title: Mouse model of Epstein-Barr virus LMP1- and LMP2A-driven germinal center B-cell lymphoproliferative disease.
abstract: Epstein-Barr virus (EBV) is a major cause of immunosuppression-related B-cell lymphomas and Hodgkin lymphoma (HL). In these malignancies, EBV latent membrane protein 1 (LMP1) and LMP2A provide infected B cells with surrogate CD40 and B-cell receptor growth and survival signals. To gain insights into their synergistic in vivo roles in germinal center (GC) B cells, from which most EBV-driven lymphomas arise, we generated a mouse model with conditional GC B-cell LMP1 and LMP2A coexpression. LMP1 and LMP2A had limited effects in immunocompetent mice. However, upon T- and NK-cell depletion, LMP1/2A caused massive plasmablast outgrowth, organ damage, and death. RNA-sequencing analyses identified EBV oncoprotein effects on GC B-cell target genes, including up-regulation of multiple proinflammatory chemokines and master regulators of plasma cell differentiation. LMP1/2A coexpression also up-regulated key HL markers, including CD30 and mixed hematopoietic lineage markers. Collectively, our results highlight synergistic EBV membrane oncoprotein effects on GC B cells and provide a model for studies of their roles in immunosuppression-related lymphoproliferative diseases.
authors.affiliation: Laboratory of Infectious Diseases and Immunity, National Institutes of Biomedical Innovation, Health, and Nutrition, Ibaraki, Osaka, Japan 567-0085.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Minamitani
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham & Woman's Hospital, Harvard Medical School, Boston, MA 02115.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham & Woman's Hospital, Harvard Medical School, Boston, MA 02115.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Hufeng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan 565-0871.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.affiliation: Department of Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan 565-0871.
authors.forename: Chao-Yuan
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan 565-0871.
authors.forename: Masanori
authors.initials: M
authors.lastname: Obana
authors.affiliation: DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan 565-0871.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan 565-0871.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.affiliation: Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Osaka, Japan 565-0871.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan 100-0004.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham & Woman's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Immune Regulation, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan 565-0871.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikutani
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham & Woman's Hospital, Harvard Medical School, Boston, MA 02115; tyasui@nibiohn.go.jp ekieff@partners.org bgewurz@partners.org.|Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Elliott
authors.initials: E
authors.lastname: Kieff
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Brigham & Woman's Hospital, Harvard Medical School, Boston, MA 02115; tyasui@nibiohn.go.jp ekieff@partners.org bgewurz@partners.org.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Gewurz
authors.affiliation: Laboratory of Infectious Diseases and Immunity, National Institutes of Biomedical Innovation, Health, and Nutrition, Ibaraki, Osaka, Japan 567-0085; tyasui@nibiohn.go.jp ekieff@partners.org bgewurz@partners.org.
authors.forename: Teruhito
authors.initials: T
authors.lastname: Yasui
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D015967:Gene Expression Regulation, Viral / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology / Q000473:pathology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000276:immunology*; D006689:Hodgkin Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins
keywords: Epstein–Barr virus; LMP1; LMP2A; plasmablast; posttransplant lymphoproliferative disorder