI, which predispose them to develop HLH 19,20 . Both primary and acquired HLH may have common overlapping clinical features and/or laboratory findings, highlighting the importance to distinguish between them to timely administer targeted therapies.…”