ICA69null nonobese diabetic mice develop diabetes, but resist disease acceleration by cyclophosphamide
ICA69null nonobese diabetic mice develop diabetes, but resist disease acceleration by cyclophosphamide
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DOI：
10.4049/jimmunol.168.1.475
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发表时间：
2002-01-01
影响因子：
4.4
通讯作者：
Dosch, HM
中科院分区：
文献类型：
--
作者：
Winer, S;Astsaturov, I;Dosch, HM
ICA 69（胰岛细胞Ag 69 kDa）是一种糖尿病相关的自身抗原，在β细胞和脑中具有高表达水平。其功能尚不清楚，但敲除其秀丽隐杆线虫同源物，ric-19，损害了神经传递。我们在129品系小鼠中破坏了鼠基因伊卡-1。这些动物年龄正常，但速度同类ICA 69（空）非肥胖糖尿病（NOD）小鼠发展中年致死性，联想到NOD特异性，谷氨酸脱羧酶65缺陷小鼠的晚期致死性癫痫发作。与野生型和杂合动物相比，ICA 69（空）NOD同源物即使在免疫后也不能产生交叉反应性T细胞，该T细胞识别ICA 69中的显性Tep 69表位及其环境模拟物Ag，BSA中的ABBOS表位。因此，这种抗原模拟是由内源性自身Ag驱动的，而不是由环境模拟物引发的。胰岛炎、自发性和过继性转移糖尿病在ICA 69（null）NOD同源基因中正常发生。与谷氨酸脱羧酶65一样，ICA 69不是糖尿病中的专性自身抗原。出乎意料的是，ICA 69（null）NOD小鼠对环磷酰胺（CY）加速的糖尿病具有抗性。造血和胰岛组织的移植实验与胰岛中对ICA 69缺乏的CY抗性有关。CYP加速的糖尿病不仅涉及淋巴细胞的消融，还涉及β细胞中ICA 69依赖性药物毒性，其增强再生淋巴系统中的自身反应性。
ICA69 (islet cell Ag 69 kDa) is a diabetes-associated autoantigen with high expression levels in beta cells and brain. Its function is unknown, but knockout of its Caenorhabditis elegans homologue, ric-19, compromised neurotransmission. We disrupted the murine gene, ica-1, in 129-strain mice. These animals aged normally, but speed-congenic ICA69(null) nonobese diabetic (NOD) mice developed mid-life lethality, reminiscent of NOD-specific, late lethal seizures in glutamic acid decarboxylase 65-deficient mice. In contrast to wild-type and heterozygous animals, ICA69(null) NOD congenics fail to generate, even after immunization, cross-reactive T cells that recognize the dominant Tep69 epitope in ICA69, and its environmental mimicry Ag, the ABBOS epitope in BSA. This antigenic mimicry is thus driven by the endogenous self Ag, and not initiated by the environmental mimic. Insulitis, spontaneous, and adoptively transferred diabetes develop normally in ICA69(null) NOD congenics. Like glutamic acid decarboxylase 65, ICA69 is not an obligate autoantigen in diabetes. Unexpectedly, ICA69(null) NOD mice were resistant to cyclophosphamide (CY)-accelerated diabetes. Transplantation experiments with hemopoietic and islet tissue linked CY resistance to ICA69 deficiency in islets. CY-accelerated diabetes involves not only ablation of lymphoid cells, but ICA69-dependent drug toxicity in beta cells that boosts autoreactivity in the regenerating lymphoid system.