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

Abstract

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.

Serum immunoglobulin G4 in Sjögren’s syndrome: a pilot study

“…However, the coincidence of EBV with low IgG4 levels in group I would contradict observations presented in the work of Nagata et al [17] in which the authors suggested that EBV-affected lymphocytes are stimulated to produce IgG4. It should be noted, however, that in the case of this research, the studied subjects were affected by Graves' disease-in which the stimulation of IgG4 production is a separate phenomenon.…”

Epstein–Barr Virus Reactivation-Induced Immunoglobulin Production: Significance on Autoimmunity

“…We found that EBV(+) lymphocytes and IgG4(+) plasma cells accumulated in the same area in 7 out of 11 resected thyroid tissue samples from Graves' disease patients [66]. These findings indicated that IgG4 was produced under the influence of EBV-reactivation in local thyroid tissue.…”

Upregulation of HLA Class I and Antiviral Tissue Responses in Hashimoto's Thyroiditis

“…Evidence of an association between autoimmune thyroid diseases (AITD) and viral infections is, however, emerging. (5)(6)(7)(8)(9)(10)(11)(12). Still, the evidence linking viral infection to disease development is limited and direct investigation of thyroid tissue for evidence of antiviral responses has rarely been undertaken.…”