The Influence of Epstein-Barr Virus Reactivation in Patients with Graves' Disease

Abstract

In Graves' disease, the IgG class autoantibody against thyrotropin receptor (TRAb) is produced excessively and induces hyperthyroidism. Epstein-Barr virus (EBV) is one of the human herpesviruses that persists for life, mainly in B lymphocytes, and is occasionally reactivated. Therefore, EBV may affect the antibody production of B lymphocytes that would normally produce TRAb. The purpose of the present study was to evaluate the association of EBV reactivation with the etiology of Graves' disease. Serum levels of EBV antibodies and IgE were determined by ELISA. TRAb levels were determined by radioreceptor assay. We performed in-situ hybridization (ISH) of EBV-encoded small RNA (EBER)1 on the thyroid tissue of one of our patients. In Graves' disease patients with TRAb levels ≥ 10%, EA antibody levels, which indicate EBV reactivation, were moderately but significantly correlated with the levels of TRAb, and weakly but significantly correlated with IgE. EBER1-ISH revealed that one of our patients had EBV-infected lymphocytes infiltrating the thyroid gland. EBV reactivation may stimulate antibody-producing B lymphocytes predisposed to make TRAb, and this may contribute to or exacerbate the disease.

Presence of Epstein–Barr virus-infected B lymphocytes with thyrotropin receptor antibodies on their surface in Graves’ disease patients and in healthy individuals

“…These results suggest that normal subjects as well as patients have TRAbs(+) EBV(+) DP cells, and together with previous reports [11–13], they support that persisting EBVs can modify TRAbs production of the host cells.…”

“…We previously reported the influence of EBV reactivation on TRAbs production using correlations between serum TRAbs levels and EBV EA antibody levels in Graves’ disease patients [11]. We considered that EBV infection could be a factor that modifies antibody production by B cells.…”

Reactivation of persistent Epstein–Barr virus (EBV) causes secretion of thyrotropin receptor antibodies (TRAbs) in EBV-infected B lymphocytes with TRAbs on their surface

“…We induced EBV reactivation in PBMCs including TRAb(+)EBV(+) cells, under the hypothesis that, in EBVinfected TRAb-predisposed B cells, the reactivation of persistent EBV would stimulate the host B cells to increase the production of TRAbs, which may cause the development or exacerbation of Graves' disease [8,9]. We detected TRAbs in 33 C culture fluids of every sample of PBMCs from Graves' disease patients and healthy controls.…”

“…Collected and fixed PBMCs were washed with PBS, and their surface TRAbs were fluorostained as per our previous report [8]. In brief, the PBMCs were incubated with 0.…”

“…On the basis of the clinical observation of Graves' disease patients, we hypothesized that in EBV-infected TRAbpredisposed B cells (TRAb-predisposed B cells, which were infected by chance with EBV, can produce TRAbs when they differentiate to plasma cells), the reactivation of persistent EBV would stimulate the host B cell to increase TRAb production, which may cause the development or exacerbation of Graves' disease [8]. We have reported that Graves' disease patients have EBV-infected B cells that have TRAbs as the surface globulin (TRAb(+)EBV(+) cells), and the same cells exist in the peripheral blood of healthy controls [9].…”