A monoclonal thyroid-stimulating antibody
A monoclonal thyroid-stimulating antibody
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DOI：
10.1172/jci200216991
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发表时间：
2002-12-01
影响因子：
15.9
通讯作者：
Davies, TF
中科院分区：
文献类型：
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作者：
Ando, T;Latif, R;Davies, TF
促甲状腺激素受体，也称为促甲状腺激素受体(TSHR)，是Graves病的主要抗原。刺激性TSHR抗体是甲状腺过度刺激的原因，最初被称为长效甲状腺刺激剂，因为它们的作用时间长。在此，我们报道了一种具有TSHR刺激活性的单抗(MS-1)的成功克隆和鉴定。MS-1在低至20 ng/ml的免疫球蛋白浓度下有明显的促甲状腺活性。MS-1还与天然TSHR竞争标记的TSH结合，并能竞争TSH诱导的刺激。MS-1识别TSHRα(或A)亚基内的构象表位，但不包括受体裂解区。用一种测定切割后抗体识别损失的方法，我们证明了与TSH相比，MS-1不能增强TSHR翻译后切割。由于受体切割后伴随着亚单位脱落和受体降解，因此受体的功能半衰期可能延长。MS-1的分离和鉴定为该病甲状腺刺激延长提供了新的解释，这可能是由于免疫球蛋白自身半衰期延长之外，缺乏受体切割所致。
The thyrotropin receptor, also known as the thyroid-stimulating hormone receptor (TSHR), is the primary antigen of Graves disease. Stimulating TSHR antibodies are the cause of thyroid overstimulation and were originally called long-acting thyroid stimulators due to their prolonged action. Here we report the successful cloning and characterization of a monoclonal antibody (MS-1) with TSHR-stimulating activity. The thyroid-stimulating activity of MS-1 was evident at IgG concentrations as low as 20 ng/ml. MS-1 also competed for radiolabeled TSH binding to the native TSHR and was able to compete for TSH-induced stimulation. MS-1 recognized a conformational epitope within the TSHR a (or A) subunit but excluding the receptor cleavage region. Using an assay measuring loss of antibody recognition after cleavage we demonstrated that MS-1, in contrast to TSH, was unable to enhance TSHR posttranslational cleavage. Since receptor cleavage is followed by a subunit shedding and receptor degradation, the functional half-life of the receptor may be extended. The isolation and characterization of MS-1 provides a novel explanation for the prolonged thyroid stimulation in this disease which maybe secondary to the lack of receptor cleavage in addition to the prolonged half-life of IgG itself.