Molecular basis for the autoreactivity against thyroid stimulating hormone receptor.
Molecular basis for the autoreactivity against thyroid stimulating hormone receptor.
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针对促甲状腺激素受体自身反应的分子基础。
DOI：
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发表时间：
1992
影响因子：
5
通讯作者：
Dinah S Singer
中科院分区：
文献类型：
--
作者：
Leonard D. Kohn;Shinji Kosugi;T. Ban;M. Saji;S. Ikuyama;C. Giuliani;Akinari Hidaka;Hiroki Shimura;Takashi Akamizu;Kazuo Tahara;John Moriarty;Bellur S. Prabhakar;Dinah S Singer
本报告确定了TSH受体的一个重要免疫原区和TSH受体的决定因素，分别在甲状腺机能亢进和甲状腺功能低下的特发性黏性水肿中发现两种类型的自身抗体，TSAbs和TSAbs。没有重要功能决定因子的免疫原结构域包含在残基303-382中，特别是涉及残基352-366。在受体c端部分的免疫原结构域两侧有一些决定因子，它们是TSBAb和高亲和力的TSH结合位点：残基295-306、387-395和酪氨酸385。外结构域n端以38-45残基为中心的决定因素是TSAb相互作用，与低亲和力TSH结合有关，对信号产生很重要：苏氨酸40和残基30-33、34-37、42-45、52-56和58-61。这些决定因素在人和大鼠受体中是保守的，在促性腺激素受体中不存在，并且各自与TSH的单独作用有关：结合与信号产生。因此，它们可以解释器官特异性自身免疫和tsb与tsb影响的不同疾病表达，即甲状腺功能低下与甲状腺功能亢进。在甲状腺中，激素（TSH、胰岛素、氢化可体松、IGF-I）抑制I类基因可能是在激素作用下保持自身耐受性的一种手段，以增加组织特异性基因如甲状腺球蛋白和甲状腺过氧化物酶的表达。在甲状腺中不适当的高I类表达，即如果被干扰素、病毒或某些未知因子诱导，将有助于自身免疫性疾病的产生。因此，它将导致抗原向免疫系统的呈递增加，特别是那些由TSH及其cAMP信号增加的自身抗原，如甲状腺球蛋白或甲状腺过氧化物酶，或由TSH及其cAMP信号增加的自身抗原，如TSH受体。在后者的情况下，已知位于受体蛋白酶敏感位点附近的肽352-366[41,49]现在将作为一种有效的自身抗原并诱导形成受体自身抗体。进一步提出甲巯咪唑和高剂量碘化物是治疗甲状腺自身免疫性疾病的有效药物，因为它们在一定程度上降低了MHC I类基因的表达。推测提出的MHC类I和TSH受体的负调控的消除是自身免疫性甲状腺疾病发展的重要因素。（摘要删节为400字）
The present report identifies an important immunogenic region of the TSH receptor and determinants on the TSH receptor for the two types of autoantibodies seen in hyperthyroid Graves' disease and hypothyroid idiopathic myxedema, TSAbs and TSBAbs, respectively. The immunogenic domain with no important functional determinants, is contained within residues 303-382 and involves residues 352-366 in particular. There are determinants flanking the immunogenic domain on the C-terminal portion of the receptor which are the TSBAb and high affinity TSH binding sites: residues 295-306, 387-395, and tyrosine 385. Determinants on the N-terminal portion of the external domain, centered on residues 38-45, are TSAb interactions linked to low affinity TSH binding important for signal generation: threonine 40 and residues 30-33, 34-37, 42-45, 52-56, and 58-61. These determinants are conserved in human and rat receptors, are not present in gonadotropin receptors, and are each related to separate actions of TSH: binding vs. signal generation. They can, therefore, account for organ specific autoimmunity and the different disease expression effected by TSBAbs vs TSAbs, i.e. hypo- vs. hyperthyroidism, respectively. It is proposed that, in the thyroid, hormonal (TSH, insulin, hydrocortisone, IGF-I) suppression of class I genes might be one means of preserving self-tolerance in the face of the hormone action to increase the expression of tissue specific genes such as thyroglobulin and thyroid peroxidase. Inappropriately high class I expression in the thyroid, i.e. if induced by interferon, viruses, or some as yet unknown agent, would contribute to the generation of autoimmune disease. Thus, it would result in increased antigen presentation to the immune system, particularly those autoantigens increased by TSH and its cAMP signal such as thyroglobulin or thyroid peroxidase, or whose turnover is increased by TSH and its cAMP signal, such as the TSH receptor. In the case of the latter, peptide 352-366, known to be near a protease sensitive site on the receptor [41,49], would now act as a potent self-antigen and induce the formation of receptor autoantibodies. It is further proposed that methimazole and high doses of iodide are therapeutically effective agents in thyroid autoimmune disease because they, in part, decrease MHC class I gene expression. Speculation is presented which suggests that elimination of negative regulation of MHC class I and the TSH receptor is an important factor in the development of autoimmune thyroid disease.(ABSTRACT TRUNCATED AT 400 WORDS)
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编码 p70 (Ku) 狼疮自身抗原的 cDNA 的分子克隆。
DOI：
--
发表时间：
1989
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Reeves,WH;Sthoeger,ZM
通讯作者：
Sthoeger,ZM
影响因子：
20.3
作者：
ASCOLI, M;SEGALOFF, DL
通讯作者：
SEGALOFF, DL
促甲状腺素黄体生成素/绒毛膜促性腺激素受体胞外域嵌合体作为促甲状腺素受体功能的探针。
DOI：
10.1073/pnas.88.3.902
发表时间：
1991
影响因子：
11.1
作者：
Nagayama,Y;Wadsworth,HL;Chazenbalk,GD;Russo,D;Seto,P;Rapoport,B
通讯作者：
Rapoport,B
促黄体激素/绒毛膜促性腺激素通过受体介导的内吞作用和受体 mRNA 的 cAMP 依赖性减少来下调其受体。
DOI：
--
发表时间：
1991
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Wang,H;Segaloff,DL;Ascoli,M
通讯作者：
Ascoli,M
影响因子：
--
作者：
ALEXANDRE, S;NAKAKI, T;LEE, AS
通讯作者：
LEE, AS