Gene expression profiling of pancreatic islets in BioBreeding rats

DRlyp/lyp and DR+/+ rats possess characteristics that make them ideal for the identification of pathways relevant to the development of T1D since they possess absolute or conditional susceptibility to T1D. The Gimap-/- Iddm2 locus conveys upon DRlyp/lyp rats a deficiency in immune regulatory capacity and the spontaneous T1D phenotype. Consistent with the concept that autoimmunity involves both a lack of self-tolerance as well as target organ-specific factors, we have discovered that DRlyp/lyp and DR+/+ (BB) rats share an islet specific stress. This is reflected by the expression of immune mediators, including the chemokine eotaxin that recruits eosinophils, certain T cell subsets, dendritic cells, and mast cells, by islet ß cells early in life, before infiltration of immune cells into the islet (insulitis). While BB and WF rats share Iddm1 (RT1u/u MHC), islet eotaxin expression in not observed in WF islets and thus is associated with the T1D susceptibility of BB rats. Further supporting the hypothesis that additional genetic factors, perhaps those working at the level of the pancreatic ß cell, are necessary for the development of T1D are the observations that 1) The generation Fischer 344 (F344) rats either homozygous for Gimap5-/- or homozygous for both RT1u/u and Gimap5-/- fail to develop T1D; and 2) genetic crosses between BB rats and non diabetic strains have identified numerous Iddm loci independent of Iddm1 and Iddm2.DRlyp/lyp与DR+/+大鼠因其对1型糖尿病（Type 1 Diabetes, T1D）具有绝对或条件性易感性，具备成为鉴定T1D发生相关通路理想动物模型的特征。携带Gimap纯合缺失（Gimap-/-）的Iddm2易感基因座，可赋予DRlyp/lyp大鼠免疫调节能力缺陷与自发性T1D表型。与“自身免疫既存在自身免疫耐受缺失，又涉及靶器官特异性因素”这一学术概念相符，本研究发现DRlyp/lyp与DR+/+（BB）大鼠存在共同的胰岛特异性应激。该应激可通过幼年时期胰岛β细胞表达免疫介导因子得以体现：其中包括招募嗜酸性粒细胞、特定T细胞亚群、树突状细胞与肥大细胞的趋化因子嗜酸性粒细胞趋化蛋白（eotaxin），且该表达发生于免疫细胞向胰岛浸润（胰岛炎（insulitis））之前。尽管BB与WF大鼠共享Iddm1（RT1u/u主要组织相容性复合体（Major Histocompatibility Complex, MHC）），但WF大鼠的胰岛中未检测到嗜酸性粒细胞趋化蛋白的表达，因此该蛋白的表达与BB大鼠的T1D易感性密切相关。进一步支持“额外的遗传因素——或许是在胰腺β细胞层面发挥功能的因素——是T1D发生的必要条件”这一假说的观察结果包括：1）纯合缺失Gimap5，或同时纯合携带RT1u/u与Gimap5-/-的费希尔344（Fischer 344, F344）大鼠均不会发生T1D；2）BB大鼠与非糖尿病品系大鼠的遗传杂交实验已鉴定出多个独立于Iddm1与Iddm2的Iddm易感基因座。