Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat
Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat
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DOI：
10.4049/jimmunol.177.10.7275
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Hessner, Martin J.
中科院分区：
文献类型：
--
作者：
Geoffrey, Rhonda;Jia, Shuang;Hessner, Martin J.
人I型糖尿病（T1 DM）是通过胰腺β细胞的自身免疫性破坏引起的，在许多方面通过淋巴细胞减少和自发性糖尿病BioBreeding（BB）DRlyp/lyp大鼠进行建模。以前，发病前的表达谱的整个DRlyp/lyp胰腺淋巴结（PLN）揭示先天性免疫活性，特别是肥大细胞和嗜酸性粒细胞。此外，我们观察到DRlyp/lyp大鼠的胰岛以及糖尿病诱导型BB DR+/+大鼠的胰岛可能通过eotaxin表达募集先天性细胞。在这里，我们确定，终身eotaxin的表达开始前40天的生活，并专门定位于β细胞。在本报告中，我们发现与相关BB DR+/+大鼠相比，DRlyp/lyp中PLN肥大细胞更丰富（占总细胞的2.1 +/- 0.9% vs 0.9 +/- 0.4%，p < 0.0001）。DRlyp/lyp PLN肥大细胞基因表达谱分析揭示了活化的群体，包括肥大细胞蛋白酶1、阳离子胰蛋白酶原、羧肽酶A、IL-5和磷脂酶C γ的转录物的显著过度表达。在DR+/+大鼠中，在T调节细胞耗竭后发生T1 DM，肥大细胞显示与脱粒负调控一致的基因表达，包括编码酪氨酸磷酸酶SHP-1、脂质磷酸酶SHIP和E3泛素连接酶c-Cbl的转录物的显著过度表达。为了概括在DR+/+大鼠中观察到的负性肥大细胞调节，我们用肥大细胞“稳定剂”克罗美因处理DRlyp/lyp大鼠，其显著（p < 0.05）延迟T1 DM发作。这些发现与人类和动物模型中越来越多的证据一致，其中肥大细胞在自身免疫性疾病的起始和进展中的作用正在显现。
Human type I diabetes mellitus (T1DM) arises through autoimmune destruction of pancreatic beta cells and is modeled in many respects by the lymphopenic and spontaneously diabetic BioBreeding (BB) DRlyp/lyp rat. Previously, preonset expression profiling of whole DRlyp/lyp pancreatic lymph nodes (PLN) revealed innate immune activity, specifically that of mast cells and eosinophils. Furthermore, we observed that pancreatic islets of DRlyp/lyp rats as well as those of diabetes-inducible BB DR+/+ rats potentially recruit innate cells through eotaxin expression. Here we determine that lifelong eotaxin expression begins before 40 days of life and is localized specifically to beta cells. In this report, we find that PLN mast cells are more abundant in DRlyp/lyp compared with related BB DR+/+ rats (2.1 +/- 0.9% vs 0.9 +/- 0.4% of total cells, p < 0.0001). DRlyp/lyp PLN mast cell gene expression profiling revealed an activated population and included significant overrepresentation of transcripts for mast cell protease 1, cationic trypsinogen, carboxypeptidase A, IL-5, and phospholipase C gamma. In the DR+/+ rat, which develops T1DM upon depletion of T regulator cells, mast cells displayed gene expression consistent with the negative regulation of degranulation, including significant overrepresentation of transcripts encoding tyrosine phosphatase SHP-1, lipid phosphatase SHIP, and E3 ubiquitin ligase c-Cbl. To recapitulate the negative mast cell regulation observed in the DR+/+ rats, we treated DRlyp/lyp rats with the mast cell "stabilizer" cromolyn, which significantly (p < 0.05) delayed T1DM onset. These findings are consistent with a growing body of evidence in human and animal models, where a role for mast cells in the initiation and progression of autoimmune disease is emerging.