Nagata Keiko, Higaki Katsumi, Nakayama Yuji, Miyauchi Hiromi, Kiritani Yui, Kanai Kyosuke, Matsushita Michiko, Iwasaki Takeshi, Sugihara Hirotsugu, Kuwamoto Satoshi, Kato Masako, Murakami Ichiro, Nanba Eiji, Kimura Hiroshi, Hayashi Kazuhiko
Division of Molecular Pathology, Department of Pathology, Faculty of Medicine, Tottori University , Yonago, Tottori , Japan .
Autoimmunity. 2014 May;47(3):193-200. doi: 10.3109/08916934.2013.879863. Epub 2014 Jan 28.
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.
格雷夫斯病是一种由促甲状腺激素受体抗体（TRAbs）引起的自身免疫性甲状腺功能亢进症。由于爱泼斯坦-巴尔病毒（EBV）持续存在于B细胞中且偶尔会重新激活，我们推测EBV通过刺激产生TRAbs的B细胞，促进格雷夫斯病患者体内TRAbs的产生。为了使EBV刺激产生抗体的细胞，EBV必须存在于这些细胞中，但目前尚未观察到这种情况。我们检查了格雷夫斯病患者外周血中是否存在表面带有TRAbs（作为膜免疫球蛋白）的EBV感染（EBV(+)）B细胞。我们通过流式细胞术和共聚焦激光显微镜分析了13例患者和11名健康对照者的培养或未培养外周血单个核细胞（PBMC），并证实8例患者的所有培养PBMC中确实存在TRAbs(+)EBV(+)双阳性细胞。我们意外地在所有健康对照者中检测到了TRAbs(+)细胞，在8名健康对照者的所有培养PBMC中检测到了TRAbs(+)EBV(+)双阳性细胞。患者培养PBMC中TRAbs(+)细胞的频率显著高于对照者（p = 0.021）。在本研究中，我们表明存在表面带有TRAbs的EBV感染B淋巴细胞，这可能是产生过量TRAbs（格雷夫斯病的致病性自身抗体）的一个因素。这是我们关于EBV促进格雷夫斯病患者TRAbs产生这一假说的基础证据。我们的结果进一步表明健康对照者具有产生TRAbs的潜力。这为我们深入了解格雷夫斯病的发病机制提供了重要线索。
