VASCULAR ADDRESSINS ARE INDUCED ON ISLET VESSELS DURING INSULITIS IN NONOBESE DIABETIC MICE AND ARE INVOLVED IN LYMPHOID-CELL BINDING TO ISLET ENDOTHELIUM
VASCULAR ADDRESSINS ARE INDUCED ON ISLET VESSELS DURING INSULITIS IN NONOBESE DIABETIC MICE AND ARE INVOLVED IN LYMPHOID-CELL BINDING TO ISLET ENDOTHELIUM
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DOI：
10.1172/jci116859
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发表时间：
1993-11-01
影响因子：
15.9
通讯作者：
MICHIE, SA
中科院分区：
文献类型：
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作者：
HANNINEN, A;TAYLOR, C;MICHIE, SA
在非肥胖型糖尿病(NOD)小鼠中，淋巴细胞和单核细胞在胰岛的渗透导致胰岛β细胞的破坏。为了研究淋巴细胞进入NOD胰腺的机制，用多种已知参与淋巴细胞与血管内皮细胞结合的黏附分子的单抗对胰腺进行免疫染色，这是淋巴细胞从血液迁移到有组织的淋巴样组织和炎症组织的第一步。这些黏附分子包括：参与淋巴细胞与外周淋巴结(L-选择素)或粘膜淋巴组织(LPAM-1，α4β7-整合素)高内皮微静脉(HEV)组织选择性结合的淋巴细胞归巢受体；HEV配体外周血管寻址蛋白(PNAD)和粘膜血管寻址蛋白(MAdCAM-1)。在NOD胰腺中，α4β7在各期胰岛的大部分浸润性细胞上均有表达，而L选择素在晚期胰岛细胞上的表达更为明显。在胰岛炎症的发展过程中，MAdCAM-1和PNAD在炎症胰岛附近和内部的血管内皮细胞上可检测到。采用Stamper-Woodruff体外实验检测淋巴样细胞与血管的结合情况。这些功能分析表明，粘膜识别系统(MAdCAM-1/α4beta7)和外周识别系统(PNAD/L-选择素)都参与了这种结合。我们的发现表明，在NOD胰腺炎症的胰岛中，外周和粘膜血管地址蛋白在内皮细胞上被诱导表达，并且这些地址蛋白通过其归巢受体参与与淋巴样细胞的结合。这表明，这些黏附分子通过参与淋巴细胞从血液中迁移到发炎的胰腺，在这些小鼠的糖尿病发病机制中发挥作用。
In the nonobese diabetic (NOD) mouse, lymphocytic and monocytic infiltration of the pancreatic islets leads to beta cell destruction. To investigate the mechanisms by which lymphocytes enter the NOD pancreas, pancreata were immunostained using monoclonal antibodies to a variety of adhesion molecules known to be involved in lymphocyte binding to vascular endothelium, an initial step in the migration of lymphocytes from blood into organized lymphoid and inflamed tissues. These adhesion molecules include: lymphocyte homing receptors involved in tissue-selective binding of lymphocytes to peripheral lymph node (L-selectin) or mucosal lymphoid tissue (LPAM-1, alpha4beta7-integrin) high-endothelial venules (HEV); and HEV ligands peripheral vascular addressin (PNAd) and mucosal vascular addressin (MAdCAM-1). In NOD pancreata, alpha4beta7 is expressed on most infiltrating cells at all stages of insulitis, whereas L-selectin expression is more pronounced on cells in the islets at later stages. During the development of insulitis, MAdCAM-1 and to a lesser extent PNAd became detectable on vascular endothelium adjacent to and within the inflamed islets. The Stamper-Woodruff in vitro assay was used to examine lymphoid cell binding to such vessels. These functional assays show that both the mucosal (MAdCAM-1 /alpha4beta7) and the peripheral (PNAd/L-selectin) recognition systems are involved in this binding. Our findings demonstrate that expression of peripheral and mucosal vascular addressins is induced on endothelium in inflamed islets in NOD pancreas, and that these addressins participate in binding lymphoid cells via their homing receptors. This suggests that these adhesion molecules play a role in the pathogenesis of diabetes in these mice by being involved in the migration of lymphocytes from blood into the inflamed pancreas.