Pathogenesis and mechanism of disease progression from hemophagocytic lymphohistiocytosis to Epstein-Barr virus-associated T-cell lymphoma: nuclear factor-kappa B pathway as a potential therapeutic target

Abstract

Epstein-Barr virus (EBV) can infect T lymphocytes and manifests as hemophagocytic lymphohistiocytosis (HLH), a distinct entity of hemophagocytic syndrome (HPS) characterized by fever, hepatosplenomegaly, cytopenia, hypercytokinemia, and systemic macrophage activation with hemophagocytosis. In a substantial percentage of HLH patients, the disease may relapse or progress to T-cell lymphoma in months to years. In the present review, the authors summarize the previous studies on the pathogenesis of HLH and the potential mechanism for the progression of disease from HLH to T-cell lymphoma. The infection of T cells by EBV could activate T cells to secrete proinflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), which subsequently activate macrophages. EBV latent membrane protein-1 (LMP-1) is the viral product responsible for the activation of the TNF receptor (TNFR) associated factors/nuclear factor-kappaB (NF-kappaB)/ERK pathway to enhance cytokine secretion mediated through the suppression of the SAP/SH2D1A gene. The activation of NF-kappaB will confer resistance to TNF-alpha-induced apoptosis on EBV-infected T cells through the down-regulation of TNFR-1. Consistent with in vitro observations, EBV-associated T or natural killer/T-cell lymphoma showed constitutive activation of NF-kappaB, explaining its drug resistance, hypercytokinemia, and poor prognosis. Therefore, similar to other inflammation-associated cancers, HLH provides a unique model to study the mechanism of disease progression from a benign virus-infected disorder (HLH) to T-cell lymphoma. Inhibition of the NF-kappaB signal pathway should provide a potential target for the treatment of HLH and EBV-associated T-cell lymphoma.

Figure 1

The disease progression of a case of hemophagocytic lymphohistiocytosis (HLH) to clonal Epstein–Barr virus (EBV)‐containing T‐lymphoproliferative disorder or T‐cell lymphoma in a 2‐year‐old boy. (a) The initial bone marrow aspiration revealed macrophage activation with hemophagocytosis (arrows). (b) Bone marrow aspiration of the relapsing disease 3 months later revealed extensive infiltration of atypical lymphoid cells that were (c) immunostained positive for CD3 (×400) and contained EBV genomes (d) (in situ EBER, hybridization, ×400).

Figure 2

A diagrammatic depiction of the pathogenesis and molecular mechanism for the progression from HLH to chronic active disease or T‐cell lymphoma in Epstein–Barr virus (EBV)‐infected T cells. EBV latent membrane protein‐1 (LMP‐1) up‐regulated tumor necrosis factor‐α (TNF‐α) via the TNF receptor (TNFR) associated factors (TRAF)/nuclear factor‐κB (NF‐κB) signals to kill the bystander lymphoid cells in one way, and down‐regulated TNFR‐1 on the other way to suppress the apoptotic signal pathway, conferring the LMP‐1‐expressed T cells to survive from TNF‐α‐induced apoptosis.