Epstein Barr. hemophagocytic lymphohistiocytosis HLH FHL X EBV AHS EBV HLH NK HLH EBV HLH HLH FHL 2 HLH HLH EBV HLH

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1 2010 Vol. 22No EpsteinBarr hemophagocytic lymphohistiocytosishlh EB HLH 3 1 HLHFHL HLH EBV 2 X XLPSAP 3 EBVHLH EB CAEBV 2 T NK EBV HLH 1 HLH HLHFHL 2 HLH EB EB HLH EBVHLH FHLX EBVAHS EBVHLHNK T EBV CAEBV HLH EBVHLH EBVHLH 2 1 EpsteinBarr virusassociated hemophagocytic lymphohistiocytosis and inflammation Key words EB X Akihiko Maeda, Tetsuya Sato, Yoshihito Ishiura, Sumitaka Dohno, Hiroaki Hisakawa, Mikiya Fujieda, Hiroshi Wakiguchi

2 HLH 5 2 LDH TG EBV EBV EBER 2EBVHLH 1 EBV 2 LDH TG Tchol DIC EBV 1 EBV viral capsid antigen VCAIgM early antigenea 2 EBV 3 in situ hybridization EBV encoded RNAEBER 1 EBVHLH HLH 3 HLH DIC 3 1 HLHHLH EBV 2 X 3 EBVHLH EB HLH NK

3 2010 Vol. 22No EBV HLH 3HLH EBV NK CTL HLH FHL1 FHL2 FHL3 FHL4 FHL5 GS2 CHS1 XLP 9q q q25 6q24 19p 15q21 1q Xq25 2HLH PFR1 induction of apoptosis UNC13D Vesicle priming STX11 Vesicle transport STXBP2 Vesicle transport RAB27A Vesicle docking LYST Vesicle transport SH2D1A Signal transduction & SAP activation of lymphocytes FHLHFamilial HLH GSGriscelli syndrome CHSChediak Higashi syndrome STX syntaxin STXBP2STX binding protein 2 Munc182 HLH 3 HLH X HLH 1 HLHFHL 15 Griscelli ChediakHigashi FHL5 2 HLH 1 EBV NK CTL EBV HLH EBV HLH 4 3 EBV B NK CD8 T cytotoxic granule cytotoxic vesicle FHL2

4 HLH 3 5Perforin LCMV HLH 4 LYSTRab27AMunc134 cytotoxic vesicle EBV HLH 5 Jordan 4 lymphocytic choriomeningitic virus LCMV HLH LCMV EB CTL LCH CD8 T IFN

5 2010 Vol. 22No EBVHLH LCMV CD8 IFN IFN CD8 T IFN HLH EB Jordan X Xlinked lymphoproliferative syndromexlp XLP EBV EBV HLH EBV SAP SH2D1A SAP EB SAP SAP NK T SAP SAP EBV T 8 EBVHLH EBVHLH HLH 20 EB CAEBV 6 EB B T NK EBV T NK TNF IFN IL1IL6IL18 T TNF 9 CAEBV XLP SAP 10 EBVHLH T NK

6 EBV EBV HLH HLH CAEBV EBV CD19CD4CD8 CD56 purity 90 DNA PCR EBV Copyg DNA EBV 7 EB IM B B IM T NK purity 100EBV EBV CD4 CD8 NK CD4 CD8 CAEBV IM HLH CD8 CD4 Kasahara 12 CAEBV CD4 T EB HLH CD8 T T NK T latent membrane proteinlmp1 LMP1 NFB SAP XLP 13 LMP1 T TNF 8 TNF Autocrine survival 14

7 2010 Vol. 22No HLH EBV T 14 EBVHLH T EBV HLH EB T T HLH CAEBV In vivo HLH T CD8 in vitro T NK EB B convertant T NK EB 15 T NK In vivo in vitro T EBVHLH HHV6 CD4 HIV EBV HHV EBVHLH HHV6 EBV EBV HHV6 HLH HHV6 EBV EBVHHV6 CD4 T EBV T

8 Imashuku S, Tabata Y, Teramura T, et altreatment strategies for EpsteinBarr virusassociated hemophagocytic lymphohistiocytosisebvhlh. Leuk Lymphoma , zur Stadt U, Rohr J, Seifert W, et alfamilial hemophagocytic lymphohistiocytosis type 5FHL 5 is caused by mutations in Munc182 and impaired binding to syntaxin 11. Am J Hum Genet , Janka GEHemophagocytic syndrome. Blood Rev , Jordan MB, Hildeman D, Kappler J, et alan animal model of hemophagocytic lymphohistiocytosis HLHCD8T cells and interferon gamma are essential for the disorder. Blood , Sayos J, Wu C, Morra M, et althe Xlinked lymphoproliferativedisease gene product SAP regulates signals induced through the coreceptor SLAM. Nature , Coffey AJ, Brooksbank RA, Brandau O, et al Host response to EBV infection in Xlinked lymphoproliferative disease from mutations is an SH2 domain encoding gene. Nature Genet , Nichols KE, Harkin DP, Levitz S, et alinactivating mutations in SH2encoding gene in Xlinked lymphoproliferative syndrome. Proc Natl Acad Sci , Nagy N, Matskova L, Kis LL, et althe proapoptotic function of SAP provides a clue to the clinical picture of Xlinked lymphoproliferative disease. Proc Natl Acad Sci USA , Kawada J, Kimura H, Shibata Y, et alevaluation of apoptosis in EpsteinBarr virusassociated hemophagocytic lymphohistiocytosis. J Med Virol , Sumegi J, Huang D, Lanyi A, et alcorrelation of mutations of the SH2D1A gene and epsteinbarr virus infection with clinical phenotype and outcome in Xlinked lymphoproliferative disease. Blood , Maeda A, Wakiguchi H, Yokoyama W, et alpersitently high EpsteinBarr virusebvloads in peripheral blood lymphocytes from patients with chronic active EBV infection. J Infect Dis , Kasahara Y, Yachie A, Takei K, et aldifferential cellular targets of EpsteinBarr virusebvinfection between acute EBVassociated hemophagocytic lymphohistiocytosis and chronic active EBV infection. Blood , Chuang HC, Wang JM, Hsieh WC, et alupregulation of activating transcription factor5 suppresses SAP expression to activate T cells in hemophagocytic syndrome associated with EpsteinBarr virus infection and immune disorders. Am J Pathol , Chuang HC, Lay JD, Chuang SE, et alepstein Barr virus EBV latent membrane protein1 downregulates tumor necrosis factoralpha TNFalphareceptor1 and confers resistance to TNFalphainduced apoptosis in T cellsimplication for the progression to Tcell lymphoma in EBVassociated hemophagocytic syndrome. Am J Pathol , Maeda A, Kiss C, Chen F, et alebna promoter usage in EBVnegative Burkitt lymphoma cell lines converted with a neomycinresistant EBV strain. Int J Cancer , EBV HHV