Department of Pediatrics, Faculty of Medicine, University of São Paulo, 05403-900 São Paulo, Brazil.
J Immunol. 2011 Sep 15;187(6):3422-30. doi: 10.4049/jimmunol.1003053. Epub 2011 Aug 19.
The Down syndrome (DS) immune phenotype is characterized by thymus hypotrophy, higher propensity to organ-specific autoimmune disorders, and higher susceptibility to infections, among other features. Considering that AIRE (autoimmune regulator) is located on 21q22.3, we analyzed protein and gene expression in surgically removed thymuses from 14 DS patients with congenital heart defects, who were compared with 42 age-matched controls with heart anomaly as an isolated malformation. Immunohistochemistry revealed 70.48 ± 49.59 AIRE-positive cells/mm(2) in DS versus 154.70 ± 61.16 AIRE-positive cells/mm(2) in controls (p < 0.0001), and quantitative PCR as well as DNA microarray data confirmed those results. The number of FOXP3-positive cells/mm(2) was equivalent in both groups. Thymus transcriptome analysis showed 407 genes significantly hypoexpressed in DS, most of which were related, according to network transcriptional analysis (FunNet), to cell division and to immunity. Immune response-related genes included those involved in 1) Ag processing and presentation (HLA-DQB1, HLA-DRB3, CD1A, CD1B, CD1C, ERAP) and 2) thymic T cell differentiation (IL2RG, RAG2, CD3D, CD3E, PRDX2, CDK6) and selection (SH2D1A, CD74). It is noteworthy that relevant AIRE-partner genes, such as TOP2A, LAMNB1, and NUP93, were found hypoexpressed in DNA microarrays and quantitative real-time PCR analyses. These findings on global thymic hypofunction in DS revealed molecular mechanisms underlying DS immune phenotype and strongly suggest that DS immune abnormalities are present since early development, rather than being a consequence of precocious aging, as widely hypothesized. Thus, DS should be considered as a non-monogenic primary immunodeficiency.
唐氏综合征（DS）的免疫表型特征为胸腺发育不全、更容易发生器官特异性自身免疫性疾病以及更易感染等。鉴于 AIRE（自身免疫调节因子）位于 21q22.3 上，我们分析了 14 例患有先天性心脏病的 DS 患者手术切除的胸腺中的蛋白质和基因表达，并与 42 例年龄匹配的单纯心脏畸形患者进行了比较。免疫组化显示 DS 组的 AIRE 阳性细胞/mm²为 70.48±49.59，而对照组为 154.70±61.16（p<0.0001），定量 PCR 和 DNA 微阵列数据也证实了这些结果。两组 FOXP3 阳性细胞/mm²数量相当。两组间胸腺转录组分析显示有 407 个基因表达明显下调，根据网络转录分析（FunNet），这些基因大多与细胞分裂和免疫有关。与免疫反应相关的基因包括 1）Ag 加工和呈递（HLA-DQB1、HLA-DRB3、CD1A、CD1B、CD1C、ERAP）和 2）胸腺 T 细胞分化（IL2RG、RAG2、CD3D、CD3E、PRDX2、CDK6）和选择（SH2D1A、CD74）。值得注意的是，相关的 AIRE 伴侣基因，如 TOP2A、LAMNB1 和 NUP93，在 DNA 微阵列和定量实时 PCR 分析中也被发现表达下调。这些关于 DS 中整体胸腺功能不全的发现揭示了 DS 免疫表型的分子机制，并强烈表明 DS 免疫异常早在发育早期就存在，而不是像广泛假设的那样是早衰的结果。因此，DS 应被视为一种非单基因原发性免疫缺陷。
