Glawe John D, Patrick D Ross, Huang Meng, Sharp Christopher D, Barlow Shayne C, Kevil Christopher G
Department of Pathology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.
Diabetes. 2009 Jun;58(6):1292-301. doi: 10.2337/db08-0804. Epub 2009 Feb 17.
Insulitis is an important pathological feature of autoimmune diabetes; however, mechanisms governing the recruitment of diabetogenic T-cells into pancreatic islets are poorly understood. Here, we determined the importance of leukocyte integrins beta(2)(Itgb2) and alphaL (ItgaL) in developing insulitis and frank diabetes.
Gene-targeted mutations of either Itgb2 or ItgaL were established on the NOD/LtJ mouse strain. Experiments were performed to measure insulitis and diabetes development. Studies were also performed measuring mutant T-cell adhesion to islet microvascular endothelial cells under hydrodynamic flow conditions. T-cell adhesion molecule profiles and adoptive transfer studies were also performed.
Genetic deficiency of either Itgb2 or ItgaL completely prevented the development of hyperglycemia and frank diabetes in NOD mice. Loss of Itgb2 or ItgaL prevented insulitis with Itgb2 deficiency conferring complete protection. In vitro hydrodynamic flow adhesion studies also showed that loss of Itgb2 completely abrogated T-cell adhesion. However, ItgaL deficiency did not alter NOD T-cell adhesion to or transmigration across islet endothelial cells. Adoptive transfer of ItgaL-deficient splenocytes into NOD/Rag-1 mice did not result in development of diabetes, suggesting a role for ItgaL in NOD/LtJ T-cell activation.
Together, these data demonstrate that genetic deficiency of Itgb2 or ItgaL confers protection against autoimmune diabetes through distinctly different mechanisms.
胰岛炎是自身免疫性糖尿病的一个重要病理特征;然而,关于致糖尿病性T细胞募集至胰岛的机制仍知之甚少。在此,我们确定了白细胞整合素β2(Itgb2)和αL(ItgaL)在胰岛炎和显性糖尿病发生过程中的重要性。
在NOD/LtJ小鼠品系上建立了Itgb2或ItgaL的基因靶向突变。进行实验以测量胰岛炎和糖尿病的发生情况。还进行了研究,测量在流体动力学流动条件下突变型T细胞与胰岛微血管内皮细胞的黏附情况。也进行了T细胞黏附分子谱分析和过继转移研究。
Itgb2或ItgaL的基因缺陷完全阻止了NOD小鼠高血糖和显性糖尿病的发生。Itgb2或ItgaL的缺失可预防胰岛炎,其中Itgb2缺陷提供了完全保护。体外流体动力学流动黏附研究还表明,Itgb2的缺失完全消除了T细胞黏附。然而,ItgaL缺陷并未改变NOD T细胞与胰岛内皮细胞的黏附或跨内皮迁移。将ItgaL缺陷的脾细胞过继转移至NOD/Rag-1小鼠中并未导致糖尿病的发生,提示ItgaL在NOD/LtJ T细胞活化中起作用。
总之,这些数据表明,Itgb2或ItgaL的基因缺陷通过截然不同的机制对自身免疫性糖尿病起到保护作用。