Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes.
Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes.
复制标题
通过在胰腺淋巴结中发育调节的胰岛细胞抗原的发育表现来启动自身免疫性糖尿病。
DOI：
10.1084/jem.189.2.331
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发表时间：
1999-01-18
期刊：
影响因子：
--
通讯作者：
Mathis D
中科院分区：
文献类型：
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作者：
Höglund P;Mintern J;Waltzinger C;Heath W;Benoist C;Mathis D
目前对自身免疫性糖尿病的发病机制尚不清楚。例如，胰岛反应性T细胞首次遇到抗原的位置尚未确定。我们使用表达识别天然胰岛β细胞抗原的受体的BDC2.5 T细胞受体转基因小鼠来解决这个问题。在BDC2.5动物中，仅在胰岛和引流它们的淋巴结中发现活化的T细胞，并且淋巴结T细胞活化与胰岛浸润之间存在密切的时间相关性。当幼稚的BDC2.5 T细胞转移到非转基因受体，增殖细胞仅在胰腺淋巴结中观察到，这发生在胰岛炎是可检测的显着。令人惊讶的是，在10天大的受体中没有看到增殖。这种年龄依赖性二分法在基于β细胞上人工表达的不相关抗原的第二转移系统中重现。我们的结论是，β细胞抗原被特异性转运到胰腺淋巴结，在那里它们触发反应性T细胞侵入胰岛。未观察到通过分子模拟或超抗原激活的全身或胰腺外T细胞引发。幼年动物胰腺淋巴结中β细胞抗原的受损呈递可能是糖尿病进展中第一个“检查点”的根源。
Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first “checkpoint” in diabetes progression.