Genetic reconstitution of autoimmune type 1 diabetes with two major susceptibility genes in the rat
Genetic reconstitution of autoimmune type 1 diabetes with two major susceptibility genes in the rat
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DOI：
10.2337/db06-1027
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发表时间：
2007-02-01
期刊：
影响因子：
7.7
通讯作者：
Seino, Susumu
中科院分区：
文献类型：
--
作者：
Yokoi, Norihide;Hayashi, Chihiro;Seino, Susumu
Komeda糖尿病易感（KDP）大鼠是人类自身免疫性1型糖尿病的动物模型。我们以前已经表明，两个主要的易感基因，主要组织相容性复合体（MHC）RT 1（u）单倍型和CblB（Casitas B-谱系淋巴瘤B）突变，是负责糖尿病的发展，在KDP大鼠，提出了一个双基因模型的疾病的发展。为了证实双基因模型，我们产生了一种在非KDP遗传背景上携带KDP大鼠突变的Cblb等位基因的同源品系，其MHC上具有RT 1（u）单倍型。尽管糖尿病发病率低且延迟发作，但同类菌株确实发生了这种疾病，这表明I型糖尿病可以在具有RT 1（u）单倍型和Cblb突变的非KDP遗传背景上重建。与KDP大鼠中的观察结果相似，同类品系显示胰岛炎和甲状腺炎，即自身免疫症状。低发病率和延迟发病的疾病强烈建议参与的遗传修饰剂，在这项研究中建立的同类菌株应是有用的映射和识别这样的修饰剂。
The Komeda diabetes-prone (KDP) rat is an animal model of human autoimmune type 1 diabetes. We have previously shown that two major susceptibility genes, the major histocompatibility complex (MHC) RT1(u) haplotype and Cblb (Casitas B-lineage lymphoma b) mutation, are responsible for the development of diabetes in KDP rats, suggesting a two-gene model for development of the disease. To confirm the two-gene model, we produced a congenic strain carrying mutated Cblb alleles of the KDP rat on a non-KDP genetic background harboring the RT1(u) haplotype on its MHC. Despite the low incidence and delayed onset of diabetes, the congenic strain did develop the disease, indicating that type I diabetes can be reconstituted on a non-KDP genetic background with the RT1(u) haplotype and Cblb mutation. Similar to observations in KDP rats, the congenic strain showed insulitis and thyroiditis, symptoms of autoimmunity. The low incidence and delayed onset of the disease strongly suggest involvement of genetic modifiers; the congenic strain established in this study should be useful for the mapping and identification of such modifiers.