Vafiadis P, Bennett S T, Todd J A, Nadeau J, Grabs R, Goodyer C G, Wickramasinghe S, Colle E, Polychronakos C
McGill University-Montreal Children's Hospital Research Institute, Montréal, Québec, Canada.
Nat Genet. 1997 Mar;15(3):289-92. doi: 10.1038/ng0397-289.
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). The short class I VNTR alleles (26-63 repeats) predispose to IDDM, while class III alleles (140-210 repeats) have a dominant protective effect. We have reported that, in human adult and fetal 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.
1型糖尿病或胰岛素依赖型糖尿病（IDDM）是由于胰腺β细胞的自身免疫性破坏所致。IDDM的遗传易感性由多个基因座编码，其中一个基因座（IDDM2）定位于胰岛素基因（INS）上游的可变数目串联重复序列（VNTR）微卫星。I类短VNTR等位基因（26 - 63个重复序列）易患IDDM，而III类等位基因（140 - 210个重复序列）具有显性保护作用。我们曾报道，在成人和胎儿胰腺体内，III类等位基因与INS mRNA水平略低于I类等位基因相关，提示VNTR的转录效应。这些效应可能与1型糖尿病的发病机制有关，因为胰岛素是已知的唯一β细胞特异性IDDM自身抗原。为了寻找III类等位基因显性效应的更合理机制，我们分析了人胎儿胸腺中胰岛素的表达，胎儿胸腺是诱导对自身蛋白产生耐受性的关键部位。在所检测的所有胸腺组织中均检测到胰岛素，并且III类VNTR等位基因与INS mRNA水平比I类等位基因高2至3倍相关。因此，我们提出胸腺中较高水平的INS表达促进免疫耐受诱导，作为III类等位基因显性保护作用的一种机制。
