McLachlan Sandra M, Rapoport Basil
Autoimmune Disease Unit, Cedars-Sinai Medical Center and UCLA Medical School, Los Angeles, California, USA.
Thyroid. 2007 Oct;17(10):939-48. doi: 10.1089/thy.2007.0169.
Thyroid peroxidase (TPO) evokes high-affinity, IgG-class autoantibodies [TPO autoantibodies (TPOAbs)] and TPO-specific T cells that are markers of thyroid infiltration or implicated in thyroid destruction, respectively. A diverse repertoire of human monoclonal TPOAbs, unparalleled in other autoimmune diseases, provides invaluable probes for investigating antibody epitopes. Human TPOAbs recognize an immunodominant region comprising overlapping A and B domains on conformationally intact TPO. Amino acids recognized by TPOAbs are located in the regions with homology to myeloperoxidase (MPO) and the complement control protein (CCP) but not in the epidermal growth factor (EGF)-like region. T cells recognize epitopes in the MPO-like region but not in the CCP- or EGF-like regions in humans. Monoclonal human TPOAbs modulate processing of TPO protein to provide peptides for some T cells. A human T cell clone expressed transgenically in mice induces lymphocytic infiltration and hypothyroidism. This T cell's epitope is only generated by thyrocyte processing of endogenous TPO. Further, intact TPO expressed in vivo is also required for induction of TPOAbs in mice that resemble human autoantibodies. Overall, some TPO-specific T cells and the majority of autoantibodies in humans develop in response to TPO presented by thyroid cells, rather than to TPO released by damaged thyrocytes.
甲状腺过氧化物酶（TPO）可诱发高亲和力的IgG类自身抗体[TPO自身抗体（TPOAbs）]和TPO特异性T细胞，它们分别是甲状腺浸润的标志物或与甲状腺破坏有关。人类单克隆TPOAbs的多样性在其他自身免疫性疾病中是无与伦比的，为研究抗体表位提供了宝贵的探针。人类TPOAbs识别一个免疫显性区域，该区域在构象完整的TPO上包含重叠的A和B结构域。TPOAbs识别的氨基酸位于与髓过氧化物酶（MPO）和补体控制蛋白（CCP）具有同源性的区域，而不在表皮生长因子（EGF）样区域。在人类中，T细胞识别MPO样区域的表位，而不识别CCP样或EGF样区域的表位。人类单克隆TPOAbs调节TPO蛋白的加工，为一些T细胞提供肽段。在小鼠中转基因表达的人类T细胞克隆可诱导淋巴细胞浸润和甲状腺功能减退。该T细胞的表位仅由甲状腺细胞对内源性TPO的加工产生。此外，在体内表达的完整TPO对于在小鼠中诱导类似于人类自身抗体的TPOAbs也是必需的。总体而言，人类中的一些TPO特异性T细胞和大多数自身抗体是针对甲状腺细胞呈递的TPO产生的，而不是针对受损甲状腺细胞释放的TPO产生的。
