Dotta Francesco, Censini Stefano, van Halteren Astrid G S, Marselli Lorella, Masini Matilde, Dionisi Sabrina, Mosca Franco, Boggi Ugo, Muda Andrea Onetti, Del Prato Stefano, Elliott John F, Covacci Antonello, Rappuoli Rino, Roep Bart O, Marchetti Piero
Department of Internal Medicine, Endocrine and Metabolic Sciences, and Biochemistry, University of Siena, 53100 Siena, Italy.
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5115-20. doi: 10.1073/pnas.0700442104. Epub 2007 Mar 14.
Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between beta cell viral infection and islet inflammation has not been established. We analyzed pancreatic tissue from six type 1 diabetic and 26 control organ donors. Immunohistochemical, electron microscopy, whole-genome ex vivo nucleotide sequencing, cell culture, and immunological studies demonstrated Coxsackie B4 enterovirus in specimens from three of the six diabetic patients. Infection was specific of beta cells, which showed nondestructive islet inflammation mediated mainly by natural killer cells. Islets from enterovirus-positive samples displayed reduced insulin secretion in response to glucose and other secretagogues. In addition, virus extracted from positive islets was able to infect beta cells from human islets of nondiabetic donors, causing viral inclusions and signs of pyknosis. None of the control organ donors showed signs of viral infection. These studies provide direct evidence that enterovirus can infect beta cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.
1型糖尿病的特征是T细胞介导的胰腺β细胞自身免疫性破坏。多项研究表明柯萨奇肠道病毒血清转化与疾病发作之间存在关联。然而，β细胞病毒感染与胰岛炎症之间的直接联系尚未确立。我们分析了6名1型糖尿病器官捐献者和26名对照器官捐献者的胰腺组织。免疫组织化学、电子显微镜、全基因组体外核苷酸测序、细胞培养和免疫学研究在6名糖尿病患者中的3名患者的标本中发现了柯萨奇B4肠道病毒。感染是β细胞特有的，表现为主要由自然杀伤细胞介导的非破坏性胰岛炎症。来自肠道病毒阳性样本的胰岛对葡萄糖和其他促分泌剂的胰岛素分泌减少。此外，从阳性胰岛中提取的病毒能够感染非糖尿病捐献者人胰岛的β细胞，导致病毒包涵体和核固缩迹象。对照器官捐献者均未显示病毒感染迹象。这些研究提供了直接证据，表明肠道病毒可感染1型糖尿病患者的β细胞，且感染与炎症和功能损害有关。
