Wen L, Chen N Y, Tang J, Sherwin R, Wong F S
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
J Clin Invest. 2001 Apr;107(7):871-80. doi: 10.1172/JCI11708.
MHC class II molecules are critical determinants of genetic susceptibility to human type 1 diabetes. In patients, the most common haplotype contains the DRA10101-DRB10401 (DR4) and DQA10301-DQB10302 (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-DQ8 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 beta 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/RIP-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/RIP-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.
MHC 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DRA10101-DRB10401（DR4）和DQA10301-DQB10302（DQ8）基因座。为了直接评估HLA-DQ8和DR4在体内糖尿病发生中的相对作用，我们构建了缺乏内源性小鼠MHC II类分子但表达HLA-DQ8和/或DR4的C57BL/6转基因小鼠。HLA-DQ和HLA-DR转基因小鼠均未发生胰岛炎或自发性糖尿病。然而，当它们与在胰腺β细胞上表达B7.1共刺激分子（通常不会发生糖尿病）的转基因小鼠（C57BL/6）杂交时，这些双转基因小鼠的T细胞不再对胰岛自身抗原耐受。大多数DQ8/RIP-B7小鼠发生了自发性糖尿病，而只有25%的DR4/RIP-B7小鼠发生了自发性糖尿病。有趣的是，当DQ8和DR4共表达时（DQ8DR4/RIP-B7），这些小鼠中只有23%发生了糖尿病，其发病率与DR4/RIP-B7小鼠无差异。与DQ8/RIP-B7小鼠的T细胞不同，DR4/RIP-B7和DQ8DR4/RIP-B7小鼠的T细胞表现出类似Th2的表型。因此，DR4的表达似乎下调了DQ8DR4/RIP-B7小鼠中受DQ8限制的自身反应性T细胞。我们的数据表明，虽然DQ8和DR4都可以在具有非自身免疫倾向遗传背景中促进小鼠自发性糖尿病，但DQ8等位基因的致糖尿病作用要大得多，而DR4的表达可能通过增强类似Th2的免疫反应来下调DQ8的致糖尿病作用。
