Role of self-tolerance and chronic stimulation in the long-term persistence of adenovirus-induced thyrotropin receptor antibodies in wild-type and transgenic mice.
Role of self-tolerance and chronic stimulation in the long-term persistence of adenovirus-induced thyrotropin receptor antibodies in wild-type and transgenic mice.
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自我耐受和慢性刺激在野生型和转基因小鼠中腺病毒诱导的促甲状腺素受体抗体长期持续存在中的作用。
DOI：
10.1089/thy.2012.0008
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
Rapoport,Basil
中科院分区：
文献类型：
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作者：
McLachlan,SandraM;Aliesky,HollyA;Chen,Chun-Rong;Rapoport,Basil
背景：用腺病毒表达人促甲状腺激素受体（TSHR）或其A亚基的DNA免疫小鼠，可以诱导Graves病样疾病（由某些小鼠品系的促甲状腺激素受体（TSHR）抗体和甲状腺功能亢进症反映）。传统的方法包括每隔3周注射两次或三次腺病毒，并在第一次注射后10周实施安乐死。为了研究TSHR抗体持久性在小鼠中具有不同程度的自身耐受性的TSHR A-亚基，我们研究了延迟安乐死，直到20周后的初始immunose.Methods的效果：野生型（WT）小鼠和转基因（TG）小鼠表达低甲状腺内水平的人TSHR A-亚基免疫A-亚基腺病毒两次;第二组小鼠免疫三次。对初次免疫后4、10和20周（安乐死）获得的血清进行促甲状腺激素（TSH）结合抑制（TBI）、抗体与TSHR A亚基蛋白包被的酶联免疫吸附测定（ELISA）平板的结合和甲状腺刺激抗体活性（TSAb;环磷酸腺苷[cAMP]生成）检测。血清甲状腺素（T4）和甲状腺组织学进行了研究，在安乐死。结果：大多数WT小鼠保留高TSHR抗体水平TBI或ELISA测定安乐死，但只有约50%的TSAb阳性。低表达tgs表现出自身耐受性，TBI或ELISA阳性小鼠较少，抗体水平低于WT同窝出生小鼠。在WT小鼠中，两次或三次免疫后抗体持久性相似;对于tgs，仅免疫三次的小鼠在20周时可检测到TSAb。不像我们以前的观察甲状腺功能亢进症在WT小鼠免疫后4或10周检查，所有的小鼠甲状腺功能正常，在20 weeks.Conclusions：我们的研究结果诱导TSHR抗体在小鼠中，类似于人类甲状腺自身抗体的数据，表明参数，有助于抗体的浓度，从而发挥关键作用，长期持久的TSHR抗体的自我耐受性的TSHR和慢性刺激的程度。
Background:Graves'-like disease, reflected by thyrotropin receptor (TSHR) antibodies and hyperthyroidism in some mouse strains, can be induced by immunization with adenovirus-expressing DNA for the human TSHR or its A-subunit. The conventional approach involves two or three adenovirus injections at 3-week intervals and euthanasia 10 weeks after the first injection. To investigate TSHR antibody persistence in mice with differing degrees of self-tolerance to the TSHR A-subunit, we studied the effect of delaying euthanasia until 20 weeks after the initial immunization.Methods:Wild-type (WT) mice and transgenic (tg) mice expressing low intrathyroidal levels of the human TSHR A-subunit were immunized with A-subunit-adenovirus on two occasions; a second group of mice was immunized on three occasions. Sera obtained 4, 10, and 20 weeks (euthanasia) after the initial immunization were tested for thyrotropin (TSH) binding inhibition (TBI), antibody binding to TSHR A-subunit protein-coated enzyme-linked immunosorbent assay (ELISA) plates, and thyroid stimulating antibody activity (TSAb; cyclic adenosine monophosphate [cAMP] generation). Serum thyroxine (T4) and thyroid histology were studied at euthanasia.Results:The majority of WT mice retained high TSHR antibody levels measured by TBI or ELISA at euthanasia but only about 50% were TSAb positive. Low-expressor tgs exhibited self-tolerance, with fewer mice positive by TBI or ELISA and antibody levels were lower than in WT littermates. In WT mice, antibody persistence was similar after two or three immunizations; for tgs, only mice immunized three times had detectable TSAb at 20 weeks. Unlike our previous observations of hyperthyroidism in WT mice examined 4 or 10 weeks after immunization, all mice were euthyroid at 20 weeks.Conclusions:Our findings for induced TSHR antibodies in mice, similar to data for human thyroid autoantibodies, indicate that the parameters that contribute to the concentration of the antibody and thereby play a critical role in long-term persistence of TSHR antibodies are the degree of self-tolerance to the TSHR and chronic stimulation.