Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice
Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice
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DOI：
10.1002/eji.201646755
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发表时间：
2017-03-01
影响因子：
5.4
通讯作者：
Dai, Yang D.
中科院分区：
文献类型：
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作者：
Bashratyan, Roman;Regn, Danielle;Dai, Yang D.
分泌的微泡（MV）是刺激自身反应性B和T细胞的有效炎症触发物，在非肥胖糖尿病（NOD）小鼠中引起1型糖尿病。从胰岛细胞中释放的纯化MV的蛋白质组学分析检测到内源性逆转录病毒（ERV）抗原的存在，包括Env和Gag序列类似于充分表征的小鼠白血病逆转录病毒。这提出了ERV抗原可能通过MV分泌在胰岛中表达的可能性。使用通过共表达ERV Env和Gag抗原以及重组gp70 Env蛋白产生的病毒样颗粒，我们证明了NOD而不是糖尿病抗性小鼠产生了随着疾病进展而滴度增加的抗Env自身抗体。基于慢病毒的RNA干扰敲低Gag揭示Gag有助于MV诱导的T细胞应答，其致糖尿病功能可以通过细胞转移到免疫缺陷小鼠中来证明。最后，我们观察到Gag和Env在NOD胰岛来源的原代间充质干细胞（MSC）中表达。然而，来源于糖尿病抗性小鼠胰岛的MSC不表达抗原。总之，异常ERV活化和MV分泌可诱导抗逆转录病毒应答以触发自身免疫。
Secreted microvesicles (MVs) are potent inflammatory triggers that stimulate autoreactive B and Tcells, causing Type 1 Diabetes in non-obese diabetic (NOD) mice. Proteomic analysis of purified MVs released from islet cells detected the presence of endogenous retrovirus (ERV) antigens, including Env and Gag sequences similar to the well-characterized murine leukemia retroviruses. This raises the possibility that ERV antigens may be expressed in the pancreatic islets via MV secretion. Using virus-like particles produced by co-expressing ERV Env and Gag antigens, and a recombinant gp70 Env protein, we demonstrated that NOD but not diabetes-resistant mice developed anti-Env autoantibodies that increase in titer as disease progresses. A lentiviral-based RNA interference knockdown of Gag revealed that Gag contributes to the MV-induced T-cell response, whose diabetogenic function can be demonstrated via cell-transfer into immune-deficient mice. Finally, we observed that Gag and Env are expressed in NOD islet-derived primary mesenchymal stem cells (MSCs). However, MSCs derived from the islets of diabetes-resistant mice do not express the antigens. Taken together, abnormal ERV activation and secretion of MVs may induce anti-retroviral responses to trigger autoimmunity.