Suarez-Pinzon W, Sorensen O, Bleackley R C, Elliott J F, Rajotte R V, Rabinovitch A
Department of Medicine, University of Alberta, Edmonton, Canada.
Diabetes. 1999 Jan;48(1):21-8. doi: 10.2337/diabetes.48.1.21.
A mechanism of autoimmune destruction of islet beta-cells in type 1 diabetes has been proposed to be the binding of Fas ligand (FasL) on T-cells to Fas receptors on beta-cells. We investigated this proposal by examining the expression of FasL and Fas on islet-infiltrating T-cells and beta-cells in relation to beta-cell destruction in a syngeneic islet transplant model in NOD mice. Diabetic NOD mice were transplanted with syngeneic islets and injected with complete Freund's adjuvant, which prevented diabetes recurrence (nondestructive insulitis), and with phosphate-buffered saline, which did not (beta-cell destructive insulitis). Two-color immunohistochemical assays revealed that FasL was expressed on CD4+ T-cells, CD8+ T-cells, and beta-cells in islet grafts from both diabetic and normoglycemic mice, and the percentage of each type of cell that expressed FasL was greater in islet grafts from normoglycemic compared with diabetic mice. In contrast, Fas was expressed on CD4+ T-cells, CD8+ T-cells, and beta-cells in islet grafts from diabetic mice, but it was nearly or totally absent on these cells in islet grafts from normoglycemic mice. Similarly, polymerase chain reaction analysis of islet grafts revealed that Fas mRNA expression was significantly lower in islet grafts from normoglycemic compared with diabetic mice. Also, mRNA levels of interleukin (IL)-1alpha, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were significantly lower in islet grafts from normoglycemic mice. Finally, Fas was induced on NOD islet cells by incubation with IL-1beta, IFN-gamma, and the combination of IL-1beta, TNF-alpha, and IFN-gamma. These findings support the concept that cytokine-induced Fas receptor expression on islet beta-cells is a mechanism for their destruction by FasL-expressing CD4+ and CD8+ T-cells and, possibly, by FasL-expressing beta-cells themselves.
1型糖尿病中胰岛β细胞自身免疫性破坏的一种机制被认为是T细胞上的Fas配体（FasL）与β细胞上的Fas受体结合。我们通过研究同基因胰岛移植模型中NOD小鼠胰岛浸润性T细胞和β细胞上FasL和Fas的表达与β细胞破坏的关系，来探究这一假说。将糖尿病NOD小鼠移植同基因胰岛，并注射完全弗氏佐剂（可预防糖尿病复发，即非破坏性胰岛炎）或磷酸盐缓冲盐水（不能预防，即β细胞破坏性胰岛炎）。双色免疫组织化学分析显示，糖尿病和血糖正常小鼠胰岛移植物中的CD4⁺T细胞、CD8⁺T细胞和β细胞均表达FasL，与糖尿病小鼠相比，血糖正常小鼠胰岛移植物中表达FasL的每种细胞类型的百分比更高。相反，糖尿病小鼠胰岛移植物中的CD4⁺T细胞、CD8⁺T细胞和β细胞表达Fas，但血糖正常小鼠胰岛移植物中的这些细胞上几乎或完全不表达Fas。同样，胰岛移植物的聚合酶链反应分析显示，与糖尿病小鼠相比，血糖正常小鼠胰岛移植物中Fas mRNA表达显著降低。此外，血糖正常小鼠胰岛移植物中白细胞介素（IL）-1α、肿瘤坏死因子（TNF）-α和干扰素（IFN）-γ的mRNA水平也显著降低。最后，用IL-1β、IFN-γ以及IL-1β、TNF-α和IFN-γ的组合孵育可诱导NOD胰岛细胞表达Fas。这些发现支持了这样一种观点，即细胞因子诱导胰岛β细胞上的Fas受体表达是其被表达FasL的CD4⁺和CD8⁺T细胞以及可能被表达FasL的β细胞自身破坏的一种机制。
