Blankenhorn Elizabeth P, Cort Laura, Greiner Dale L, Guberski Dennis L, Mordes John P
Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
Diabetes. 2009 Dec;58(12):2930-8. doi: 10.2337/db09-0387. Epub 2009 Aug 31.
To identify genes that confer susceptibility to autoimmune diabetes following viral infection in the LEW.1WR1 rat.
About 2% of LEW.1WR1 rats develop spontaneous autoimmune diabetes. Immunological perturbants including viral infection increase both the frequency and tempo of diabetes onset. To identify diabetes susceptibility genes (LEW.1WR1 x WF), F2 rats were infected with Kilham rat virus following brief pretreatment with polyinosinic:polycytidylic acid. This treatment induces diabetes in 100% of parental LEW.1WR1 rats and 0% of parental WF rats. Linkage to diabetes was analyzed by genome-wide scanning.
Among 182 F2 rats, 57 (31%) developed autoimmune diabetes after a mean latency of 16 days. All diabetic animals and approximately 20% of nondiabetic animals exhibited pancreatic insulitis. Genome-wide scanning revealed a requirement for the Iddm14 locus, long known to be required for diabetes in the BB rat. In addition, a new locus near the RT1 major histocompatibility complex (MHC) was found to be a major determinant of disease susceptibility. Interestingly, one gene linked to autoimmune diabetes in mouse and human, UBD, lies within this region.
The Iddm14 diabetes locus in the rat is a powerful determinant of disease penetrance in the LEW.1WR1 rat following viral infection. In addition, a locus near the MHC (Iddm37) conditions diabetes susceptibility in these animals. Other, as-yet-unidentified genes are required to convert latent susceptibility to overt diabetes. These data provide insight into the polygenic nature of autoimmune diabetes in the rat and the interplay of genetic and environmental factors underlying disease expression.
鉴定在LEW.1WR1大鼠中病毒感染后导致自身免疫性糖尿病易感性的基因。
约2%的LEW.1WR1大鼠会自发发生自身免疫性糖尿病。包括病毒感染在内的免疫干扰因素会增加糖尿病发病的频率和速度。为了鉴定糖尿病易感基因（LEW.1WR1×WF），先用聚肌苷酸:聚胞苷酸进行短暂预处理，然后给F2大鼠感染Kilham大鼠病毒。这种处理可使100%的亲代LEW.1WR1大鼠发生糖尿病，而亲代WF大鼠的发病率为0%。通过全基因组扫描分析与糖尿病的连锁关系。
在182只F2大鼠中，57只（31%）在平均潜伏期16天后发生了自身免疫性糖尿病。所有糖尿病动物以及约20%的非糖尿病动物均表现出胰腺胰岛炎。全基因组扫描显示需要Iddm14位点，该位点长期以来已知是BB大鼠发生糖尿病所必需的。此外，发现靠近RT1主要组织相容性复合体（MHC）的一个新位点是疾病易感性的主要决定因素。有趣的是，在小鼠和人类中与自身免疫性糖尿病相关的一个基因UBD位于该区域内。
大鼠中的Iddm14糖尿病位点是病毒感染后LEW.1WR1大鼠疾病外显率的一个重要决定因素。此外，MHC附近的一个位点（Iddm37）决定了这些动物的糖尿病易感性。还需要其他尚未鉴定的基因来将潜在易感性转化为显性糖尿病。这些数据为大鼠自身免疫性糖尿病的多基因性质以及疾病表达背后的遗传和环境因素的相互作用提供了见解。
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