title: Evasion of affinity-based selection in germinal centers by Epstein-Barr virus LMP2A.
abstract: Epstein-Barr virus (EBV) infects germinal center (GC) B cells and establishes persistent infection in memory B cells. EBV-infected B cells can cause B-cell malignancies in humans with T- or natural killer-cell deficiency. We now find that EBV-encoded latent membrane protein 2A (LMP2A) mimics B-cell antigen receptor (BCR) signaling in murine GC B cells, causing altered humoral immune responses and autoimmune diseases. Investigation of the impact of LMP2A on B-cell differentiation in mice that conditionally express LMP2A in GC B cells or all B-lineage cells found LMP2A expression enhanced not only BCR signals but also plasma cell differentiation in vitro and in vivo. Conditional LMP2A expression in GC B cells resulted in preferential selection of low-affinity antibody-producing B cells despite apparently normal GC formation. GC B-cell-specific LMP2A expression led to systemic lupus erythematosus-like autoimmune phenotypes in an age-dependent manner. Epigenetic profiling of LMP2A B cells found increased H3K27ac and H3K4me1 signals at the zinc finger and bric-a-brac, tramtrack domain-containing protein 20 locus. We conclude that LMP2A reduces the stringency of GC B-cell selection and may contribute to persistent EBV infection and pathogenesis by providing GC B cells with excessive prosurvival effects.
authors: Department of Molecular Immunology, Research Institute for Microbial Diseases, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan;
authors: Takeharu
authors: T
authors: Minamitani
authors: Department of Molecular Immunology, Research Institute for Microbial Diseases, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; tyasui@biken.osaka-u.ac.jp ekieff@rics.bwh.harvard.edu kikutani@biken.osaka-u.ac.jp.
authors: Teruhito
authors: T
authors: Yasui
authors: Division of Infectious Disease, Department of Medicine, Microbiology and Immunobiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors: Yijie
authors: Y
authors: Ma
authors: Division of Infectious Disease, Department of Medicine, Microbiology and Immunobiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors: Hufeng
authors: H
authors: Zhou
authors: DNA-chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors: Daisuke
authors: D
authors: Okuzaki
authors: Department of Molecular Immunology, Research Institute for Microbial Diseases, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan;
authors: Chiau-Yuang
authors: CY
authors: Tsai
authors: Department of Molecular Immunology, Research Institute for Microbial Diseases, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan;
authors: Shuhei
authors: S
authors: Sakakibara
authors: Division of Infectious Disease, Department of Medicine, Microbiology and Immunobiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors: Benjamin E
authors: BE
authors: Gewurz
authors: Division of Infectious Disease, Department of Medicine, Microbiology and Immunobiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; tyasui@biken.osaka-u.ac.jp ekieff@rics.bwh.harvard.edu kikutani@biken.osaka-u.ac.jp.
authors: Elliott
authors: E
authors: Kieff
authors: Department of Molecular Immunology, Research Institute for Microbial Diseases, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; tyasui@biken.osaka-u.ac.jp ekieff@rics.bwh.harvard.edu kikutani@biken.osaka-u.ac.jp.
authors: Hitoshi
authors: H
authors: Kikutani
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000737:chemistry; D001327:Autoimmune Diseases / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation; D019070:Cell Lineage; D003433:Crosses, Genetic; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006579:Heterozygote; D056724:Immunity, Humoral; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D014763:Viral Matrix Proteins / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D001323:Autoantibodies; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011947:Receptors, Antigen, B-Cell; D014763:Viral Matrix Proteins; D049452:Green Fluorescent Proteins
keywords: B cells; LMP2A; autoimmune diseases; germinal center; plasma cell differentiation