Ludgate M, Crisp M, Lane C, Costagliola S, Vassart G, Weetman A, Daunerie C, Many M C
Department of Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.
Thyroid. 1998 May;8(5):411-3. doi: 10.1089/thy.1998.8.411.
Thyroid eye disease (TED) has an autoimmune etiology, but the nature of the autoantigen that is the target of the initiating event remains unknown. A number of candidates have been proposed based on Western blotting, library screening, and deduction from sequence similarity. A strong favorite is the thyrotropin receptor (TSHR), which is the target of the thyroid stimulating antibodies (TSAB) of Graves' disease (GD). We have recently demonstrated TSHR transcripts in orbital adipose tissue from a patient with TED by Northern blot, transcripts in normal adipose tissue being at the limit of detection. We have shown that the transcripts are translated into protein by immunohistochemical analysis using two monoclonal antibodies to the TSHR generated by genetic immunization. TSHR immunoreactivity is associated with elongated cells with the appearance of a fibroblast, often adjacent to clusters of adipocytes, in orbital biopsies from patients with TED but not in strabismus or pseudotumor biopsies. In animal studies, we have transferred thyroiditis to naive BALBc and NOD mice, using T cells primed to the human TSHR, either using the receptor expressed as a bacterial fusion protein or by genetic immunization. The BALBc develop a Th2-type response to the receptor, but the NOD a Th1-type with thyrocyte destruction. Orbital pathology, edema, infiltration by mast cells and lymphocytes, and adipose accumulation was also induced in 68% of the BALBc but none of the NOD mice. Together these data indicate that the preadipocyte expresses the TSHR and that a Th2 autoimmune response to the receptor may be an initiating event in TED.
甲状腺眼病（TED）具有自身免疫病因，但作为起始事件靶点的自身抗原的性质仍不清楚。基于蛋白质印迹法、文库筛选以及序列相似性推导，已提出了一些候选抗原。最有可能的是促甲状腺激素受体（TSHR），它是格雷夫斯病（GD）中甲状腺刺激抗体（TSAB）的靶点。我们最近通过Northern印迹法在一名TED患者的眼眶脂肪组织中证实了TSHR转录本，正常脂肪组织中的转录本处于检测极限。我们通过使用两种经基因免疫产生的针对TSHR的单克隆抗体进行免疫组织化学分析表明，这些转录本可被翻译成蛋白质。在TED患者的眼眶活检组织中，TSHR免疫反应性与具有成纤维细胞外观的细长细胞相关，这些细胞通常邻近脂肪细胞簇，而在斜视或假瘤活检组织中则未发现。在动物研究中，我们使用针对人TSHR致敏的T细胞，通过将受体表达为细菌融合蛋白或基因免疫，将甲状腺炎转移至未接触过抗原的BALBc和NOD小鼠。BALBc小鼠对该受体产生Th2型反应，而NOD小鼠产生伴有甲状腺细胞破坏的Th1型反应。68%的BALBc小鼠还出现了眼眶病理改变、水肿、肥大细胞和淋巴细胞浸润以及脂肪堆积，而NOD小鼠均未出现。这些数据共同表明，前脂肪细胞表达TSHR，并且对该受体的Th2自身免疫反应可能是TED的起始事件。
