A transgenic model of Gcaves disease bearing human autoantibody genes

携带人类自身抗体基因的 Gcaves 病转基因模型

基本信息

批准号：
14370326
负责人：
AKAMIZU Takashi
金额：
$ 8.96万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

Graves' disease (GD) is. an organ-specific autoimmune disease characterized by hyperthyroidism. Agonistic anti-thyrotropin receptor antibodies (Thyroid-stimulating ([TS]-Ab), which mimic the 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 the 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 B 1 cells expressing the TSAb persisted and accumulated in the peritoneal cavity, a finding consistent with previous, demonstrations that the maintenance of B 1 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。激动性抗促甲状腺素受体抗体（促甲状腺素 ([TS]-Ab) 模仿 TSH 作用，被认为会导致 GD。然而，TSAb 产生的精确免疫机制仍然难以捉摸。以前使用 TSH 受体导致的免疫方法短暂性甲状腺功能亢进症，但似乎不足以全面了解自身免疫反应的发展。为了在小鼠中产生 GD 相关的自身免疫，我们在这里产生了 TSAb 转基因。在 B 细胞中表达患者来源的 TSAb 的小鼠中，人类 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 TSH 水平降低、甲状腺对高锝酸的摄取增加、体温过高和甲状腺功能亢进。我们发现人 TSAb 免疫球蛋白和游离甲状腺素的血清水平之间存在相关性。此外，表达 TSAb 的常规 B 细胞也存在部分相关性。外周细胞被删除，而表达 TSAb 的 B 1 细胞在腹膜腔中持续存在和积累，这一发现与之前的结果一致，表明 B 1 细胞的维持在自身免疫性疾病的发展中发挥着重要作用。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。