Estradiol Affects Epstein–Barr Virus Reactivation-Induced Thyrotropin Receptor Antibody and Immunoglobulin Production in Graves’ Disease Patients and Healthy Controls

Abstract

Epstein–Barr virus (EBV) is a gamma-herpesvirus persisting mainly in human B lymphocytes. EBV reactivation induces host cells to differentiate into plasma cells and is related to autoimmune diseases. Graves’ disease, an autoimmune hyperthyroidism, is caused by the thyrotropin receptor antibody (TRAb), which overstimulates thyroid stimulating hormone receptor. The disease occurs predominantly in women, which suggests involvement with estrogen. Graves’ disease patients and healthy controls have EBV-infected lymphocytes with TRAb on the surface (TRAb(+)EBV(+) cells) in peripheral blood mononuclear cells (PBMCs). TRAb can be produced by reactivation of EBV in vitro, which is an alternative system of antibody production. In this study, we cultured PBMCs from Graves’ disease patients and healthy controls with 0, 1, and 100 nM estradiol, corresponding to control, midluteal, and pregnancy levels, respectively, and analyzed the levels of TRAb, total-IgG, and total-IgM during EBV reactivation. We found that 1 nM estradiol increased TRAb levels and 100 nM estradiol slightly lowered them in both patients and controls. In patients, IgM production at 100 nM estradiol was significantly lower than that at 0 nM estradiol (p = 0.028). Estradiol increased the ratio of IgG production to immunoglobulin G (IgG) and immunoglobulin M (IgM) production (IgG/IgG + IgM), which suggested an increase in class switch recombination in the process of EBV reactivation-induced Ig production. Moreover, TRAb production was stimulated by a midluteal level of estradiol and was suppressed by a pregnancy level of estradiol in controls and patients. These results were consistent with premenstrual worsening and maternity improving of autoimmune diseases, including Graves’ disease.

High Level Estradiol Induces EBV Reactivation and EBV gp350/220(+)CD138(+) Double-positive B Cell Population in Graves’ Disease Patients and Healthy Controls

“…1). However, in our previous study, production of TRAb and IgM at 100 nM estradiol is lower than that at 0 nM estradiol, 12 which seems to contradict our current data, but we often observed abundant antibodies in culture supernatant in plate wells with only a few cells. In our previous study (0 nM estradiol), the percentage of gp350/220(+) cells or CD138(+) cells increased at day 12 compared with day 0 of reactivation.…”

“…The present results and our previous results showing that high estradiol concentrations decrease TRAb and IgM production are consistent with the clinical observations of improvement of Graves' disease during maternity and exacerbation postpartum. 6,12,13…”

Gender and the Sex Hormone Estradiol Affect Multiple Sclerosis Risk Gene Expression in Epstein-Barr Virus-Infected B Cells

“…Estrogen could also interact with EBV. One research group have indicated that high estradiol levels (representative of the third trimester of pregnancy) reduced EBV reactivation ( 56 , 57 ). Such a mechanism whereby estrogen controls EBV infection could explain the reduced MS disease activity typical of the third trimester of pregnancy, when estrogen is highest.…”

“…We used estradiol (E2, or 17b-estradiol) in this study as it is the major form of endogenous estrogen in humans (53). A concentration of 100 nM estradiol was chosen based on prior studies (including those in LCLs) which corresponds to pregnancy level (54)(55)(56)(57).…”

Evaluation of the Activities of Thyroid Hormones Among Pre- and Post-menopausal Euthyroid Women: A Cross-sectional Study from a Tertiary Care Teaching Hospital in India

“…Thyroid disease was also attributed to the reactivation of Epstein-Barr virus (EBV) in a recent study from Japan. This study had noted that during EBV reactivation, thyrotropin receptor antibodies (TRAbs) are formed, which in turn stimulates the TSH receptors and causes thyroid dysfunction [30].…”