Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection.
Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection.
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发表时间：
2012-03
影响因子：
7.4
通讯作者：
Jiangyan Xia;Hongjun Wang;Jianfei Guo;Zhijie Zhang;Brandon D. Coder;D. Su
中科院分区：
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作者：
Jiangyan Xia;Hongjun Wang;Jianfei Guo;Zhijie Zhang;Brandon D. Coder;D. Su
胸腺髓质通过胸腺阴性选择消除自身反应性T细胞克隆，形成自然调节性T细胞，在中枢耐受的产生中发挥重要作用。年龄相关的FoxN1下降诱导胸腺髓上皮细胞（mTECs）的破坏。然而，尚不清楚这是否会扰乱中枢耐受性，从而增加老年人的自身免疫易感性。使用FoxN1（FoxN1(flox)）小鼠模型，该模型显示FoxN1随着年龄的增长而自发普遍缺失，从而加速胸腺衰老，我们研究了稳态胸腺髓质的破坏是否会导致与年龄相关的自身免疫倾向增加。我们证明了FoxN1（flox）形成的二维胸腺上皮囊肿的年龄相关的普遍丢失主要位于髓质。这导致胸腺髓质稳态的破坏，有证据表明负选择受到干扰，包括自身免疫调节因子（Aire）基因的表达减少和胸腺树突状细胞在髓质中的积累被破坏，这是负选择所必需的。这些引起自身免疫表型，包括在这些小鼠的多个器官中增加炎症细胞浸润。在动物模型中的这一发现为老年人自身免疫易感性增加提供了机制解释，尽管它们在没有诱导的情况下可能不会表现出临床表现。
The hymic medulla plays an essential role in the generation of central tolerance by eliminating self-reactive T-cell clones through thymic negative selection and developing natural regulatory T cells. Age-related FoxN1 decline induces disruption of medullary thymic epithelial cells (mTECs). However, it is unknown whether this perturbs central tolerance to increase autoimmune predisposition in the elderly. Using a loxP-floxed-FoxN1 (FoxN1(flox)) mouse model, which exhibits a spontaneous ubiquitous deletion of FoxN1 with age to accelerate thymic aging, we investigated whether disruption of steady-state thymic medulla results in an increase of autoimmune-prone associated with age. We demonstrated age-associated ubiquitous loss of FoxN1(flox)-formed two-dimensional thymic epithelial cysts were primarily located in the medulla. This resulted in disruption of thymic medullary steady state, with evidence of perturbed negative selection, including reduced expression of the autoimmune regulator (Aire) gene and disrupted accumulation of thymic dendritic cells in the medulla, which are required for negative selection. These provoke autoimmune phenotypes, including increased inflammatory cell infiltration in multiple organs in these mice. This finding in an animal model provides a mechanistic explanation of increased susceptibility to autoimmunity in aged humans, although they may not show clinic manifestations without induction.