Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity.
Neonatal tolerance revisited: a perinatal window for Aire control of autoimmunity.
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DOI：
10.1084/jem.20090300
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发表时间：
2009-06-08
期刊：
影响因子：
--
通讯作者：
Mathis D
中科院分区：
文献类型：
--
作者：
Guerau-de-Arellano M;Martinic M;Benoist C;Mathis D
长期以来，免疫系统发育的初始阶段对于建立对自身的耐受性特别重要，这一概念得到了概念和实验的支持，但也受到了挑战。胸腺上皮细胞展示自身抗原是诱导T淋巴细胞区室耐受的关键，这一过程由Aire转录因子增强。使用强力霉素调节的转基因靶向Aire表达的胸腺上皮，补充Aire敲除在时间上控制的方式，我们发现，Aire是必不可少的围产期，以防止多器官自身免疫，这是典型的Aire缺乏症。令人惊讶的是，Aire可以在此后不久关闭并长时间关闭，几乎没有有害后果。新生儿中存在的淋巴细胞减少状态是这种二分法中的一个因素，因为在成人中Aire关闭期间诱导淋巴细胞减少会重新产生疾病，相反，可以通过向新生儿补充成人淋巴细胞来改善。简而言之，围产期期间的Aire表达对于诱导持久耐受和避免自身免疫是必要的和充分的。中枢耐受的中枢控制机制在成人中很大程度上是不稳定的，因为先前耐受的T细胞库可以缓冲可能出现的新产生的自身反应性T细胞。
There has long been conceptual and experimental support for, but also challenges to, the notion that the initial period of the immune system's development is particularly important for the establishment of tolerance to self. The display of self-antigens by thymic epithelial cells is key to inducing tolerance in the T lymphocyte compartment, a process enhanced by the Aire transcription factor. Using a doxycycline-regulated transgene to target Aire expression to the thymic epithelium, complementing the Aire knockout in a temporally controlled manner, we find that Aire is essential in the perinatal period to prevent the multiorgan autoimmunity that is typical of Aire deficiency. Surprisingly, Aire could be shut down soon thereafter and remain off for long periods, with few deleterious consequences. The lymphopenic state present in neonates was a factor in this dichotomy because inducing lymphopenia during Aire turnoff in adults recreated the disease, which, conversely, could be ameliorated by supplementing neonates with adult lymphocytes. In short, Aire expression during the perinatal period is both necessary and sufficient to induce long-lasting tolerance and avoid autoimmunity. Aire-controlled mechanisms of central tolerance are largely dispensable in the adult, as a previously tolerized T cell pool can buffer newly generated autoreactive T cells that might emerge.
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DOI：
10.1084/jem.20050693
发表时间：
2005-09-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jiang W;Anderson MS;Bronson R;Mathis D;Benoist C
通讯作者：
Benoist C
DOI：
10.1126/science.1159407
发表时间：
2008-08-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
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DOI：
10.1084/jem.20070795
发表时间：
2007-10-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
Mathis D
影响因子：
56.9
作者：
Alferink, J;Tafuri, A;Arnold, B
通讯作者：
Arnold, B
影响因子：
15.3
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通讯作者：
MAURER, PH