McLachlan Sandra M, Rapoport Basil
Thyroid Autoimmune Disease Unit, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States.
Front Immunol. 2017 Dec 20;8:1845. doi: 10.3389/fimmu.2017.01845. eCollection 2017.
Evidence for original antigenic sin in spontaneous thyroid autoimmunity is revealed by autoantibody interactions with immunodominant regions on thyroid autoantigens, thyroglobulin (Tg), thyroid peroxidase (TPO), and the thyrotropin receptor (TSHR) A-subunit. In contrast, antibodies induced by immunization of rabbits or mice recognize diverse epitopes. Recognition of immunodominant regions persists despite fluctuations in autoantibody levels following treatment or over time. The enhancement of spontaneously arising pathogenic TSHR antibodies in transgenic human thyrotropin receptor/NOD. mice by injecting a non-pathogenic form of TSHR A-subunit protein also provides evidence for original antigenic sin. From other studies, antigen presentation by B cells, not dendritic cells, is likely responsible for original antigenic sin. Recognition of restricted epitopes on the large glycosylated thyroid autoantigens (60-kDa A-subunit, 100-kDa TPO, and 600-kDa Tg) facilitates exploring the amino acid locations in the immunodominant regions. Epitope spreading has also been revealed by autoantibodies in thyroid autoimmunity. In humans, and in mice that spontaneously develop autoimmunity to all three thyroid autoantigens, autoantibodies develop first to Tg and later to TPO and the TSHR A-subunit. The pattern of intermolecular epitope spreading is related in part to the thyroidal content of Tg, TPO and TSHR A-subunit and to the molecular sizes of these proteins. Importantly, the epitope spreading pattern provides a rationale for future antigen-specific manipulation to block the development of all thyroid autoantibodies by inducing tolerance to Tg, first in the autoantigen cascade. Because of its abundance, Tg may be the autoantigen of choice to explore antigen-specific treatment, preventing the development of pathogenic TSHR antibodies.
自身抗体与甲状腺自身抗原、甲状腺球蛋白（Tg）、甲状腺过氧化物酶（TPO）和促甲状腺激素受体（TSHR）A亚基上的免疫显性区域相互作用，揭示了自发性甲状腺自身免疫中原始抗原罪的证据。相比之下，通过免疫兔子或小鼠诱导产生的抗体识别多种表位。尽管治疗后或随时间推移自身抗体水平有所波动，但对免疫显性区域的识别仍然持续存在。通过注射非致病性形式的TSHR A亚基蛋白增强转基因人促甲状腺激素受体/NOD小鼠中自发产生的致病性TSHR抗体，也为原始抗原罪提供了证据。从其他研究来看，B细胞而非树突状细胞的抗原呈递可能是原始抗原罪的原因。对大的糖基化甲状腺自身抗原（60 kDa A亚基、100 kDa TPO和600 kDa Tg）上受限表位的识别有助于探索免疫显性区域中的氨基酸位置。甲状腺自身免疫中的自身抗体也揭示了表位扩展现象。在人类以及自发对所有三种甲状腺自身抗原产生自身免疫的小鼠中，自身抗体首先针对Tg产生，随后针对TPO和TSHR A亚基产生。分子间表位扩展模式部分与Tg、TPO和TSHR A亚基的甲状腺含量以及这些蛋白质的分子大小有关。重要的是，表位扩展模式为未来的抗原特异性操作提供了理论依据，通过诱导对Tg的耐受性，首先在自身抗原级联反应中阻断所有甲状腺自身抗体的产生。由于Tg含量丰富，它可能是探索抗原特异性治疗以预防致病性TSHR抗体产生的首选自身抗原。
