Evidence that a peptide spanning the B-C junction of proinsulin is an early autoantigen epitope in the pathogenesis of type 1 diabetes
Evidence that a peptide spanning the B-C junction of proinsulin is an early autoantigen epitope in the pathogenesis of type 1 diabetes
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DOI：
10.4049/jimmunol.167.9.4926
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发表时间：
2001-11-01
影响因子：
4.4
通讯作者：
Delovitch, TL
中科院分区：
文献类型：
--
作者：
Chen, W;Bergerot, I;Delovitch, TL
胰岛素原在胸腺中的表达可能导致胰岛素原自身反应性T细胞的阴性选择以及1型糖尿病（T1D）中对这种自身抗原的外周耐受。我们研究了胰岛素原是否在幼年非肥胖糖尿病（NOD）小鼠的胸腺中表达，刚断奶的未免疫NOD雌性小鼠的T细胞是否对小鼠胰岛素原有反应，以及胰岛素原作为1型糖尿病致病性自身抗原的作用。在2周龄NOD小鼠的胸腺中检测到胰岛素原II mRNA转录本，其水平与其他对照品系相似。尽管有这种表达，但在2 - 3周龄未免疫的NOD小鼠外周检测到胰岛素原自身反应性T细胞。在这些小鼠中还检测到对胰岛素、谷氨酸脱羧酶65（GAD65）、GAD67和胰岛细胞抗原p69自身抗原具有反应性的外周T细胞，这表明NOD小鼠在幼年时对这些胰岛自身抗原均不耐受。对胰岛素原和胰岛细胞抗原p69的T细胞反应性超过了对GAD67的反应性，并且脾脏和胰腺淋巴结中对胰岛素原的T细胞反应性主要针对跨越B链/C肽连接的p24 - 33表位。从18日龄开始在围产期用胰岛素原进行腹腔免疫可延迟1型糖尿病的发病并降低其发病率。然而，在5周龄开始用胰岛素原进行皮下免疫会加速雌性NOD小鼠的糖尿病进程。我们的研究结果支持胰岛素原p24 - 33可能是NOD小鼠1型糖尿病发病机制中的主要自身抗原表位这一观点。
The expression of pro(insulin) in the thymus may lead to the negative selection of pro(insulin) autoreactive T cells and peripheral tolerance to this autoantigen in type 1 diabetes (T1D). We investigated whether proinsulin is expressed in the thymus of young nonobese diabetic (NOD) mice, whether T cells from naive NOD female mice at weaning are reactive to mouse proinsulin, and the role of proinsulin as a pathogenic autoantigen in T1D. Proinsulin II mRNA transcripts were detected in the thymus of 2-wk-old NOD mice at similar levels to other control strains. Despite this expression, proinsulin autoreactive T cells were detected in the periphery of 2- to 3-wk-old naive NOD mice. Peripheral T cells reactive to the insulin, glutamic acid decarboxylase 65 (GAD65), GAD67, and islet cell Ag p69 autoantigens were also detected in these mice, indicating that NOD mice are not tolerant to any of these islet autoantigens at this young age. T cell reactivities to proinsulin and islet cell Ag p69 exceeded those to GAD67, and T cell reactivity to proinsulin in the spleen and pancreatic lymph nodes was directed mainly against a p24-33 epitope that spans the B chain/C peptide junction. Intraperitoneal immunization with proinsulin perinatally beginning at 18 days of age delayed the onset and reduced the incidence of T1D. However, s.c. immunization with proinsulin initiated at 5 wk of age accelerated diabetes in female NOD mice. Our findings support the notion that proinsulin p24-33 may be a primary autoantigen epitope in the pathogenesis of T1D in NOD mice.