TSHR与自身免疫性甲状腺疾病关系的研究进展

自身免疫性甲状腺疾病 (AITD)是一组器官特异性自身免疫性疾病 ,促甲状腺素受体 (TSHR)是其重要的自身抗原 ,在遗传和环境因素共同作用下 ,可以诱导机体产生特异性抗体 ,即TSHR抗体 (TRAb) ,它介导损伤性免疫应答。TSHR基因突变可能与AITD的发生有关     

TSHR与自身免疫性甲状腺疾病关系的研究进展

自身免疫性甲状腺疾病（AITD）是一组器官特异性自身免疫性疾病，促甲状腺素受体（TSHR）是其重要的自身抗原，在遗传和环境因素共同作用下，可以诱导机体产生特异性抗体，即TSHR抗体（TRAb)，它介导损伤性免疫应答，TSHR基因突变可能与AITD的发生有关。     

促甲状腺素受体抗体检测技术的回顾与展望

促甲状腺素受体抗体 (TRAb)与多种自身免疫性甲状腺疾病的发病密切相关 ,是临床诊断这些疾病的重要指标。目前已建立了两种较为成熟的TRAb检测技术 ,即根据TRAb可竞争抑制12 5I标记促甲状腺素 (TSH)与受体结合的原理设计的放射受体分析法 (RRA)和根据TRAb可模拟或阻断TSH作用影响体外细胞系cAMP产生的原理设计的生物分析法。RRA法简单易操作 ,灵敏度和特异度也比较高 ,在临床上应用广泛 ;而生物分析法则能够进一步区分甲状腺刺激性抗体和甲状腺刺激阻断性抗体 ,成为TRAb检测技术发展的重大突破。本文将对上述两种方法不同的诊断价值、局限性以及临床实用性作一综述。     

促甲状腺素受体抗体检测技术的回顾与展望

促甲状腺素受体抗体(TRAb)与多种自身免疫性甲状腺疾病的发病密切相关,是临床诊断这些疾病的重要指标.目前已建立了两种较为成熟的TRAb检测技术,即根据TRAb可竞争抑制125I标记促甲状腺素(TSH)与受体结合的原理设计的放射受体分析法(RRA)和根据TRAb可模拟或阻断TSH作用影响体外细胞系cAMP产生的原理设计的生物分析法.RRA法简单易操作,灵敏度和特异度也比较高,在临床上应用广泛;而生物分析法则能够进一步区分甲状腺刺激性抗体和甲状腺刺激阻断性抗体,成为TRAb检测技术发展的重大突破.本文将对上述两种方法不同的诊断价值、局限性以及临床实用性作一综述.     

促甲状腺素受体抗体检测技术的回顾与展望

促甲状腺素受体抗体(TRAb)与多种自身免疫性甲状腺疾病的发病密切相关，是临床诊断这些疾病的重要指标。目前已建立了两种较为成熟的TRAb检测技术，即根据TRAb可竞争抑制^125I标记促甲状腺素(TSH)与受体结合的原理设计的放射受体分析法(RRA)和根据TRAb可模拟或阻断TSH作用影响体外细胞系cAMP产生的原理设计的生物分析法。RRA法简单易操作，灵敏度和特异度也比较高，在临床上应用广泛；而生物分析法则能够进一步区分甲状腺刺激性抗体和甲状腺刺激阻断性抗体，成为TRAb检测技术发展的重大突破。本文将对上述两种方法不同的诊断价值、局限性以及临床实用性作一综述。     

