Ligers A, Teleshova N, Masterman T, Huang W X, Hillert J
Division of Neurology, NEUROTEC, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden.
Genes Immun. 2001 May;2(3):145-52. doi: 10.1038/sj.gene.6363752.
CTLA-4, expressed mainly on activated T cells, helps maintain, through its inhibitory function, immune-system homeostasis. Polymorphisms in the CTLA-4 gene (CTLA4) are known to be important in several autoimmune diseases, including multiple sclerosis (MS). Here, we have performed genotyping for CTLA4 polymorphisms, and investigated expression by peripheral blood mononuclear cells of CTLA-4 mRNA and protein, in patients with MS and myasthenia gravis and in healthy controls. Expression levels for mRNA and protein were similar in the patient and control groups; however, there was a clear relationship between genotype and CTLA-4 expression. Specifically, individuals carrying thymine at position -318 of the CTLA4 promoter (T(-318)) and homozygous for adenine at position 49 in exon 1 showed significantly increased expression both of cell-surface CTLA-4 after cellular stimulation and of CTLA-4 mRNA in non-stimulated cells. The association was seen most clearly for unsorted CD3(+) cells and was absent in the CD8(+) subset. The T(-318) allele has been shown to be negatively associated with susceptibility to MS in an earlier study by our group. Thus, we propose that the susceptibility-influencing role of CTLA4 in MS may be related to genotypically conditioned promoter function, whereby high gene expression may decrease the risk of disease.
CTLA-4主要表达于活化的T细胞上，通过其抑制功能帮助维持免疫系统的稳态。已知CTLA-4基因（CTLA4）的多态性在包括多发性硬化症（MS）在内的几种自身免疫性疾病中具有重要意义。在此，我们对MS和重症肌无力患者以及健康对照者进行了CTLA4多态性的基因分型，并研究了外周血单核细胞中CTLA-4 mRNA和蛋白的表达情况。患者组和对照组中mRNA和蛋白的表达水平相似；然而，基因型与CTLA-4表达之间存在明显的关系。具体而言，在CTLA4启动子-318位携带胸腺嘧啶（T(-318)）且外显子1中49位为腺嘌呤纯合子的个体，在细胞刺激后细胞表面CTLA-4的表达以及未刺激细胞中CTLA-4 mRNA的表达均显著增加。这种关联在未分选的CD3(+)细胞中最为明显，而在CD8(+)亚群中不存在。在我们小组早期的一项研究中，T(-318)等位基因已被证明与MS易感性呈负相关。因此，我们提出CTLA4在MS中影响易感性的作用可能与基因型决定的启动子功能有关，即高基因表达可能降低疾病风险。
