High-level intrathymic thyrotrophin receptor expression in thyroiditis-prone mice protects against the spontaneous generation of pathogenic thyrotrophin receptor autoantibodies.
High-level intrathymic thyrotrophin receptor expression in thyroiditis-prone mice protects against the spontaneous generation of pathogenic thyrotrophin receptor autoantibodies.
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甲状腺炎易感小鼠胸腺内促甲状腺素受体的高水平表达可防止致病性促甲状腺素受体自身抗体的自发产生。
DOI：
10.1111/cei.12928
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发表时间：
2017
影响因子：
4.6
通讯作者：
Rapoport,B
中科院分区：
文献类型：
--
作者：
McLachlan,SM;Aliesky,HA;Banuelos,B;Lesage,S;Collin,R;Rapoport,B
促甲状腺激素受体（TSHR）A亚单位是致病性自身抗体靶向的自身抗原，导致Graves甲状腺功能亢进症，一种常见的自身免疫性疾病。以前，我们报道了在甲状腺炎易感的非肥胖型糖尿病（NOD）H2 h4小鼠中自发产生致病性TSHR抗体，该小鼠携带人TSHR A亚基转基因，在甲状腺和胸腺中均以低水平表达（Lo-表达转基因）。本研究测试了最近的证据表明，胸腺内高TSHR表达保护免受人类致病性TSHR抗体的发展。通过连续回交，我们将甲状腺和胸腺中高水平表达的人TSHR A亚基转基因（Hi-表达转基因）转移到NOD.H2h4背景中。在第6代回交（> 98%NOD.H2h4基因组）中，仅转基因后代自发产生免疫球蛋白（IG）G类非致病性人TSHR A亚单位抗体。相反，转基因和非转基因后代都产生了甲状腺球蛋白和甲状腺过氧化物酶抗体。然而，非致病性人类TSHR抗体水平在高表达后代低于低表达转基因小鼠。此外，通过抑制TSH与TSHR结合检测到的致病性TSHR抗体仅在携带Lo-表达子而非Hi-表达子转基因的回交后代中产生。在NOD.H2h4胸腺中高表达和低表达的人TSHR A亚基不能用转基因位置来解释，即2号染色体（127-147 Mb;高表达）和1号染色体（22.9-39.3 Mb;低表达）。然而，使用甲状腺炎易感NOD.H2h4小鼠和两个转基因品系，我们的数据支持人类研究的相关性，即胸腺内TSHR低表达与发展致病性TSHR抗体的易感性相关，而胸腺内TSHR高表达具有保护作用。
The thyrotrophin receptor (TSHR) A-subunit is the autoantigen targeted by pathogenic autoantibodies that cause Graves' hyperthyroidism, a common autoimmune disease in humans. Previously, we reported that pathogenic TSHR antibodies develop spontaneously in thyroiditis-susceptible non-obese diabetic (NOD).H2h4mice bearing a human TSHR A-subunit transgene, which is expressed at low levels in both the thyroid and thymus (Lo-expressor transgene). The present study tested recent evidence that high intrathymic TSHR expression protects against the development of pathogenic TSHR antibodies in humans. By successive back-crossing, we transferred to the NOD.H2h4background a human TSHR A-subunit transgene expressed at high levels in the thyroid and thymus (Hi-expressor transgene). In the sixth back-cross generation (> 98% NOD.H2h4genome), only transgenic offspring produced spontaneously immunoglobulin (Ig)G class non-pathogenic human TSHR A-subunit antibodies. In contrast, both transgenic and non-transgenic offspring developed antibodies to thyroglobulin and thyroid peroxidase. However, non-pathogenic human TSHR antibody levels in Hi-expressor offspring were lower than in Lo-expressor transgenic mice. Moreover, pathogenic TSHR antibodies, detected by inhibition of TSH binding to the TSHR, only developed in back-cross offspring bearing the Lo-expressor, but not the Hi-expressor, transgene. Highversuslow expression human TSHR A-subunit in the NOD.H2h4thymus was not explained by the transgene locations, namely chromosome 2 (127–147 Mb; Hi-expressor) and chromosome 1 (22.9–39.3 Mb; low expressor). Nevertheless, using thyroiditis-prone NOD.H2h4mice and two transgenic lines, our data support the association from human studies that low intrathymic TSHR expression is associated with susceptibility to developing pathogenic TSHR antibodies, while high intrathymic TSHR expression is protective.