促甲状腺激素受体抗体的检测方法

1　促甲状腺激素受体抗体 (TRAb)概况及临床意义1.1　TRAb概况　TRAb是人类特有的一种直接抗促甲状腺激素受体 (TSHR)的自身抗体 ,也是一种由不同B淋巴细胞产生的不均一性的多克隆抗体。根据其生物学活性不同 ,分为兴奋性抗体 (刺激性抗体 )与抑制性抗体 (阻断性抗体 )。兴奋性抗体包括 :①甲状腺刺激抗体 (TSAb) ,又称甲状腺刺激免疫球蛋白 (TSI) ,能与促甲状腺激素 (TSH)受体结合引起甲状腺功能亢进 ;②甲状腺生长刺激免疫球蛋白(TGI) ,它能识别TSH受体 ,刺激甲状腺细胞生长、增殖 ,使甲状腺肿大。抑制性抗体相应可分为 :①T…     

促甲状腺激素受体抗体检测的临床意义

50年前人们发现了促甲状腺激素受体抗体(TRAb),随着对促甲状腺激素受体(TSHR)结构和功能认识的不断更新,加之TSHR信号转导和与TRAb相互作用的逐步阐明,人们对TRAb及其临床应用的认识得到了进一步提高.TRAb的检测在Graves病(GD)及Graves眼病的诊断中有重要作用,并有效预测GD经抗甲状腺药物或放射性碘治疗后复发.其亦可应用于近期服碘的孕妇和乳母,因为甲状腺扫描对她们来说是禁忌的.另外,TRAb有助于胎儿、新生儿甲状腺功能亢进及其他类型的甲状腺毒症的诊断和鉴别诊断.目前,已有文献报道TRAb阳性的GD患者发生甲状腺肿瘤及不良预后之间的可能联系,但尚需更多的前瞻性研究来证实.     

促甲状腺激素受体抗体检测的临床意义

50年前人们发现了促甲状腺激素受体抗体(TRAb),随着对促甲状腺激素受体(TSHR)结构和功能认识的不断更新,加之TSHR信号转导和与TRAb相互作用的逐步阐明,人们对TRAb及其临床应用的认识得到了进一步提高.TRAb的检测在Graves病(GD)及Graves眼病的诊断中有重要作用,并有效预测GD经抗甲状腺药物或放射性碘治疗后复发.其亦可应用于近期服碘的孕妇和乳母,因为甲状腺扫描对她们来说是禁忌的.另外,TRAb有助于胎儿、新生儿甲状腺功能亢进及其他类型的甲状腺毒症的诊断和鉴别诊断.目前,已有文献报道TRAb阳性的GD患者发生甲状腺肿瘤及不良预后之间的可能联系,但尚需更多的前瞻性研究来证实.     

关于促甲状腺素受体抗体的研究

促甲状腺素受体抗体（TRAb）是针对促甲状腺素受体（TSHR）的自身抗体，与Grawes病（GD）和自身免疫性甲状腺功能减退症（甲减）的发病密切相关。TRAb主要包括甲状腺刺激性抗体（TSAb）和甲状腺刺激阻断性抗体（TSBAb），可与TSHR分子上不同位点作用产生不同生物学效应。     

影响自身免疫性甲状腺病环境因素研究进展

正自身免疫性甲状腺疾病(autoimmune thyroid disease,AITD)是一组以甲状腺为靶器官的自身免疫性疾病。主要包括Graves病、桥本甲状腺炎、产后甲状腺炎、药物诱导甲状腺炎等。AITD患者体内存在多种甲状腺自身抗体,其中最主要的是甲状腺过氧化物酶抗体(TPOAb)、甲状腺球蛋白抗体(TgAb)及促甲状腺激素受体抗体(TRAb)。AITD受基因易     

