Kohn L D, Kosugi S, Ban T, Saji M, Ikuyama S, Giuliani C, Hidaka A, Shimura H, Akamizu T, Tahara K
Cell Regulation Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Int Rev Immunol. 1992;9(2):135-65. doi: 10.3109/08830189209061788.
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)
本报告鉴定出促甲状腺激素（TSH）受体的一个重要免疫原性区域，以及在甲状腺功能亢进的格雷夫斯病和甲状腺功能减退的特发性黏液性水肿中分别出现的两种自身抗体（TSAbs和TSBAbs）在TSH受体上的决定簇。这个没有重要功能决定簇的免疫原性结构域包含在303 - 382位氨基酸残基内，尤其涉及352 - 366位氨基酸残基。在受体C端部分免疫原性结构域两侧存在决定簇，它们是TSBAb和高亲和力TSH结合位点：295 - 306位、387 - 395位氨基酸残基以及酪氨酸385。位于胞外结构域N端部分、以38 - 45位氨基酸残基为中心的决定簇，是与低亲和力TSH结合相关的TSAb相互作用，对信号产生很重要：苏氨酸40以及30 - 33位、34 - 37位、42 - 45位、52 - 56位和58 - 61位氨基酸残基。这些决定簇在人和大鼠受体中保守，不存在于促性腺激素受体中，并且各自与TSH的不同作用相关：结合与信号产生。因此，它们可以解释器官特异性自身免疫以及TSBAbs与TSAbs所导致的不同疾病表现，即分别为甲状腺功能减退和甲状腺功能亢进。有人提出，在甲状腺中，激素（TSH、胰岛素、氢化可的松、IGF - I）对I类基因的抑制可能是在面对激素作用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）表达时维持自身耐受性的一种方式。甲状腺中I类基因表达过高（即如果由干扰素、病毒或某些未知因素诱导）会导致自身免疫性疾病的发生。因此，这会导致向免疫系统呈递的抗原增加，特别是那些因TSH及其cAMP信号而增加的自身抗原，如甲状腺球蛋白或甲状腺过氧化物酶，或者其周转因TSH及其cAMP信号而增加的抗原，如TSH受体。就后者而言，已知位于受体上蛋白酶敏感位点附近的352 - 366肽段，现在将作为一种强效自身抗原并诱导受体自身抗体的形成。进一步提出，甲巯咪唑和高剂量碘化物是甲状腺自身免疫性疾病的有效治疗药物，因为它们部分降低了MHC I类基因的表达。有人推测，消除MHC I类和TSH受体的负调控是自身免疫性甲状腺疾病发展的一个重要因素。（摘要截断于400字）
