Department Biochemistry and Molecular Biology, Monash University, Wellington Rd, Clayton, VIC 3800, Australia.
J Med Genet. 2013 Jul;50(7):444-54. doi: 10.1136/jmedgenet-2013-101522. Epub 2013 May 3.
People with Down syndrome (DS) are more susceptible to infections and autoimmune disease, but the molecular genetic basis for these immune defects remains undetermined. In this study, we tested whether increased expression of the chromosome 21 gene RCAN1 contributes to immune dysregulation.
We investigated the immune phenotype of a mouse model that overexpresses RCAN1. RCAN1 transgenic (TG) mice exhibit T cell abnormalities that bear a striking similarity to the abnormalities described in individuals with DS.
RCAN1-TG mice display T cell developmental defects in the thymus and peripheral immune tissues. Thymic cellularity is reduced by substantial losses of mature CD4 and CD8 thymocytes and medullary epithelium. In peripheral immune organs T lymphocytes are reduced in number and exhibit reduced proliferative capacity and aberrant cytokine production. These T cell defects are stem cell intrinsic in that transfer of wild type bone marrow into RCAN1-TG recipients restored medullary thymic epithelium and T cell numbers in the thymus, spleen and lymph nodes. However, bone marrow transplantation failed to improve T cell function, suggesting an additional role for RCAN1 in the non-haemopoietic compartment.
RCAN1 therefore facilitates T cell development and function, and when overexpressed, may contribute to immune dysfunction in DS.
唐氏综合征（DS）患者更容易感染和自身免疫性疾病，但这些免疫缺陷的分子遗传基础仍未确定。在这项研究中，我们测试了增加 21 号染色体基因 RCAN1 的表达是否有助于免疫失调。
我们研究了过表达 RCAN1 的小鼠模型的免疫表型。RCAN1 转基因（TG）小鼠表现出 T 细胞异常，与 DS 个体中描述的异常非常相似。
RCAN1-TG 小鼠在胸腺和外周免疫组织中表现出 T 细胞发育缺陷。成熟的 CD4 和 CD8 胸腺细胞和皮质上皮细胞的大量丧失导致胸腺细胞减少。在外周免疫器官中，T 淋巴细胞数量减少，增殖能力降低，细胞因子产生异常。这些 T 细胞缺陷是干细胞内在的，因为将野生型骨髓移植到 RCAN1-TG 受者中恢复了胸腺、脾脏和淋巴结中的皮质胸腺上皮细胞和 T 细胞数量。然而，骨髓移植未能改善 T 细胞功能，表明 RCAN1 在非造血细胞中发挥额外作用。
因此，RCAN1 促进了 T 细胞的发育和功能，当过度表达时，可能导致 DS 中的免疫功能障碍。
