Upregulation of Tumor Necrosis Factor- a Gene by Epstein-Barr Virus and Activation of Macrophages in Epstein-Barr Virus–infected T Cells in the Pathogenesis of Hemophagocytic Syndrome

A potentially fatal hemophagocytic syndrome has been noted in patients with malignant lymphomas, particularly in EBV-infected T cell lymphoma. Cytokines, such as interferong (IFNg ), TNFa , and IL-1 a , are elevated in patients’ sera. To verify whether infection of T cells by EBV will upregulate specific cytokine genes and subsequently activate macrophages leading to hemophagocytic syndrome, we studied the transcripts of TNFa , IFNg , and IL-1 a in EBV-infected and EBV-negative lymphoma tissues. By reverse transcription PCR analysis, transcripts of TNFa were detected in 8 (57%) of 14 EBV-infected T cell lymphomas, higher than that detected in EBV-negative T cell lymphoma (one of six, 17%), EBV-positive B cell lymphoma (two of five, 40%) and EBV-negative B cell lymphomas (one of seven, 14%). Transcripts of IFNg were consistently detected in T cell lymphoma and occasionally in B cell lymphoma, but were independent of EBV status. IL-1 a expression was not detectable in any category. Consistent with these in vivo observations, in vitro EBV infection of T cell lymphoma lines caused upregulation of TNFa gene, and increased secretion of TNFa , but not IFNg or IL-1 a . Expression of TNFa , IFNg , and IL-1 a was not changed by EBV infection of B cell lymphoma lines. To identify the specific cytokine(s) responsible for macrophage activation, culture supernatants from EBV-infected T cells were cocultured with a monocytic cell line U937 for 24 h. Enhanced phagocytosis and secretion of TNFa , IFNg , and IL-1 a by U937 cells were observed, and could be inhibited to a large extent by antiTNFa (70%), less effectively by anti-IFNg (31%), but almost completely by the combination of anti-TNFa and anti-IFNg (85%). Taken together, the in vivo and in vitro observations suggest that infection of T cells by EBV selectively upregulates the TNFa expression which, in combination with IFNg and probably other cytokines, can activate macrophages. This study not only highlights a probable pathogenesis for virus-associated hemophagocytic syndrome, but also suggests that anti-TNFa will have therapeutic potential in the context of their fatal syndrome. ( J. Clin. Invest. 1997. 100:1969–1979.)