Luo Yuqian, Yoshihara Aya, Oda Kenzaburo, Ishido Yuko, Suzuki Koichi
Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University , Tokyo , Japan.
Department of Clinical Laboratory Science, Faculty of Medical Technology, Teikyo University, Tokyo, Japan; Department of Education Planning and Development, Faculty of Medicine, Toho University, Tokyo, Japan.
Front Endocrinol (Lausanne). 2016 Nov 14;7:144. doi: 10.3389/fendo.2016.00144. eCollection 2016.
Graves' hyperthyroidism is caused by autoantibodies directed against the thyroid-stimulating hormone receptor (TSHR) that mimic the action of TSH. The establishment of Graves' hyperthyroidism in experimental animals has proven to be an important approach to dissect the mechanisms of self-tolerance breakdown that lead to the production of thyroid-stimulating TSHR autoantibodies (TSAbs). "Shimojo's model" was the first successful Graves' animal model, wherein immunization with fibroblasts cells expressing TSHR and a major histocompatibility complex (MHC) class II molecule, but not either alone, induced TSAb production in AKR/N (H-2) mice. This model highlights the importance of coincident MHC class II expression on TSHR-expressing cells in the development of Graves' hyperthyroidism. These data are also in agreement with the observation that Graves' thyrocytes often aberrantly express MHC class II antigens mechanisms that remain unclear. Our group demonstrated that cytosolic self-genomic DNA fragments derived from sterile injured cells can induce aberrant MHC class II expression and production of multiple inflammatory cytokines and chemokines in thyrocytes , suggesting that severe cell injury may initiate immune responses in a way that is relevant to thyroid autoimmunity mediated by cytosolic DNA signaling. Furthermore, more recent successful Graves' animal models were primarily established by immunizing mice with TSHR-expressing plasmids or adenovirus. In these models, double-stranded DNA vaccine contents presumably exert similar immune-activating effect in cells at inoculation sites and thus might pave the way toward successful Graves' animal models. This review focuses on evidence suggesting that cell injury-derived self-DNA fragments could act as Graves' disease triggers.
格雷夫斯氏甲状腺功能亢进症是由针对促甲状腺激素受体（TSHR）的自身抗体引起的，这些自身抗体模拟了促甲状腺激素的作用。在实验动物中建立格雷夫斯氏甲状腺功能亢进症已被证明是剖析导致促甲状腺TSHR自身抗体（TSAbs）产生的自身耐受破坏机制的重要方法。“下条模型”是第一个成功的格雷夫斯氏动物模型，其中用表达TSHR和主要组织相容性复合体（MHC）II类分子的成纤维细胞进行免疫，但单独使用这两种细胞均不能诱导AKR/N（H-2）小鼠产生TSAb。该模型突出了在表达TSHR的细胞上同时表达MHC II类分子在格雷夫斯氏甲状腺功能亢进症发展中的重要性。这些数据也与格雷夫斯氏甲状腺细胞经常异常表达MHC II类抗原这一观察结果一致，但其机制尚不清楚。我们的研究小组表明，来自无菌损伤细胞的胞质自身基因组DNA片段可诱导甲状腺细胞异常表达MHC II类分子并产生多种炎性细胞因子和趋化因子，这表明严重的细胞损伤可能以与胞质DNA信号介导的甲状腺自身免疫相关的方式引发免疫反应。此外，最近更多成功的格雷夫斯氏动物模型主要是通过用表达TSHR的质粒或腺病毒免疫小鼠建立的。在这些模型中，双链DNA疫苗成分可能在接种部位的细胞中发挥类似的免疫激活作用，从而可能为成功建立格雷夫斯氏动物模型铺平道路。这篇综述重点关注表明细胞损伤衍生的自身DNA片段可能作为格雷夫斯病触发因素的证据。
