Epstein-Barr virus (EBV) is a human herpes virus that latently infects B lymphocytes. When EBV is reactivated, host B cells differentiate into plasma cells and produce IgM-dominant antibodies as well as many progeny virions. The aims of the present study were to confirm the IgM dominance of thyrotropin-receptor antibodies (TRAbs) produced by EBV reactivation and investigate the roles of TRAb-IgM in Graves' disease. Peripheral blood mononuclear cells (PBMCs) containing TRAb-producing cells were stimulated for EBV reactivation, and TRAb-IgM and TRAb-IgG were measured by ELISA. TRAb-IgM were purified and TSH-binding inhibitory activities were assessed using a radio-receptor assay. Porcine thyroid follicular epithelial cells were cultured with TRAb-IgM and/or complements to measure the intracellular levels of cAMP and the amount of LDH released. TRAb-IgM/TRAb-IgG (the MG ratio) was examined in sequential serum samples of Graves' disease and compared among groups of thyroid function. The results obtained showed that IgM-dominant TRAb production was induced by EBV reactivation. TRAb-IgM did not inhibit TSH binding to TSH receptors and did not transduce hormone-producing signals. However, it destroyed thyroid follicular epithelial cells with complements. The MG ratio was significantly higher in samples of hyperthyroidism or hypothyroidism than in those with normal function or in healthy controls. A close relationship was observed between TRAb-IgM produced by EBV reactivation and the development and exacerbation of Graves' disease. The present results provide novel insights for the development of prophylaxis and therapeutics for Graves' disease.
Background: Atrial fibrillation (AF) is the most common arrhythmia. AF is highly correlated with multiple risk factors including heart failure, age, obesity, and type 2 diabetes. Among risk factors, the incidence in obesity is increasing worldwide. Recently, it was reported that SGLT2 inhibitors reduced the incidence of atrial fibrillation. However, it is unclear how the treatment with SGLT2 inhibitors has effects on vulnerability to AF. In this study, we examined the effects on the inducibility and duration of AF by treatment with SGLT2 inhibitors in diet-induced obese mice. Methods: Mice were fed a normal chow diet (NCD) or high-fat diet (HFD). Following diet-loading, we randomly divided the animals into groups: NCD+vehicle, HFD+vehicle, and HFD+ SGLT2 treatments. Induction of AF was performed by transesophageal atrial burst pacing. Furthermore, we evaluated cardiac function, blood pressure, atrial fibrosis, and glucose tolerance at the end of the treatments. Results: The results showed that HFD-fed mice increased the inducibility of AF compared to NCD mice. In addition, treatment with the SGLT2 inhibitor in HFD-fed mice dose-dependently reduced the inducibility and duration of AF. There were no significant differences in cardiac function, blood pressure, and fibrosis among all groups. Impairment of glucose tolerance in HFD-induced obesity was improved by treatment with the SGLT2 inhibitor. Conclusion: Treatment with the SGLT2 inhibitor reduced the inducibility of AF and shortened the duration of AF without affecting atrial structural remodeling, suggesting that the SGLT2 inhibitor effectively prevents AF in obesity.
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