title: Reactivation of persistent Epstein-Barr virus (EBV) causes secretion of thyrotropin receptor antibodies (TRAbs) in EBV-infected B lymphocytes with TRAbs on their surface.
abstract: Epstein-Barr virus (EBV) is a ubiquitous virus that infects most adults latently. It persists in B lymphocytes and reactivates occasionally. Graves' disease is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies (TRAbs). We have reported that Graves' disease patients and healthy controls have EBV-infected lymphocytes that have TRAbs on their surface (TRAb(+)EBV(+) cells) in peripheral blood mononuclear cells (PBMCs). EBV reactivation is known to be associated with plasma cell differentiation and antibody production of B cells. In this study, we investigated whether TRAb(+)EBV(+) cells really produce TRAbs or not when persistent EBV is reactivated. We cultured PBMCs from 12 Graves' disease patients and 12 healthy controls for several days with cyclosporine A to expand the EBV-infected cell population, and then compared TRAb levels between EBV reactivation by 33 °C culture and EBV nonreactivation by 37 °C culture of PBMCs. Flow cytometry confirmed that all samples at day 0 (reactivation starting point) contained TRAb(+)EBV(+) cells. During 33 °C culture, EBV-reactivated cells with EBV-gp350/220 expression increased from about 1 to 4%. We quantified TRAb levels in culture fluids by radio-receptor assay, and detected an increased concentration for at least one sampling point at 33 °C (from days 0 to 12) for all patients and healthy controls. TRAb levels were significantly higher in supernatants of 33 °C culture than of 37 °C culture, and also significantly higher in supernatants from patients than those from controls. This study revealed TRAb production from TRAb(+)EBV(+) cells in response to reactivation induction of persistent EBV in different efficiencies between patients and controls.
authors.affiliation: Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Tottori , Japan .
authors.forename: Keiko
authors.initials: K
authors.lastname: Nagata
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Marika
authors.initials: M
authors.lastname: Ochi
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kanai
authors.forename: Michiko
authors.initials: M
authors.lastname: Matsushita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwamoto
authors.forename: Masako
authors.initials: M
authors.lastname: Kato
authors.forename: Ichiro
authors.initials: I
authors.lastname: Murakami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Eiji
authors.initials: E
authors.lastname: Nanba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hayashi
mesh_terms: D000328:Adult; D000917:Antibody Formation / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology*; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D006111:Graves Disease / Q000175:diagnosis / Q000209:etiology / Q000628:therapy; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011989:Receptors, Thyrotropin / Q000276:immunology*; D014775:Virus Activation / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D011989:Receptors, Thyrotropin
keywords: Autoantibody; Graves'; disease; latent virus; pathogenesis; plasma cell differentiation