Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes
Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes
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DOI：
10.4049/jimmunol.179.12.8341
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发表时间：
2007-12-15
影响因子：
4.4
通讯作者：
Wicker, Linda S.
中科院分区：
文献类型：
--
作者：
Hunter, Kara;Rainbow, Dan;Wicker, Linda S.
决定NOD小鼠对1型糖尿病（T1D）易感性的两个基因座Idd5.1和Idd5.2位于1号染色体上。Idd5.1可能是由Ctla4外显子2的同义单核苷酸多态性引起的：b10衍生的t1d抗性等位基因增加了CTLA-4 （liCTLA-4）的配体非依赖性异构体的表达，这是一种在T细胞中介导负信号传导的分子。Idd5.2可能是Nramp1 (Slc11a1)，它编码一种吞噬体膜蛋白，该蛋白是金属外排泵，对宿主防御和银呈递很重要。在本研究中，两个额外的位点Idd5.3和Idd5.4分别被定义在1号染色体连锁区域的3.553和78 Mb区域。然而，最引人注目的发现是我们获得的这四个疾病位点之间强相互作用的证据，这些证据有助于解释人类CTLA4与T1D的关联。在Idd5.4处存在易感等位基因时，CTLA-4抗性等位基因导致T1D减少80%，而在Idd5.4处存在保护性等位基因时，Ctla4抗性等位基因的影响不大，或者在Idd5.2和Idd5.3处存在抗性等位基因的情况下，其影响完全被掩盖。不同遗传背景对CTLA-4等位基因的屏蔽解释了我们的观察，即人类CTLA-4基因仅与具有抗甲状腺自身免疫的人类T1D患者亚组中的T1D相关。
Two loci, Idd5.1 and Idd5.2, that determine susceptibility to type I diabetes (T1D) in the NOD mouse are on chromosome 1. Idd5.1 is likely accounted for by a synonymous single nucleotide polymorphism in exon 2 of Ctla4: the B10-derived T1D-resistant allele increases the expression of the ligand-independent isoform of CTLA-4 (liCTLA-4), a molecule that mediates negative signaling in T cells. Idd5.2 is probably Nramp1 (Slc11a1), which encodes a phagosomal membrane protein that is a metal efflux pump and is important for host defense and Ag presentation. In this study, two additional loci, Idd5.3 and Idd5.4, have been defined to 3.553 and 78 Mb regions, respectively, on linked regions of chromosome 1. The most striking findings, however, concern the evidence we have obtained for strong interactions between these four disease loci that help explain the association of human CTLA4 with T1D. In the presence of a susceptibility allele at Idd5.4, the CTLA-4 resistance allele causes an 80% reduction in T1D, whereas in the presence of a protective allele at Idd5.4, the effects of the resistance allele at Ctla4 are modest or, as in the case in which resistance alleles at Idd5.2 and Idd5.3 are present, completely masked. This masking of CTLA-4 alleles by different genetic backgrounds provides an explanation for our observation that the human CTLA-4 gene is only associated with T1D in the subgroup of human T1D patients with anti-thyroid autoimmunity.