Genetic interactions among Idd3, Idd5.1, Idd5.2, and Idd5.3 protective loci in the nonobese diabetic mouse model of type 1 diabetes.
Genetic interactions among Idd3, Idd5.1, Idd5.2, and Idd5.3 protective loci in the nonobese diabetic mouse model of type 1 diabetes.
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DOI：
10.4049/jimmunol.1203422
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发表时间：
2013-04-01
期刊：
影响因子：
--
通讯作者：
Sherman LA
中科院分区：
文献类型：
--
作者：
Lin X;Hamilton-Williams EE;Rainbow DB;Hunter KM;Dai YD;Cheung J;Peterson LB;Wicker LS;Sherman LA
在 1 型糖尿病 (T1D) 的非肥胖糖尿病 (NOD) 小鼠模型中，胰岛素依赖性糖尿病 (Idd) 位点控制胰岛素炎和糖尿病的发展。独立地，Idd3/Il2 或 Idd5 的保护性等位基因能够部分保护同源 NOD 小鼠免受胰岛炎和糖尿病，并部分耐受胰岛特异性 CD8+ T 细胞。然而，当这两个区域结合在一起时，小鼠几乎受到完全保护，强烈表明这两个基因座之间存在遗传相互作用。 Idd5 包含至少三个保护性亚区域/候选致病基因，Idd5.1/Ctla4、Idd5.2/Slc11a1 和 Idd5.3/Acadl，但尚不清楚其中哪一个与 Idd3/Il2 相互作用。通过使用一系列包含 Idd3/Il2 区域和 Idd5 子区域不同组合的新型同源菌株，我们定义了这些遗传相互作用。 Idd3/Il2 和 Idd5.3/Acadl 的组合能够提供几乎完全的针对 T1D 的保护，但需要所有三个 Idd5 子区域来预防胰岛炎并完全恢复自我耐受。通过将 Slc11a1 KO 等位基因回交到 NOD 遗传背景，我们证明 Slc11a1 负责 Idd5.2 产生的糖尿病保护作用。我们还使用 Slc11a1 KO-SCID 和 Idd5.2-SCID 小鼠来证明，当单独在 SCID 宿主上表达时，这两种功能丧失等位基因都可以提供免受胰岛素炎的保护。这些结果进一步支持了Slc11a1是Idd5.2的假设。
In the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D), insulin-dependent diabetes (Idd) loci control the development of insulitis and diabetes. Independently, protective alleles of Idd3/Il2 or Idd5 are able to partially protect congenic NOD mice from insulitis and diabetes, and to partially tolerize islet-specific CD8+ T cells. However, when the two regions are combined, mice are almost completely protected, strongly suggesting the existence of genetic interactions between the two loci. Idd5 contains at least three protective sub-regions/causative gene candidates, Idd5.1/Ctla4, Idd5.2/Slc11a1 and Idd5.3/Acadl, yet it is unknown which of them interacts with Idd3/Il2. Through the use of a series of novel congenic strains containing the Idd3/Il2 region and different combinations of Idd5 sub-region(s), we defined these genetic interactions. The combination of Idd3/Il2 and Idd5.3/Acadl was able to provide nearly complete protection from T1D, but all three Idd5 sub-regions were required to protect from insulitis and fully restore self-tolerance. By backcrossing a Slc11a1 KO allele onto the NOD genetic background, we have demonstrated that Slc11a1 is responsible for the diabetes protection resulting from Idd5.2. We also used Slc11a1 KO-SCID and Idd5.2-SCID mice to show that both loss-of-function alleles provide protection from insulitis when expressed on the SCID host alone. These results lend further support to the hypothesis that Slc11a1 is Idd5.2.
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DOI：
10.1084/jem.20050693
发表时间：
2005-09-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jiang W;Anderson MS;Bronson R;Mathis D;Benoist C
通讯作者：
Benoist C
影响因子：
30.8
作者：
Barrett, Jeffrey C.;Clayton, David G.;Concannon, Patrick;Akolkar, Beena;Cooper, Jason D.;Erlich, Henry A.;Julier, Cecile;Morahan, Grant;Nerup, Jorn;Nierras, Concepcion;Plagnol, Vincent;Pociot, Flemming;Schuilenburg, Helen;Smyth, Deborah J.;Stevens, Helen;Todd, John A.;Walker, Neil M.;Rich, Stephen S.
通讯作者：
Rich, Stephen S.
影响因子：
7.7
作者：
Howson JM;Cooper JD;Smyth DJ;Walker NM;Stevens H;She JX;Eisenbarth GS;Rewers M;Todd JA;Akolkar B;Concannon P;Erlich HA;Julier C;Morahan G;Nerup J;Nierras C;Pociot F;Rich SS;Type 1 Diabetes Genetics Consortium
通讯作者：
Type 1 Diabetes Genetics Consortium
影响因子：
5.4
作者：
Goudy, Kevin S.;Johnson, Mark C.;Garland, Alaina;Li, Chengwen;Samulski, Richard J.;Wang, Bo;Tisch, Roland
通讯作者：
Tisch, Roland
影响因子：
7.7
作者：
Hamilton-Williams, Emma E.;Cheung, Jocelyn;Sherman, Linda A.
通讯作者：
Sherman, Linda A.