Type 1 diabetes-predisposing MHC alleles influence the selection of glutamic acid decarboxylase (GAD) 65-specific T cells in a transgenic model
Type 1 diabetes-predisposing MHC alleles influence the selection of glutamic acid decarboxylase (GAD) 65-specific T cells in a transgenic model
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DOI：
10.4049/jimmunol.166.2.1370
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发表时间：
2001-01-15
影响因子：
4.4
通讯作者：
David, CS
中科院分区：
文献类型：
--
作者：
Abraham, RS;Wen, L;David, CS
导致1型糖尿病病因的遗传因素在很大程度上仍未确定。然而，MHC（人类HLA）基因一直与疾病易感性相关。我们使用在实验室产生的几种携带易感或耐药HLA等位基因的转基因小鼠，在缺乏内源性MHC II类（A β）的情况下，研究对自身抗原谷氨酸脱羧酶（GAD） 65的免疫反应及其在确定自身反应性与疾病发病机制之间的相关性。携带糖尿病易感单倍型HLA DR3 （DRB1*0301）或DQ8 （DQB1*0302）的小鼠，单独或组合对大鼠GAD 65表现出自发的T细胞反应，这与自身的Ag，小鼠GAD 65高度同源。糖尿病抵抗性或中性等位基因，如HLA DQ6 （DQB1*0602）和DR2 （DRB1*1502）的存在阻止了对大鼠GAD产生任何自我反应性反应。此外，未处理的A betao/DR3、A betao/ DQ8和A betao/DR3/DQ8小鼠识别特异性肽，主要来自GAD 65分子的n端区域。这些区域在人类、小鼠和大鼠GAD 65之间是保守的。进一步分析表明，这种反应性主要是由CD4(+) T细胞介导的。大鼠GAD 65对这些T细胞的刺激导致a β /DR3/DQ8、a β /DR3和a β /DQ8小鼠中产生混合的Th1/Th2细胞因子谱。因此，糖尿病相关基因的存在决定了对胰岛自身抗原的免疫耐受是否维持，但自身反应性本身并不足以诱发糖尿病。
The genetic factors that contribute to the etiology of type 1 diabetes are still largely uncharacterized. However, the genes of the MHC (HLA in humans) have been consistently associated with susceptibility to disease. We have used several transgenic mice generated in our laboratory, bearing susceptible or resistant HLA alleles, in the absence of endogenous MHC class II (A betao), to study immune responses to the autoantigen glutamic acid decarboxylase (GAD) 65 and its relevance in determining the association between autoreactivity and disease pathogenesis. Mice bearing diabetes-susceptible haplotypes, HLA DR3 (DRB1*0301) or DQ8 (DQB1*0302), singly or in combination showed spontaneous T cell reactivity to rat GAD 65, which is highly homologous to the self Ag, mouse GAD 65. The presence of diabetes-resistant or neutral alleles, such as HLA DQ6 (DQB1*0602) and DR2 (DRB1*1502) prevented the generation of any self-reactive responses to rat GAD. In addition, unmanipulated A betao/DR3, A betao/ DQ8, and A betao/DR3/DQ8 mice recognized specific peptides, mainly from the N-terminal region of the GAD 65 molecule. Most of these regions are conserved between human, mouse, and rat GAD 65. Further analysis revealed that the reactivity was mediated primarily by CD4(+) T cells. Stimulation of these T cells by rat GAD 65 resulted in the generation of a mixed Th1/Th2 cytokine profile in the A betao/DR3/DQ8, A betao/DR3, and A betao/DQ8 mice. Thus, the presence of diabetes-associated genes determines whether immune tolerance is maintained to islet autoantigens, but autoreactivity in itself is not sufficient to induce diabetes.