Comment on Saito et al, page 1366

Hemophagocytic syndrome is a disorder characterized by fever, hepatosplenomegaly, pancytopenia, and the presence in the bone marrow, lymph nodes, liver, and spleen of macrophages that have phagocytized red cells, erythroblasts, platelets, or other hematopoietic cells.

Hemophagocytic syndrome is part of fatal primary Epstein-Barr virus (EBV) infection that occurs in children with X-linked lymphoproliferative disorder and familial hemophagocytic lymphohistiocytosis. The former is associated with mutations in the SAP/SH2D1A gene that results in abnormal T-cell activation specific to EBV infection and the latter with either mutation of perforin 1 gene (PRF1), or the UNC13D gene leading to defective granule exocytosis, or mutations of the STX11 gene associated with abnormal intracellular trafficking. In both diseases there is an abnormal production of T helper 1 (Th-1) cytokines leading to macrophage activation.1,2 

In adults, the hemophagocytic syndrome is associated with a variety of viral, bacterial, and parasitic infections, autoimmune disorders, and lymphomas, predominantly of the T-cell type. In all these conditions, there is an uncontrolled T-cell activation, with overproduction of Th-1 cytokines as well. In sporadic cases of EBV infection associated with the hemophagocytic syndrome, it has been shown that EBV late membrane protein 1 suppresses the transcription of normal SAP/SH2D1A.3 

In this issue of Blood, Saito and colleagues describe the first in vitro observation of hemophagocytosis in cultures of CD34+ cells in the presence of thrombopoietin and tumor necrosis factor-α (TNF-α). Under these conditions the number of generated megakaryocytes decreased with appearance of monocytic cells having the immunophenotype of dendritic cells. These dendritic cells were in close association with developing megakaryocytes and contained CD61+ intracellular material indicative of phagocytosis of megakaryocyte cytoplasm. In addition, these dendritic cells were capable of activating autologous T lymphocytes in vitro. They went further to investigate the type of phagocytic cells in bone marrow smears from patients with the hemophagocytic syndrome and identified a significant percentage of these cells as having the immunophenotypic characteristics of dendritic cells. Previous work by the same group has shown phagocytosis of immature erythroid cells by dendritic cells in cultures of CD34+ cells in the presence of erythropoietin (EPO) and TNF-α.4 

These observations shed more light on the role of dendritic cells in the hemophagocytic syndrome, in particular their contribution to the process of hemophagocytosis and its propagation through further activation of autologous T lymphocytes. In addition, they raise the possibility that dendritic cells with phagocytic activity may contribute during their development in the bone marrow to the development of tolerance to molecules released from dying or damaged hematopoietic cells. ▪

Coffey AJ, Brooksbark RA, Brandau O, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.
Nat Genet
Stadt UZ, Beutel K, Kolberg S, et al. Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analysis of PRF1, UNC13D, STX11 and RAB27A.
Hum Mutat
. In press.
Chuang HC, Lay JD, Hsieh WC, et al. Epstein-Barr virus LMP1 inhibits the expression of SAP gene and up-regulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome.
Fukaya A, Xiao W, Inaba K, et al. Codevelopment of dendritic cells along with erythroid differentiation from human CD34+ cells by tumor necrosis factor-α.
Exp Hematol