Epstein-Barr virus LMP1 inhibits the expression of SAP gene and upregulates Th1 cytokines in the pathogenesis of hemophagocytic syndrome.
The primary infection of Epstein-Barr virus (EBV) may result in fatal infectious mononucleosis or hemophagocytic syndrome (HPS) in 2 diseases; that is, X-linked lymphoproliferative disorder (XLP) and hemophagocytic lymphohistiocytosis (HLH). XLP is linked to mutations of the SAP/SH2D1A gene with dysregulated T-cell activation in response to EBV infection. Patients with sporadic HLH, however, usually have no mutation of the SAP/SH2D1A gene, and EBV latent membrane protein-1 (LMP1) can up-regulate Th1 cytokines in EBV-infected T cells. Since both diseases share common manifestations of HPS, it is important to clarify whether a cross-talk exists between signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) and LMP1-mediated pathways to explain the common pathogenesis of HPS. In this study, no mutation of the SAP/SH2D1A gene at exon 2/3 was detected in 7 HLH cases. Interestingly, EBV LMP1 could transcriptionally inhibit the expression of SAP/SH2D1A and activate downstream molecules ERK and interferon-gamma (IFN-gamma). LMP1-mediated SAP/ERK/IFN-gamma signals appear to act via the TNF receptor-associated factor (TRAF)2,5/nuclear factor kappaB (NF-kappaB) pathway, since dominant-negative TRAF2/5 and NF-kappaB inhibitor could rescue SAP expression and downregulate IFN-gamma. Although HLH is genetically distinct from XLP, our data suggest that both diseases share a common signal pathway, through either the mutation or LMP1-mediated suppression of the SAP gene, leading to overt T-cell activation and enhanced Th1 cytokine secretion in response to EBV infection.
Division of Clinical Research, National Health Research Institutes, 12C, 138, Sheng-Li Rd, Tainan, Taiwan.
Huai-Chia
HC
Chuang
Jong-Ding
JD
Lay
Wen-Chuan
WC
Hsieh
Hui-Ching
HC
Wang
Yao
Y
Chang
Shuang-En
SE
Chuang
Ih-Jen
IJ
Su
D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002648:Child; D015536:Down-Regulation; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048008:TNF Receptor-Associated Factor 3; D018417:Th1 Cells / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C114953:SH2D1A protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014763:Viral Matrix Proteins; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases