Armengol M P, Sabater L, Fernández M, Ruíz M, Alonso N, Otero M J, Martínez-Cáceres E, Jaraquemada D, Pujol-Borrell R
Laboratory of Immunobiology for Research and Applications to Diagnosis, Banc de Sang i Teixits, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Spain.
Clin Exp Immunol. 2008 Sep;153(3):338-50. doi: 10.1111/j.1365-2249.2008.03706.x. Epub 2008 Jul 11.
Autoimmune thyroid diseases (AITD) are considered as prototypic organ-specific autoimmune diseases, yet their underlying aetiology remains poorly understood. Among the various pathophysiological mechanisms considered, a failure of central tolerance has received little attention. Here we present evidence in favour of dysregulated thymic function playing a role in AITD. Flow-cytometric analyses conducted in peripheral blood lymphocytes from 58 AITD patients and 48 age- and-sex-matched controls showed that AITD patients have significantly higher blood levels of CD4(+)CD45RA(+), CD4(+)CD31(+) and CD4/CD8 double-positive T lymphocytes, all markers of recent thymic emigrants (RTE). In addition, the alpha-signal joint T cell receptor excision circles (TRECs) content (a molecular marker of RTEs) was higher in the group of AITD patients older than 35 years than in age-matched controls. This was independent from peripheral T cell expansion as assessed by relative telomere length. Comparisons of TREC levels in peripheral blood lymphocytes and intrathyroidal lymphocytes in paired samples showed higher levels within the thyroid during the initial 30 months of the disease, indicating an influx of RTE into the thyroid during the initial stages of AITD. Additionally, a lack of correlation between TREC levels and forkhead box P3 expression suggests that the intrathyroidal RTE are not natural regulatory T cells. These results uncover a hitherto unknown correlation between altered thymic T cell export, the composition of intrathyroidal T cells and autoimmune pathology.
自身免疫性甲状腺疾病（AITD）被认为是典型的器官特异性自身免疫性疾病，但其潜在病因仍知之甚少。在众多被考虑的病理生理机制中，中枢耐受失败很少受到关注。在此，我们提供证据支持胸腺功能失调在AITD中起作用。对58例AITD患者和48例年龄及性别匹配的对照者外周血淋巴细胞进行的流式细胞术分析表明，AITD患者血液中CD4(+)CD45RA(+)、CD4(+)CD31(+)和CD4/CD8双阳性T淋巴细胞水平显著更高，这些都是近期胸腺迁出细胞（RTE）的标志物。此外，年龄大于35岁的AITD患者组中，α信号联合T细胞受体切除环（TREC）含量（RTE的分子标志物）高于年龄匹配的对照组。这与通过相对端粒长度评估的外周T细胞扩增无关。对配对样本中外周血淋巴细胞和甲状腺内淋巴细胞的TREC水平进行比较，发现在疾病最初30个月内甲状腺内的水平更高，表明在AITD初始阶段有RTE流入甲状腺。此外，TREC水平与叉头框P3表达之间缺乏相关性，提示甲状腺内的RTE不是天然调节性T细胞。这些结果揭示了胸腺T细胞输出改变、甲状腺内T细胞组成与自身免疫病理之间迄今未知的相关性。
