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Viral Immunol. 2018 Oct;31(8):540-547. doi: 10.1089/vim.2018.0042. Epub 2018 Sep 17.

Epstein-Barr Virus Lytic Reactivation Induces IgG4 Production by Host B Lymphocytes in Graves' Disease Patients and Controls: A Subset of Graves' Disease Is an IgG4-Related Disease-Like Condition.

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1 Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Japan .
2 Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University , Yonago, Japan .
3 Department of Pathobiological Science and Technology, School of Health Science, Faculty of Medicine, Tottori University , Yonago, Japan .
4 Division of Oral and Maxillofacial Biopathological Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University , Yonago, Japan .
5 Division of Organ Regeneration Surgery, Department of Surgery, Faculty of Medicine, Tottori University , Yonago, Japan .


Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a newly recognized systemic fibroinflammatory disease with characteristic histological findings and high serum IgG4 levels. Epstein-Barr virus (EBV) is a persistent herpesvirus in B lymphocytes, and we previously reported EBV reactivation-induced Ig production. We showed that EBV reactivation induced the production of thyrotropin receptor antibodies, the causative antibodies of Graves' disease. In the present study, we investigated whether EBV reactivation induced IgG4 production and if EBV-positive B cells or IgG4-positive plasma cells are present in the thyroid tissues of Graves' disease patients with lymphoplasmacytic infiltration. EBV-encoded small RNA1 (EBER1) in situ hybridization and immunohistochemistry for IgG and IgG4 were performed on seven resected thyroid tissues with lymphoplasmacytic infiltration collected from the thyroids of 11 Graves' disease patients. We then cultured the lymphocytes of 13 Graves' disease patients and 14 controls and induced EBV reactivation to measure IgG4 levels in culture fluids. We detected EBER1-positive cells and IgG4-positive plasma cells in the same area of thyroid tissues. EBV-reactivated cells with IgG4 on their surface were observed in culture cells, and IgG4 production was detected in culture fluids. The IgG4/IgG percentage was higher than that in normal serum level. A subset of Graves' disease is an IgG4-RD-like condition, not an IgG4-RD. EBV reactivation stimulates IgG4 production, which may result in high serum IgG4 levels and promote IgG4-positive plasma cell infiltration. EBER1 needs to be examined when an increase in IgG4-positive plasma cell numbers is noted.


Epstein–Barr virus; Epstein–Barr virus reactivation; Epstein–Barr virus-encoded small RNA1; Graves' disease; IgG4-related disease

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