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Original Articles

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

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Pages 193-200 | Received 30 Sep 2013, Accepted 27 Dec 2013, Published online: 28 Jan 2014
 

Abstract

Graves’ disease is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies (TRAbs). Because Epstein–Barr virus (EBV) persists in B cells and is occasionally reactivated, we hypothesized that EBV contributes to TRAbs production in Graves’ disease patients by stimulating the TRAbs-producing B cells. In order for EBV to stimulate antibody-producing cells, EBV must be present in those cells but that have not yet been observed. We examined whether EBV-infected (EBV(+)) B cells with TRAbs on their surface (TRAbs(+)) as membrane immunoglobulin were present in peripheral blood of Graves’ disease patients. We analyzed cultured or non-cultured peripheral blood mononuclear cells (PBMCs) from 13 patients and 11 healthy controls by flow-cytometry and confocal laser microscopy, and confirmed all cultured PBMCs from 8 patients really had TRAbs(+) EBV(+) double positive cells. We unexpectedly detected TRAbs(+) cells in all healthy controls, and TRAbs(+) EBV(+) double positive cells in all cultured PBMC from eight healthy controls. The frequency of TRAbs(+) cells in cultured PBMCs was significantly higher in patients than in controls (p = 0.021). In this study, we indicated the presence of EBV-infected B lymphocytes with TRAbs on their surface, a possible player of the production of excessive TRAbs, the causative autoantibody for Graves’ disease. This is a basic evidence for our hypothesis that EBV contributes to TRAbs production in Graves’ disease patients. Our results further suggest that healthy controls have the potential for TRAbs production. This gives us an important insight into the pathogenesis of Graves’ disease.

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Erratum

Acknowledgements

The authors would like to thank Enago (www.enago.jp) for the English language review. The authors thank Dr. Shuji Fukata (Tajiri Clinic), Professor Shin-Ichi Hayashi (Tottori University), Professor Takeshi Sairenji (EM Research Organization), and Dr. Yoshiko Hoshikawa (Tottori University) for kind guidance and discussion. We also thank Dr. Kiyosuke Ishiguro (Tottori University) for providing suggestive samples. The authors thank Dr. Kaoru Kato (Tottori University), Dr. Hitoshi Sano (Tottori University), and Mr. Kiyoshige Yamamoto (Tottori University) for helpful assistance.

Supplementary material available online

Supplementary Figures 1–3