Characterization of Epstein-Barr virus (EBV)-infected cells in EBV-associated hemophagocytic lymphohistiocytosis in two patients with X-linked lymphoproliferative syndrome type 1 and type 2

EBV-infected cells in two patients (XLP-1 and XLP-2) presenting EBV-HLH were evaluated by in EBER-1 in situ hybridization or quantitative PCR methods.Both XLP patients showed that the dominant population of EBV-infected cells was CD19+ B cells, whereas EBV-infected CD8+ T cells were very few.In XLP-related EBV-HLH, EBV-infected cells appear to be predominantly B cells. B cell directed therapy such as rituximab may be a valuable option in the treatment of EBV-HLH in XLP patients.Hemophagocytic lymphohistiocytosis (HLH) is clinically characterized by prolonged fever, hepatosplenomegaly, hypertriglyceridemia, systemic hypercytokinemia and cytopenia [1]. HLH consists of primary (familial) and secondary (infection, lymphoma or autoimmune disease-associated) types. Approximately half of all infection-associated HLH cases involves the Epstein-Barr virus (EBV) [2]. Most cases of EBV-HLH are sporadic, but a few cases may present the first presentation of X-linked lymphoproliferative syndrome (XLP) [3]. XLP is a rare, inherited immunodeficiency that is characterized by an extreme vulnerability to EBV infection and shows variable clinical phenotypes, including severe or fatal EBV-HLH (60%), malignant B-cell lymphoma (30%), and progressive dysgammaglobulinemia (30%) [3]. The first genes that is responsible for XLP was identified as the SH2D1A/SLAM-associated protein (SAP) gene in 1998 [4-6], and mutations in the X-linked inhibitor of apoptosis protein (XIAP) gene can also lead to the clinical phenotype of XLP in 2006 [7]. XLP is now considered to comprise two distinct diseases, namely XLP-1 (SAP deficiency) and XLP-2 (XIAP deficiency).In addition to B cells, EBV can infect other cell types, including epithelial cells, T cells and natural killer (NK) cells [8]. Studies have shown that activated T cells, particularly CD8+ T cells, are the primary cellular target of EBV infection in sporadic EBV-HLH [9,10], which reflects the pathogenic role of EBV-infected CD8+ T cells in sporadi