Epstein-Barr Virus Lytic Reactivation Activates B Cells Polyclonally and Induces Activation-Induced Cytidine Deaminase Expression: A Mechanism Underlying Autoimmunity and Its Contribution to Graves' Disease.
Graves' disease is an autoimmune disease that results in and is the most common cause of hyperthyroidism, and the reactivation of persisting Epstein-Barr virus (EBV) in B lymphocytes induces the differentiation of host B cells into plasma cells. We previously reported that some EBV-infected B cells had thyrotropin receptor antibodies (TRAbs) as surface immunoglobulins (Igs), and EBV reactivation induced these TRAb+EBV+ cells to produce TRAbs. EBV reactivation induces Ig production from host B cells. The purpose of the present study was to examine total Ig productions from B cell culture fluids and to detect activation-induced cytidine deaminase (AID), nuclear factor kappa B (NF-κB), and EBV latent membrane protein (LMP) 1 in culture B cells during EBV reactivation induction and then we discussed the mechanisms of EBV reactivation-induced Ig production in relation to autoimmunity. We showed that the EBV reactivation induces the production of every isotype of Ig and suggested that the Ig production was catalyzed by AID through LMP1 and NF-κB. The results that the amount of IgM was significantly larger compared with IgG suggested the polyclonal B cell activation due to LMP1. We proposed the pathway of EBV reactivation induced Ig production; B cells newly infected with EBV are activated by polyclonal B cell activation and produce Igs through plasma cell differentiation induced by EBV reactivation. LMP1-induced AID enabled B cells to undergo class-switch recombination to produce every isotype of Ig. According to this mechanism, EBV rescues autoreactive B cells to produce autoantibodies, which contribute to the development and exacerbation of autoimmune diseases.
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Keiko
K
Nagata
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Keisuke
K
Kumata
2 Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , Yonago, Japan .
Yuji
Y
Nakayama
3 Division of Biosignaling, Department of Biomedical Sciences, Faculty of Medicine, Tottori University , Yonago, Japan .
Yukio
Y
Satoh
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Hirotsugu
H
Sugihara
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Sayuri
S
Hara
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Michiko
M
Matsushita
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Satoshi
S
Kuwamoto
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Masako
M
Kato
4 Department of Pathology, Kochi University Medical School Medical Course , Nankoku-shi, Japan .
Ichiro
I
Murakami
1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
Kazuhiko
K
Hayashi
D000328:Adult; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism*; D005260:Female; D006111:Graves Disease / Q000503:physiopathology*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis; D015854:Up-Regulation; D014763:Viral Matrix Proteins / Q000032:analysis; D014775:Virus Activation
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016328:NF-kappa B; D014763:Viral Matrix Proteins; D003564:Cytidine Deaminase
Epstein–Barr virus; Graves' disease; activation-induced cytidine deaminase; autoreactive B cells; polyclonal B cell activation; reactivation