Tagami Tetsuya, Moriyama Kenji
Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto 612-8555, Japan.
Department of Medicine and Clinical Science, Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo 663-8179, Japan.
J Endocr Soc. 2022 Apr 25;6(7):bvac070. doi: 10.1210/jendso/bvac070. eCollection 2022 Jul 1.
The thyrotropin (TSH) receptor (TSH-R) autoantibody activity is clinically measured by inhibition of labeled ligand (TSH or M22) binding to the TSH-R (TSH-binding inhibitory immunoglobulin [TBII]) or by stimulation (TSH-R stimulating antibody [TSAb]) or inhibition (TSH-R blocking antibody [TSBAb]) of 3',5'-cyclic adenosine 5'-monophosphate (cAMP) production in isolated cells.
We experienced a patient with hypothyroid Graves disease (GD) having strong positive TBII but with almost neutral bioactivities on the TSH-R. The aim of this study is the characterization of this apparently paradoxical TBII (serum sample S).
We first compared the TBII, TSAb, and TSBAb activities of serum sample S with mixtures of stimulating (S-mAb) and blocking monoclonal Ab (B-mAb). Next, we serially measured cAMPs stimulated by various serum samples in the presence or absence of TSH.
Mixtures of S-mAb and B-mAb did not reproduce the characteristics of serum sample S. Instead, serum sample S had a unique feature that blocked the TSH-stimulated cAMP initially but disappeared the blocking activity thereafter to reach the control level.
We present here the TBIIs with neutral bioactivities found in the patient with autoimmune thyroid disease, which strongly inhibit TSH binding to the TSH-R but exerts neither TSAb nor TSBAb activity. Differences in the methods of detecting TRAb between TBII in vitro and bioassay may cause the discrepancy. Although serum sample S may be an extreme example, a variety of TRAb that not only stimulates or blocks but also interferes with TSH-R binding for only a short time may exist in the serum samples of GD patients.
促甲状腺激素（TSH）受体（TSH-R）自身抗体活性在临床上通过抑制标记配体（TSH或M22）与TSH-R的结合（TSH结合抑制性免疫球蛋白[TBII]），或通过刺激（TSH-R刺激抗体[TSAb]）或抑制（TSH-R阻断抗体[TSBAb]）分离细胞中3',5'-环腺苷酸（cAMP）的产生来测量。
我们遇到一位甲状腺功能减退的格雷夫斯病（GD）患者，其TBII呈强阳性，但对TSH-R的生物活性几乎呈中性。本研究的目的是对这种明显矛盾的TBII（血清样本S）进行特征描述。
我们首先将血清样本S的TBII、TSAb和TSBAb活性与刺激单克隆抗体（S-mAb）和阻断单克隆抗体（B-mAb）的混合物进行比较。接下来，我们连续测量了在有或无TSH存在的情况下，各种血清样本刺激产生的cAMP。
S-mAb和B-mAb的混合物未能重现血清样本S的特征。相反，血清样本S具有独特的特征，即最初阻断TSH刺激的cAMP，但随后阻断活性消失，达到对照水平。
我们在此展示了在自身免疫性甲状腺疾病患者中发现的具有中性生物活性的TBII，其强烈抑制TSH与TSH-R的结合，但既不发挥TSAb活性也不发挥TSBAb活性。体外TBII检测方法与生物测定法之间检测促甲状腺素受体抗体（TRAb）方法的差异可能导致这种差异。尽管血清样本S可能是一个极端例子，但在GD患者的血清样本中可能存在多种不仅能刺激或阻断，而且仅在短时间内干扰TSH-R结合的TRAb。
