Kim-Saijo Misa, Akamizu Takashi, Ikuta Koichi, Iida Yasuhiko, Ohmori Katsuyuki, Matsubara Kazumi, Matsuda Yoichi, Suzuki Misao, Matsuda Fumihiko, Nakao Kazuwa
Department of Medicine and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Eur J Immunol. 2003 Sep;33(9):2531-8. doi: 10.1002/eji.200324255.
Graves' disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism. Agonistic anti-thyrotropin receptor antibodies (thyroid-stimulating antibodies, TSAb), which mimic the thyrotropin (TSH) action, are thought to cause GD. The precise immunological mechanism of TSAb production, however, remains elusive. Previous immunization approaches using TSH receptor led to transient hyperthyroidism, but did not seem sufficient for comprehensive understanding of the development of autoimmune responses. To create GD-related autoimmunity in mice, we here generated TSAb-transgenic mice in which a patient-derived TSAb is expressed in B cells. Expression of the human TSAb in mice resulted in various manifestations of hyperthyroidism including increased free thyroxine levels with concomitantly decreased TSH levels, increased thyroid uptake of technetium pertechnetate, hyperthermia and thyroid hyperplasia. We found a correlation between the serum levels of human TSAb immunoglobulin and free thyroxine. In addition, conventional B cells expressing the TSAb were partially deleted in the periphery while B1 cells expressing the TSAb persisted and accumulated in the peritoneal cavity, a finding consistent with previous demonstrations that the maintenance of B1 cells plays an important role in the development of autoimmune diseases. Thus, our transgenic mouse may provide a novel and useful animal model for elucidating the pathogenesis and pathophysiology of GD.
格雷夫斯病（GD）是一种以甲状腺功能亢进为特征的器官特异性自身免疫性疾病。模拟促甲状腺激素（TSH）作用的刺激性抗促甲状腺激素受体抗体（甲状腺刺激抗体，TSAb）被认为可导致GD。然而，TSAb产生的确切免疫机制仍不清楚。以往使用促甲状腺激素受体的免疫方法会导致短暂的甲状腺功能亢进，但似乎不足以全面了解自身免疫反应的发展。为了在小鼠中建立与GD相关的自身免疫，我们在此生成了TSAb转基因小鼠，其中在B细胞中表达患者来源的TSAb。人TSAb在小鼠中的表达导致了甲状腺功能亢进的各种表现，包括游离甲状腺素水平升高，同时促甲状腺激素水平降低，高锝酸盐的甲状腺摄取增加，体温过高和甲状腺增生。我们发现人TSAb免疫球蛋白的血清水平与游离甲状腺素之间存在相关性。此外，表达TSAb的常规B细胞在外周部分缺失，而表达TSAb的B1细胞在腹腔中持续存在并积累，这一发现与先前的证明一致，即B1细胞的维持在自身免疫性疾病的发展中起重要作用。因此，我们的转基因小鼠可能为阐明GD的发病机制和病理生理学提供一种新颖且有用的动物模型。
