Age-dependent loss of tolerance to an immunodominant epitope of glutamic acid decarboxylase in diabetic-prone RIP-B7/DR4 mice
Age-dependent loss of tolerance to an immunodominant epitope of glutamic acid decarboxylase in diabetic-prone RIP-B7/DR4 mice
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DOI：
10.1016/j.clim.2006.08.002
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发表时间：
2006-12-01
影响因子：
8.6
通讯作者：
Nepom, Gerald T.
中科院分区：
文献类型：
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作者：
Gebe, John A.;Unrath, Kellee A.;Nepom, Gerald T.
我们首次在RIP-B7/DRB 1 *0404 HLA转基因小鼠中鉴定了对来自推定的糖尿病相关抗原谷氨酸脱羧酶（GAD 65）和胶质细胞酸性蛋白（GFAP）的两个自身抗原表位的年龄依赖性自发耐受性丧失。糖尿病小鼠和老年非糖尿病小鼠对来自GAD 65（555-567）和GFAP（240-252）的免疫显性表位表现出增殖反应，但对来自糖尿病相关胰岛特异性葡萄糖-6-磷酸酶催化亚基相关蛋白的免疫原性表位不表现出增殖反应。在年轻小鼠中未观察到对这两种自身抗原的反应，但在老年非糖尿病小鼠中观察到，并且在没有明显糖尿病的情况下伴有胰岛炎的组织学证据。老年非糖尿病小鼠和糖尿病小鼠的胰岛浸润含有CD 4（+）/FoxP 3（+）细胞，提示糖尿病之前和期间存在调节机制。RIP-B7/DR 0404小鼠的糖尿病发病率为23%，平均发病年龄为40周龄，与RIP-B7/DR 0401小鼠的报告相似。观察到性别偏好，38%的雌性小鼠患糖尿病，而8%的雄性小鼠患糖尿病。(c)2006爱思唯尔公司All rights reserved.
We have identified for the first time an age-dependent spontaneous loss of tolerance to two self-antigenic epitopes derived from putative diabetes-associated antigens glutamic acid decarboxytase (GAD65) and glial fibrillary acidic protein (GFAP) in RIP-B7/DRB1*0404 HLA transgenic mice. Diabetic and older non-diabetic mice exhibited a proliferative response to an immunodominant epitope from GAD65 (555-567) and also from GFAP (240-252) but not from an immunogenic epitope from diabetes-associated islet-specific glucose-6-phosphatase catalytic subunit-related protein. The response to both of these self-antigens is not observed in young mice but is observed in older non-diabetic mice and is accompanied by histological evidence of insulitis in the absence of overt diabetes. Islet infiltrates in older nondiabetic mice and diabetic mice contain CD4(+)/FoxP3(+) cells and suggest the presence of a regulatory mechanism prior and during diabetic disease. Diabetes penetrance in RIP-B7/DR0404 mice is 23% with a mean onset age of 40 weeks and is similar to that reported for RIP-B7/DR0401 mice. A gender preference is observed in that 38% of female mice become diabetic compared to 8% of mate mice. (c) 2006 Elsevier Inc. All rights reserved.