AIRE Deficiency Leads to the Development of Alopecia Areata‒Like Lesions in Mice.
AIRE Deficiency Leads to the Development of Alopecia Areata‒Like Lesions in Mice.
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AIRE 缺乏会导致斑秃的发生，就像小鼠的病变一样。
DOI：
10.1016/j.jid.2022.09.656
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Hobbs,RyanP
中科院分区：
文献类型：
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作者：
Maglakelidze,Natella;Gao,Ting;Feehan,RobertP;Hobbs,RyanP
斑秃(AA)是一种无法治愈的自身免疫性脱发疾病。具有AIRE序列变异的患者患再生障碍性贫血的可能性是普通人群的15倍，但AIRE在再生障碍性贫血发病机制中的作用尚不清楚。在这项研究中，我们报告了62%的C57BL/6J雌性Aire/-小鼠自发地发生了持续性的AA样皮损，显示出人类AA的几个特征。脱发皮肤表现为毛囊营养不良，表现为生发毛囊数量减少，生发毛囊增殖减少，毛发色素改变，毛发宽度和长度减少。CD8+T细胞、CD4+T细胞、CD68+巨噬细胞和肥大细胞等炎性细胞浸润在Aire-/-HFs中显著。从基因表达分析中，我们发现受损的Aire-/-皮肤显著增加了人AA信号基因的表达，包括H2-Ab1，干扰素γ，干扰素-γ诱导的趋化因子(CCL5，CxCl9-11)，γ家族细胞因子受体IL2RA，以及JAK信号转导和转录激活因子(STAT)信号元件(STAT1，STAT2，STAT4)。通过免疫染色，LesionalAire-/-HFs还显示主要组织相容性复合体I类上调，α-黑素细胞刺激素下调，标志着免疫赦免崩溃，并增加了HF角质形成细胞中STAT1的激活。我们的研究强调了AIRE在HF生物学中的作用，并表明Aire-/-小鼠可能成为研究AA发病机制的一个有价值的模型系统。
Alopecia areata (AA) is an autoimmune hair loss disorder with no cure. Patients with sequence variation inAIREare 15 times more likely to develop AA than the general population, yet the roles of AIRE in AA pathogenesis are unknown. In this study, we report that 62% of C57BL/6J femaleAire‒/‒mice spontaneously developed persistent AA-like lesions that displayed several hallmarks of human AA. LesionalAire‒/‒skin exhibited hair follicle (HF) dystrophy as determined by a reduced number of anagen HFs, decreased anagen HF proliferation, hair pigmentary changes, and decreased hair width and length. Inflammatory infiltrate comprising CD8+T cells, CD4+T cells, CD68+macrophages, and mast cells was prominent in lesionalAire‒/‒HFs. From gene expression analyses, we found lesionalAire‒/‒skin to have significantly increased expression of human AA signature genes, includingH2-Ab1,Ifnγ, IFN-γ‒induced chemokines (Ccl5,Cxcl9‒11), γcfamily cytokine receptorIl2RA, and JAK‒signal transducer and activator of transcription (STAT) signaling components (Stat1,Stat2,Stat4). By immunostaining, lesionalAire‒/‒HFs also show upregulated major histocompatibility complex class I and downregulated α-melanocyte-stimulating hormone, signifying immune privilege collapse, and increased STAT1 activation in HF keratinocytes. Our study highlights a role for AIRE in HF biology and shows thatAire‒/‒mice may serve as a valuable model system to study AA pathogenesis.