TSH受体活性片段反义肽的免疫调节作用

目的通过观察TSH受体(TSHR)活性片段及其反义肽(RHST)对大鼠免疫活性的影响,探讨反义肽的免疫调节作用。方法TSHR片段TR1、TR2、TR3及相应的反义肽RT1、RT2、RT3,或3对互补肽被分别注入不同组大鼠体内,观察免疫前后各组大鼠血清中TT3、TT4、TSH受体抗体(TRAb)、甲状腺刺激型抗体、甲状腺刺激抑制型抗体和TSH抗体(TSHAb)等指标以及甲状腺组织的病理变化。结果3条TSHR片段均刺激TRAb的产生;RT1和RT2可同时诱导出TRAb和TSHAb;TR2引发的甲状腺上皮细胞增生和淋巴细胞浸润可因RT2的注入而缓解。结论实验证明,3条TSHR片段均具有免疫源性;RT1和RT2具有免疫调节作用,可能是TSHR片段的独特型;反义肽可减轻由天然肽引发的体液和细胞免疫,证明了反义肽通过免疫网络进行免疫调节的可能性。     

促甲状腺激素受体抗体检测的临床意义

50年前人们发现了促甲状腺激素受体抗体(TRAb),随着对促甲状腺激素受体(TSHR)结构和功能认识的不断更新,加之TSHR信号转导和与TRAb相互作用的逐步阐明,人们对TRAb及其临床应用的认识得到了进一步提高.TRAb的检测在Graves病(GD)及Graves眼病的诊断中有重要作用,并有效预测GD经抗甲状腺药物或放射性碘治疗后复发.其亦可应用于近期服碘的孕妇和乳母,因为甲状腺扫描对她们来说是禁忌的.另外,TRAb有助于胎儿、新生儿甲状腺功能亢进及其他类型的甲状腺毒症的诊断和鉴别诊断.目前,已有文献报道TRAb阳性的GD患者发生甲状腺肿瘤及不良预后之间的可能联系,但尚需更多的前瞻性研究来证实.

Abstract：

It has been 50 years since the discovery of thyrotropin receptor autoantibody (TRAb). Advances in the knowledge of thyrotropin receptor ( TSHR) structure and function, combined with the elucidation of TSHR signaling and TSHR-autoantibody interaction have greatly facilitated our understanding of TRAb and their clinical applications. Measurement of TRAb activity plays an important role in the diagnosis of Graves' disease ( GD) and Graves' opthalmopathy. It has also been well recognized that TRAb is an effective predictor of GD relapse or remission after antithyroid drug and radioactive iodine treatment. TRAb test is of particular help in pregnant women and lactating mothers with recent iodine load, where radioactive iodine or technetium tests are contraindicated. In addition, it is useful in the diagnosis and differential diagnosis of fetal and neonatal hyperthyroidism as well as some rare forms of thyrotoxicosis in clinical practice. Accumulating evidence also indicates the possible correlation between thyroid cancer occurring in GD patients with positive TRAb and adverse outcomes. However, further innovation and standardization of TRAb tests are required to help pave the way for clinical applications.     

Multiple SNPs in intron 7 of thyrotropin receptor are associated with Graves' disease

Our previous studies using microsatellite markers near or in the TSH receptor (TSHR) gene revealed significant association between autoimmune thyroid disease (AITD) in Japanese patients and TSHR microsatellite alleles. In the present study, we performed a case-control analysis of AITD using single-nucleotide polymorphisms (SNPs) spaced 3-50 kb apart spanning the TSHR gene. We observed significant associations between AITD/Graves' disease (GD)/Hashimoto's thyroiditis and multiple SNPs. Specifically, the SNP JST022302 and several adjacent SNPs in intron 7 of the TSHR gene were significantly associated with GD (P = 0.039-0.0004) but not Hashimoto's thyroiditis. Furthermore, we identified three haplotype blocks around intron 7 by linkage disequilibrium analysis. A single SNP haplotype [AATG(CT)6(TT)AG] in the haplotype block including JST022302 showed significant association with GD in haplotype case-control analysis (P = 0.0058). These findings suggest that alleles of intron 7 of the TSHR gene contribute to GD susceptibility.     

Reactivity of thyrotropin receptor autoantibodies with the thyrotropin receptor on western blots.

