McLachlan Sandra M, Nagayama Yuji, Pichurin Pavel N, Mizutori Yumiko, Chen Chun-Rong, Misharin Alexander, Aliesky Holly A, Rapoport Basil
Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Endocrinology. 2007 Dec;148(12):5724-33. doi: 10.1210/en.2007-1024. Epub 2007 Sep 6.
Hyperthyroidism in Graves' disease is caused by thyroid-stimulating autoantibodies to the TSH receptor (TSHR), whereas hypothyroidism in Hashimoto's thyroiditis is associated with thyroid peroxidase and thyroglobulin autoantibodies. In some Graves' patients, thyroiditis becomes sufficiently extensive to cure the hyperthyroidism with resultant hypothyroidism. Factors determining the balance between these two diseases, the commonest organ-specific autoimmune diseases affecting humans, are unknown. Serendipitous findings in transgenic BALB/c mice, with the human TSHR A-subunit targeted to the thyroid, shed light on this relationship. Of three transgenic lines, two expressed high levels and one expressed low intrathyroidal A-subunit levels (Hi- and Lo-transgenics, respectively). Transgenics and wild-type littermates were depleted of T regulatory cells (Treg) using antibodies to CD25 (CD4(+) T cells) or CD122 (CD8(+) T cells) before TSHR-adenovirus immunization. Regardless of Treg depletion, high-expressor transgenics remained tolerant to A-subunit-adenovirus immunization (no TSHR antibodies and no hyperthyroidism). Tolerance was broken in low-transgenics, although TSHR antibody levels were lower than in wild-type littermates and no mice became hyperthyroid. Treg depletion before immunization did not significantly alter the TSHR antibody response. However, Treg depletion (particularly CD25) induced thyroid lymphocytic infiltrates in Lo-transgenics with transient or permanent hypothyroidism (low T(4), elevated TSH). Neither thyroid lymphocytic infiltration nor hypothyroidism developed in similarly treated wild-type littermates. Remarkably, lymphocytic infiltration was associated with intermolecular spreading of the TSHR antibody response to other self thyroid antigens, murine thyroid peroxidase and thyroglobulin. These data suggest a role for Treg in the natural progression of hyperthyroid Graves' disease to Hashimoto's thyroiditis and hypothyroidism in humans.
格雷夫斯病中的甲状腺功能亢进是由针对促甲状腺激素受体（TSHR）的甲状腺刺激自身抗体引起的，而桥本甲状腺炎中的甲状腺功能减退则与甲状腺过氧化物酶和甲状腺球蛋白自身抗体有关。在一些格雷夫斯病患者中，甲状腺炎会变得足够广泛，从而治愈甲状腺功能亢进并导致甲状腺功能减退。决定这两种疾病（影响人类的最常见器官特异性自身免疫性疾病）之间平衡的因素尚不清楚。在将人类TSHR A亚基靶向甲状腺的转基因BALB/c小鼠中的意外发现，揭示了这种关系。在三个转基因品系中，两个表达高水平，一个表达低水平的甲状腺内A亚基（分别为高表达和低表达转基因小鼠）。在TSHR腺病毒免疫之前，使用抗CD25（CD4(+) T细胞）或抗CD122（CD8(+) T细胞）抗体使转基因小鼠和野生型同窝小鼠的调节性T细胞（Treg）耗竭。无论Treg是否耗竭，高表达转基因小鼠对A亚基腺病毒免疫仍保持耐受（无TSHR抗体且无甲状腺功能亢进）。低表达转基因小鼠的耐受性被打破，尽管TSHR抗体水平低于野生型同窝小鼠，且没有小鼠出现甲状腺功能亢进。免疫前Treg耗竭并未显著改变TSHR抗体反应。然而，Treg耗竭（尤其是CD25）在低表达转基因小鼠中诱导了甲状腺淋巴细胞浸润，并伴有短暂或永久性甲状腺功能减退（T(4)降低，TSH升高）。在同样处理的野生型同窝小鼠中，既未出现甲状腺淋巴细胞浸润，也未出现甲状腺功能减退。值得注意的是，淋巴细胞浸润与TSHR抗体反应向其他自身甲状腺抗原（小鼠甲状腺过氧化物酶和甲状腺球蛋白）的分子间扩散有关。这些数据表明Treg在人类甲状腺功能亢进的格雷夫斯病向桥本甲状腺炎和甲状腺功能减退的自然进展中起作用。
