The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model
The regulatory role of DR4 in a spontaneous diabetes DQ8 transgenic model
复制标题
DOI：
10.1172/jci11708
复制
发表时间：
2001-04-01
影响因子：
15.9
通讯作者：
Wong, FS
中科院分区：
文献类型：
--
作者：
Wen, L;Chen, NY;Wong, FS
MWC II 类分子是人类 1 型糖尿病遗传易感性的关键决定因素。在患者中，最常见的单倍型包含 DRA1*0101-DRB1*0401 (DR4) 和 DQA1*0301-DQB1*0302 (DQ8) 位点。为了直接评估 HLA-DQ8 和 DR4 在体内糖尿病发展中的相对作用，我们生成了缺乏内源性小鼠 MHC II 类分子但表达 HLA-DQ 和/或 DR4 的 C57BL/6 转基因小鼠。 HLA-DQ 和 HLA-DR 转基因小鼠均未出现胰岛炎或自发性糖尿病。然而，当它们与通常不会患糖尿病的胰腺 P 细胞上表达 B7.1 共刺激分子的转基因小鼠 (C57BL/6) 杂交时，来自这些双转基因小鼠的 T 细胞不再耐受胰岛自身抗原。大多数 DQ8/RIP-B7 小鼠会出现自发性糖尿病，而 DR4/RIP-B7 小鼠中只有 25% 会出现这种情况。有趣的是，当 DQ8 和 DR4 共表达 (DQ8DR4/RIP-B7) 时，这些小鼠中只有 23% 患上糖尿病，这一发病率与 DR4/RIP-B7 小鼠没有区别。与 DQ8/RIP-B7 小鼠不同，DR4/RIP-B7 和 DQ8DR4/RTP-B7 小鼠的 T 细胞表现出 Th2 样表型。因此，DR4 的表达似乎下调了 DQ8DR4/RTP-B7 小鼠中 DQ8 限制性自身反应性 T 细胞。我们的数据表明，虽然 DQ8 和 DR4 都可以促进具有非自身免疫倾向遗传背景的小鼠自发性糖尿病，但 DQ8 等位基因的致糖尿病作用要大得多，而 DR4 表达可能通过增强 Th2 样免疫反应下调 DQ8 的致糖尿病作用。
MWC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA1*0101-DRB1*0401 (DR4) and DQA1*0301-DQB1*0302 (DQ8) loci. To assess directly the relative roles of HLA-DQ8 and DR4 for diabetes development in vivo, we generated C57BL/6 transgenic mice that lack endogenous mouse MHC class II molecules but express HLA-DQs and/or DR4. Neither HLA-DQ nor HLA-DR transgenic mice developed insulitis or spontaneous diabetes. However, when they were crossed to transgenic mice (C57BL/6) expressing the B7.1 costimulatory molecules on pancreatic P cells that do not normally develop diabetes, T cells from these double transgenic mice were no longer tolerant to islet autoantigens. The majority of DQ8/RIP-B7 mice developed spontaneous diabetes, whereas only 25% of DR4/RIP-B7 mice did so. Interestingly, when DQ8 and DR4 were coexpressed (DQ8DR4/RIP-B7), only 23% of these mice developed diabetes, an incidence indistinguishable from the DR4/RIP-B7 mice. T cells from both DR4/RIP-B7 and DQ8DR4/RTP-B7 mice, unlike those from DQ8/RIP-B7 mice, exhibited a Th2-like phenotype. Thus, the expression of DR4 appeared to downregulate DQ8-restricted autoreactive T cells in DQ8DR4/RTP-B7 mice. Our data suggest that although both DQ8 and DR4 can promote spontaneous diabetes in mice with a non-autoimmune-prone genetic background, the diabetogenic effect of the DQ8 allele is much greater, whereas DR4 expression downregulates the diabetogenic effect of DQ8, perhaps by enhancing Th2-like immune responses.