Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus persistently infecting more than 90% of adult population in the world. Primary cellular targets for EBV infection are B cells and epithelial cells. Except for infectious mononucleosis (IM) caused by delayed primary infection in adolescents and young adults and various EBV-associated malignancies, EBV infection is usually asymptomatic. In immunocompromised hosts, however, the virus may cause various opportunistic diseases. Rarely, in apparently immunocompetent hosts, EBV induces a chronic disease with prolonged IM-like symptoms and sustained EBV DNA load in the peripheral blood. This condition has been termed chronic active EBV infection or chronic active EBV disease; both are abbreviated as CAEBV. Interestingly, while EBV-induced B-cell proliferation has been observed in most patients with CAEBV in western countries, in east Asian countries including Japan, the virus has been mainly found in T or NK cells that are proliferating clonally. The prognosis of CAEBV is highly variable; some patients remain stable without therapeutic interventions, whereas others rapidly develop severe complications such as multi-organ dysfunction and malignant lymphomas. Initially, CAEBV was thought to be mainly a pediatric disease, but recently many adult cases have been identified with substantially different clinical features compared to those of pediatric cases. Mainly in east Asian countries, EBV-positive T/NK-cell proliferation has been also observed in three other related diseases, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), hydroa vacciniforme (HV), and hypersensitivity to mosquito bites (HMB). EBV infection of T or NK cells is also known in lymphoid malignancies such as extranodal NK/T-cell lymphoma (ENKL) and aggressive NK-cell leukemia (ANKL). The term EBV-associated T/NK-cell lymphoproliferative diseases (EBV-T/NK-LPDs) has been therefore generated to include these diseases. However, the disease concept of CAEBV, including its relationship to other EBV-T/NK-LPDs, has not been fully established and there are unsolved major questions concerning these diseases. How does EBV infect T and NK cells and induce their proliferation? Why are EBV-infected T/NK cells not removed by host immune responses?　 What explains the heterogenous nature of CAEBV and other EBV-T/NK-LPDs; do they include different conditions with different etiologies? Are they immunodeficiency, or malignant diseases? What explains their uneven geographical distribution? Is there any genetic predisposition? What are the ideal timing and protocol for stem cell transplantation for CAEBV? This research topic invites both original works and reviews on EBV-T/NK-LPDs; articles concerning but not restricted to the above listed questions are welcome. We hope this topic will stimulate discussions on the enigmatic pathogenesis and the disease concept of these diseases, and will eventually facilitate the establishment of their standard therapy.