Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus
Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus
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DOI：
10.1038/ng0397-289
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发表时间：
1997-03-01
期刊：
影响因子：
30.8
通讯作者：
Polychronakos, C
中科院分区：
文献类型：
--
作者：
Vafiadis, P;Bennett, ST;Polychronakos, C
1型糖尿病或胰岛素依赖型糖尿病（IDDM）是由于自身免疫破坏胰腺β细胞。IDDM的遗传易感性是由几个基因座编码的，其中一个（IDDM2）映射到胰岛素基因（INS）上游的可变数量串联重复序列（VNTR）小卫星（1-5）。短的1类VNTR等位基因（26-63重复）易患IDDM，而III类等位基因（140-210重复）具有显性保护作用（1-6）。我们已经报道，在人体成人（4,6）和胎儿(7)胰腺中，III类等位基因与INS mRNA水平的相关性略低于I类，这表明VNTR具有转录作用。这些可能与1型糖尿病的发病机制有关，因为胰岛素是唯一已知的β细胞特异性IDDM自身抗原。为了寻找III类等位基因主导作用的更合理的机制，我们分析了人类胎儿胸腺中胰岛素的表达，这是诱导对自身蛋白耐受的关键部位。在所有检查的胸腺组织中都检测到胰岛素，III类VNTR等位基因的INS mRNA水平比i类高2- 3倍。因此，我们提出胸腺中更高水平的INS表达，促进免疫耐受诱导，是III类等位基因发挥主要保护作用的机制。
Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) is due to autoimmune destruction of pancreatic beta-cells. Genetic susceptibility to IDDM is encoded by several loci, one of which (IDDM2) maps to a variable number of tandem repeats (VNTR) minisatellite, upstream of the insulin gene (INS)(1-5). The short class 1 VNTR alleles (26-63 repeats) predispose to IDDM, while class III alleles (140-210 repeats) have a dominant protective effect(1-6). We have reported that, in human adult(4,6) and fetal(7) pancreas in vivo, class III alleles are associated with marginally lower INS mRNA levels than class I, suggesting transcriptional effects of the VNTR. These may be related to type 1 diabetes pathogenesis, as insulin is the only known beta-cell specific IDDM autoantigen. In search of a more plausible mechanism for the dominant effect of class III alleles, we analysed expression of insulin in human fetal thymus, a critical site for tolerance induction to self proteins. Insulin was detected in all thymus tissues examined and class III VNTR alleles were associated with 2- to 3-fold higher INS mRNA levels than class I. We therefore propose higher levels of thymic INS expression, facilitating immune tolerance induction, as a mechanism for the dominant protective effect of class III alleles.