Affinity purified recombinant human thyrotropin receptor (TSHR) was run on sodium dodecyl sulfate (SDS) gels and subjected to a renaturing and blotting procedure. Twenty sera from thyrotropin receptor autoantibodies (TRAb)-positive patients with a history of hyperthyroidism and 20 sera with high levels of TSH blocking activity were analyzed. Four of 20 sera with blocking-type of TRAb (i.e., TSH antagonist activity) were able to recognize the mature, fully glycosylated 120-kd form of the receptor on blots of gels run under reducing conditions. No sera recognized the 100-kd high mannose precursor form of the TSHR. Three of the four recognized a 74-kd band and 2 of the 4 recognized a 50-kd band. These bands are probably proteolytic cleavage fragments of the mature 120-kd TSHR. In the absence of reducing agent the same 4 of 20 sera described above together with a further serum sample (i.e., 5/20 in total) reacted with the 120-kd form of the receptor. No specific reaction with the TSHR was observed on Western blots with the remaining 15 sera with TSH blocking activity, nor with 20 sera from patients with a history of hyperthyroidism, nor with sera from 10 healthy blood donors, 10 Hashimoto sera (negative for TRAb) and 10 systemic lupus erythematosus sera. No clear differences were observed in the TRAb positive sera that were reactive and nonreactive on Western blots in terms of their ability to inhibit TSH binding or to immunoprecipitate 125I-labeled TSHR. Overall, our results indicate that the mature 120-kd form of the TSHR that is principally responsible for binding TSH is also responsible for binding TRAb (when this binding can be detected). These observations together with immunoprecipitation and TSH binding inhibition studies, emphasize the close relationship between the receptor's binding sites for TSH and TRAb.     

促甲状腺激素受体抗体的检测及应用进展

促甲状腺激素(thyroid stimulating hormone,TSH)受体抗体(TSH receptor antibody,TRAb)在自身免疫性甲状腺病患者体内特异性存在,其中甲状腺刺激性抗体(thyroid stimulating anti-body,TSAb)/TSI受体刺激性免疫球蛋白(TSI)被认为是...     

Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients.

In a previous study we identified a microsatellite marker near the thyrotropin receptor (TSHR) gene. Studies with this marker, TSHR-CA, revealed a significant association between autoimmune thyroid disease (AITD) in Japanese patients and one specific allele (allele 1; 180 base pair [bp]) of the microsatellite sequence. In addition, weak evidence for association of AITD with two alleles of the CTLA-4 gene was observed. In the present study, TSHR-CA has been mapped to approximately 600 kb of the TSHR gene using radiation hybrid mapping. TSHR-CA and another TSHR microsatellite marker, TSHR-AT, which is located in intron 2 of TSHR gene, were genotyped in a set of 349 unrelated Japanese AITD patients and 218 Japanese controls. The TSHR-AT marker showed association in this Japanese AITD population with a significant increase in allele 5 (294 bp; p < 0.05) and a significant decrease in allele 7 (298 bp; p < 0.05). The association of allele 5 of TSHR-AT was also significant in hypothyroid patients (thyrotropin-binding inhibitory immunoglobulin-positive [TBII+], P < 0.01; thyrotropin-binding inhibitory immunoglobulin-negative [TBII-], p < 0.05). The association of allele 7 of TSHR-AT were also significant for the hypothyroid TBII+ patients (p < 0.05). The CTLA-4 gene was also genotyped in this expanded set of Japanese AITD patients and controls. Association between AITD susceptibility and allele 2 (102 bp; p < 0.01) and allele 4 (106 bp; p < 0.01) were observed. These associations were also observed with GD patients (allele 2, p < 0.01; allele 4, p < 0.01). Associations with TSHR-CA were observed for Hashimoto's thyroiditis (HT) patients with respect to alleles 3 (179 bp; p < 0.05) and 5 (175 bp; p < 0.05) and with hypothyroid TBII- patients for allele 4 (177 bp; p < 0.05). The presence of specific alleles of TSHR-CA, TSHR-AT, and CTLA-4 contribute significant increase in risk of development of AITD. These results confirm and expand on our previous study suggesting that alleles of the TSHR and CTLA-4 genes, or genes near them contribute to AITD susceptibility and set the stage for future studies of interactions between these genes and AITD.     

