Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice
Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice
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DOI：
10.1172/jci57379
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发表时间：
2011-09-01
影响因子：
15.9
通讯作者：
Amagai, Masayuki
中科院分区：
文献类型：
--
作者：
Takahashi, Hayato;Kouno, Michiyoshi;Amagai, Masayuki
寻常型天疱疮是一种严重的自身免疫性疾病，主要表现为皮肤和粘膜起泡。它是由抗桥粒芯糖蛋白3（Dsg 3）的自身抗体引起的，Dsg 3是一种对维持皮肤、口腔粘膜和食管上皮完整性至关重要的粘附分子。了解自身抗体靶向的抗原使PV成为有价值的自身免疫模型。最近，在PV小鼠模型中证实了Dsg 3特异性CD 4（+）T辅助细胞在自身抗体产生中的作用，但这些细胞是否在组织中发挥细胞毒性尚不清楚。在这里，我们使用转基因小鼠和逆转录病毒诱导分析了3个Dsg 3特异性TCR。Dsg 3特异性转基因（Dsg 3 H1）T细胞在体内Dsg 3存在下经历缺失。当与来自Dsg 3（-/-）小鼠的B细胞共转移到免疫缺陷小鼠中时，在Dsg 3不存在的情况下发育的Dsg 3 H1 T细胞引起严重的类天疱疮表型。引人注目的是，除了体液应答之外，表达Dsg 3的组织的T细胞浸润导致界面皮炎，这是T细胞介导的自身免疫的一种独特形式，其引起角质形成细胞凋亡，并且在各种炎症/自身免疫性皮肤病中可见，包括副肿瘤性天疱疮。逆转录病毒产生的Dsg 3特异性T细胞的使用揭示了界面皮炎以IFN-γ和TCR亲合力依赖的方式发生。这种自身免疫模型表明，特异性的生理性皮肤相关的自身抗原的T细胞能够诱导界面皮炎，并应提供一个有价值的工具，进一步探索T细胞介导的皮肤病的免疫病理生理。
Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4(+) T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3(-/-) mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell-mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-gamma- and TCR avidity-dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell-mediated skin diseases.