RegII is a β-cell protein and autoantigen in diabetes of NOD mice
RegII is a β-cell protein and autoantigen in diabetes of NOD mice
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DOI：
10.2337/db06-0669
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发表时间：
2007-01-01
期刊：
影响因子：
7.7
通讯作者：
Sherwin, Robert
中科院分区：
文献类型：
--
作者：
Gurr, Werner;Shaw, Margaret;Sherwin, Robert
Reg蛋白家族已经在包括胰岛在内的几种器官的生长和再生的背景下进行了研究。我们以前认为Reg蛋白在I型糖尿病中作为自身抗原，基于Reg家族成员（肝细胞癌肠胰腺[HIP]/胰腺炎相关蛋白[PAP]）在1型糖尿病突然发作后死亡的患者的胰岛中过表达的证据，并且在NOD小鼠中，Reg特异性T细胞过继转移糖尿病。在目前的研究中，我们开发了抗血清来检测小鼠胰岛中的单个Reg成员，并发现RegIII α存在于胰岛的非β细胞部分，而RegII主要在β细胞中表达。用单独表达的RegII的N-末端（NtfrII）或C-末端（CtfrII）部分接种NOD小鼠揭示了二分法：NtfrII接种加速和CtfrII接种延迟1型糖尿病。在1型糖尿病发病机制的后期阶段接种CtfrII疫苗更有效，这种时间依赖性与NOD小鼠中其他抗原依赖性疫苗策略不同，这可能具有治疗意义。总之，RegII是NOD小鼠中一种新的β细胞衍生的自身抗原。针对这种蛋白质的自身免疫反应可能会将再生转化为胰岛破坏性过程，加速1型糖尿病的发展。
The Reg family of proteins has been studied in the context of growth and regeneration in several organs including pancreatic islets. We previously suggested that Reg proteins act as autoantigens in type I diabetes, based on evidence that a member of the Reg family (hepatocellular carcinoma intestine pancreas [HIP]/pancreatitis-associated protein [PAP]) was overexpressed in the islets of a patient who died after sudden onset of type 1 diabetes, and that, in NOD mice, Reg-specific T-cells adoptively transferred diabetes. In the current study, we developed antisera to detect individual Reg members in mouse islets and found that RegIII alpha was present in the non-beta-cell portion of the islets, while RegII was predominantly expressed in beta-cells. Vaccination of NOD mice with the separately expressed N-terminal (NtfrII) or C-terminal (CtfrII) portion of RegII revealed a dichotomy: NtfrII vaccination accelerated and CtfrII vaccination delayed type 1 diabetes. Vaccination with CtfrII was more effective when given at later stages in the pathogenesis of type 1 diabetes, a time dependency different from that seen with other antigen-dependent vaccine strategies in NOD mice, which might have therapeutic implications. In conclusion, RegII is a novel beta-cell-derived autoantigen in NOD mice. The autoimmune response against this protein may convert a regenerative into an islet-destructive process accelerating development of type 1 diabetes.