大多功能蛋白酶2基因Arg60His变异与上海地区自身免疫性甲状腺病的相关性

目的 探讨大多功能蛋白酶2（LMP2）基因Arg60His变异与上海地区中国人自身免疫性甲状腺病（ATD）的关系。方法 运用限制性片段长度多态性PCR（PCR－RFLP）技术在367例无亲缘关系的上海地区中国人[正常对照162例;AITD者205例,其中促甲状腺激素受体抗体（TRAb)阳性者78例,TRAb阴性但在甲状腺球蛋白抗体（TGAb)、甲状腺微粒体抗体（TMAb)或甲状腺过氧化物酶抗体（TPOAb)中至少有1项阳性者127例]中检测LMP2基因Arg60His变异。结果 上海地区汉族人（R0.89,H0.11)与白种人（R0.29,H0.71)LMP2基因R／H60等位基因频率分布有显著差异（P＝0.000)。AITD中TRAb阳性亚组与正常对照组间基因型及等位基因分布频率均有显著差异,TRAb阳性亚组RH基因型和H等位基因频率显著高于正常对照组（P值分别为0.037,0.047)。AITD其他抗体阳性亚组与抗体阴性亚组间基因型及等位基因频率分布无显著差异。结论 LMP2基因Arg60His变异与上海地区中国人自身免疫性甲状腺病的发病可能相关。     

Autoantibodies to the thyrotropin receptor

This review considers recent developments in our understanding of the properties of TRAb, particularly measurement of the antibodies and their sites of action and synthesis. Two new assay methods have allowed considerable improvements in the sensitivity, specificity, precision, and ease of measuring TRAb. In particular: 1) receptor assays based on inhibition of receptor-purified labeled TSH binding to detergent-solubilized TSH receptors and 2) bioassays based on stimulation of cAMP release from monolayer cultures of isolated thyroid cells. Detailed studies with the two assays indicate that TSH receptor antibodies nearly always act as TSH agonists in patients with a history of Graves' hyperthyroidism. Studies in areas of dietary iodine sufficiency suggest that measurement of the antibodies at various stages in the course of treating Graves' disease can be of value in predicting the outcome of therapy. However, in areas of iodine deficiency, difficulties in the ability of patients' thyroid tissue to recover from the effects of antithyroid drugs may prevent the receptor antibodies from causing a relapse of thyrotoxicosis. Consequently, the predictive value of receptor antibody measurements would be expected to be lower in these geographical areas. Although patients with a history of Graves' hyperthyroidism nearly always have TRAb which act as TSH agonists, about 20% of patients with frank hypothyroidism due to autoimmune destruction of the thyroid have TRAb which act as TSH antagonists (blocking antibodies). There is some evidence that these blocking antibodies can cause hypothyroidism particularly in the neonate. With regard to the site of synthesis of TRAb, there is now direct evidence that they are synthesized by thyroid lymphocytes, particularly the lymphocytes in close proximity to thyroid follicular cells. This is consistent with the well established effects of antithyroid treatment (drugs, radioiodine, or surgery) on TRAb levels in addition to their effects on thyroid hormone synthesis. Recent studies using affinity labeling with 125I-labeled TSH have enabled elucidation of the structure of the TSH receptor. TSH receptors in human, porcine, and guinea pig thyroid tissue have a two-chain structure in which the TSH binding site is formed on the outside surface of the cell membrane by a water-soluble A subunit (Mr approximately 50 K). The A subunit is linked by a disulfide bridge and weak noncovalent bonds to the amphiphilic B subunit (Mr approximately 30 K). This subunit, which penetrates the lipid bilayer, probably forms the site for interaction of the receptor with the regulatory subunits of adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)