Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves' Disease.
Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves' Disease.
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DOI：
10.3389/fendo.2016.00120
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发表时间：
2016
影响因子：
5.2
通讯作者：
Akamizu T
中科院分区：
文献类型：
--
作者：
Inaba H;De Groot LJ;Akamizu T
Graves病（GD）是一种器官特异性自身免疫性疾病，促甲状腺激素（TSH）受体（TSHR）是GD的主要自身抗原。由于人TSHR的细胞外结构域（TSHR-ECD）脱落到循环中，TSHR-ECD是TSHR的优先免疫原性部分。遗传因素和环境因素共同参与GD的发生发展。人类白细胞抗原（HLA）基因的遗传，尤其是HLA-DR 3，与GD相关。TSHR-ECD蛋白被内吞到抗原呈递细胞（APC）中，并被加工成TSHR-ECD肽。这些肽表位与HLA-II类分子结合，随后将HLA-II类和TSHR-ECD表位的复合物呈递给CD 4 + T细胞。活化的CD 4 + T细胞分泌刺激B细胞产生TSAb的细胞因子/趋化因子，进而发生甲状腺功能亢进。已经进行了许多研究来鉴定TSHR-ECD中的T细胞表位和B细胞表位，包括（1）计算机模拟，（2）体外，（3）体内，和（4）临床实验。GD和HLA转基因小鼠的小鼠模型在阐明免疫机制中发挥了关键作用。迄今为止，TSHR-ECD的线性或构象表位以及HLA-DR中表位结合沟的分子结构被报道与GD的发病机制相关。胸腺或外周耐受（如调节性T细胞）的中枢耐受功能障碍可能导致GD的发生。使用TSHR拮抗剂或突变的TSHR肽的新型治疗已被报道是有效的。本文综述了TSHR表位和HLA在GD中的作用，并对TSHR表位特异性治疗提供了展望。
Graves’ disease (GD) is an organ-specific autoimmune disease, and thyrotropin (TSH) receptor (TSHR) is a major autoantigen in this condition. Since the extracellular domain of human TSHR (TSHR-ECD) is shed into the circulation, TSHR-ECD is a preferentially immunogenic portion of TSHR. Both genetic factors and environmental factors contribute to development of GD. Inheritance of human leukocyte antigen (HLA) genes, especially HLA-DR3, is associated with GD. TSHR-ECD protein is endocytosed into antigen-presenting cells (APCs), and processed to TSHR-ECD peptides. These peptide epitopes bind to HLA-class II molecules, and subsequently the complex of HLA-class II and TSHR-ECD epitope is presented to CD4+ T cells. The activated CD4+ T cells secrete cytokines/chemokines that stimulate B-cells to produce TSAb, and in turn hyperthyroidism occurs. Numerous studies have been done to identify T- and B-cell epitopes in TSHR-ECD, including (1) in silico, (2) in vitro, (3) in vivo, and (4) clinical experiments. Murine models of GD and HLA-transgenic mice have played a pivotal role in elucidating the immunological mechanisms. To date, linear or conformational epitopes of TSHR-ECD, as well as the molecular structure of the epitope-binding groove in HLA-DR, were reported to be related to the pathogenesis in GD. Dysfunction of central tolerance in the thymus, or in peripheral tolerance, such as regulatory T cells, could allow development of GD. Novel treatments using TSHR antagonists or mutated TSHR peptides have been reported to be effective. We review and update the role of immunogenic TSHR epitopes and HLA in GD, and offer perspectives on TSHR epitope specific treatments.