Aire-Dependent Thymic Expression of Desmoglein 3, the Autoantigen in Pemphigus Vulgaris, and Its Role in T-Cell Tolerance
Aire-Dependent Thymic Expression of Desmoglein 3, the Autoantigen in Pemphigus Vulgaris, and Its Role in T-Cell Tolerance
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DOI：
10.1038/jid.2010.330
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发表时间：
2011-02-01
影响因子：
6.5
通讯作者：
Amagai, Masayuki
中科院分区：
文献类型：
--
作者：
Wada, Naoko;Nishifuji, Koji;Amagai, Masayuki
在胸腺诱导的中枢耐受机制中，转录因子Aire已被证明可以促进髓质胸腺上皮细胞（mTEC）中多种外周器官特异性抗原（Ag）的表达，这些抗原在负选择中充当自身Ag。我们检测了桥粒芯糖蛋白 3 (Dsg3)（寻常型天疱疮 (PV) 中的自身抗原）在小鼠胸腺中的表达以及 Aire 对 Dsg3 耐受性的参与。免疫荧光和原位杂交揭示了 C57BL/6 小鼠胸腺皮质髓质连接处附近类似 3% mTEC 中的单细胞或簇中存在 Dsg3。表达 Dsg3 的 mTEC 还同时表达一些与皮肤无关的外周器官的 Ag。相反，在 Aire(-/-) 胸腺中未检测到 Dsg3 阳性 mTEC。来自用Dsg3免疫的Aire(-/-)小鼠的脾细胞的过继转移不会在Rag2(-/-)受体小鼠中诱导抗Dsg3 IgG产生或PV表型。然而，当与Dsg3(-/-) B细胞一起转移时，Aire(-/-) CD4(+) T细胞而非Aire(+/+) CD4(+) T细胞诱导低水平的抗Dsg3 IgG产生。这些发现表明，Aire 在 Dsg3 表达以及帮助 B 细胞在胸腺中产生抗 Dsg3 IgG 的 T 细胞选择中发挥着重要作用。
In the mechanism of thymus-induced central tolerance, the transcription factor Aire has been demonstrated to promote the expression of a wide range of peripheral organ-specific antigens (Ags) in the medullary thymic epithelial cells (mTECs), which serve as self-Ags in negative selection. We examined the expression of desmoglein 3 (Dsg3), the autoantigen in pemphigus vulgaris (PV), in mouse thymus and the involvement of Aire in tolerance to Dsg3. Immunofluorescence and in situ hybridization revealed Dsg3 in single cells or in clusters in similar to 3% of mTECs near the cortico-medullary junction of the thymus in C57BL/6 mice. Dsg3-expressing mTECs also expressed some Ags of skin-unrelated peripheral organs simultaneously. In contrast, Dsg3-positive mTECs were not detected in the Aire(-/-) thymus. Adoptive transfer of splenocytes from Aire(-/-) mice immunized with Dsg3 did not induce anti-Dsg3 IgG production or PV phenotype in Rag2(-/-) recipient mice. However, Aire(-/-) CD4(+) T cells, but not Aire(+/+) CD4(+) T cells, induced low levels of anti-Dsg3 IgG production when transferred with Dsg3(-/-) B cells. These findings indicate that Aire has an important role in Dsg3 expression as well as in selection of T cells that help B cells to produce anti-Dsg3 IgG in thymus.