Gastrointestinal Autoimmunity Associated With Loss of Central Tolerance to Enteric α-Defensins
Gastrointestinal Autoimmunity Associated With Loss of Central Tolerance to Enteric α-Defensins
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DOI：
10.1053/j.gastro.2015.05.009
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发表时间：
2015-07-01
期刊：
影响因子：
29.4
通讯作者：
Filipp, Dominik
中科院分区：
文献类型：
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作者：
Dobes, Jan;Neuwirth, Ales;Filipp, Dominik
背景与目的：自身免疫性多内分泌病变念珠菌病外表皮营养不良（APECED）是一种以慢性皮肤粘膜念珠菌病、甲状旁腺功能低下和肾上腺功能不全为特征的自身免疫性疾病，但患者也会出现肠道疾病。APECED是一种常染色体隐性遗传病，由自身免疫调节因子（AIRE，调节免疫耐受）的突变引起，其允许自反应性T细胞进入外周。肠a-防御素是由Paneth细胞分泌的抗菌肽。APECED患者经常出现胃肠道症状和对Paneth细胞分泌颗粒的血清反应。我们研究了肠a-防御素在人和AIRE缺乏小鼠体内是否是自身抗原。方法：我们分析了来自欧洲多个中心的50例APECED患者的临床资料、血清和粪便样本以及可用的十二指肠活检。通过定量逆转录聚合酶链反应和流式细胞术检测样品中防御素和其他分子的表达；通过免疫组织化学和免疫印迹分析测定抗体和其他蛋白的水平。对活检标本进行组织学分析。我们以Aire（-/-）小鼠作为APECED模型，研究了将这些小鼠的免疫细胞转移到胸腺小鼠的效果。结果：在APECED患者的肠外组织中检测到肠防御素，尤其是胸腺髓质上皮细胞。一些APECED患者缺乏Paneth细胞，防御素特异性自身抗体血清阳性；自身抗体的存在与频繁腹泻相关。Aire（-/-）小鼠产生了防御素特异性T细胞。将这些T细胞过继转移到胸腺发育不良的小鼠体内，导致T细胞浸润肠道，Paneth细胞丧失，微生物生态失调，并诱导T辅助17细胞介导的自身免疫反应，类似于在APECED患者中观察到的情况。结论：在APECED患者中，AIRE的丢失似乎会引起针对肠防御素的自身免疫反应和Paneth细胞的丢失。Aire（-/-）小鼠产生防御素特异性T细胞，引起与APECED患者相似的肠道缺陷。这些发现提供了air介导的免疫耐受丧失导致APECED患者肠道疾病的机制。
BACKGROUND & AIMS: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autoimmune disorder characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency, but patients also develop intestinal disorders. APECED is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE, which regulates immune tolerance) that allow self-reactive T cells to enter the periphery. Enteric a-defensins are antimicrobial peptides secreted by Paneth cells. Patients with APECED frequently have gastrointestinal symptoms and seroreactivity against secretory granules of Paneth cells. We investigated whether enteric a-defensins are autoantigens in humans and mice with AIRE deficiency. METHODS: We analyzed clinical data, along with serum and stool samples and available duodenal biopsies from 50 patients with APECED collected from multiple centers in Europe. Samples were assessed for expression of defensins and other molecules by quantitative reverse transcription polymerase chain reaction and flow cytometry; levels of antibodies and other proteins were measured by immunohistochemical and immunoblot analyses. Histologic analyses were performed on biopsy samples. We used Aire(-/-) mice as a model of APECED, and studied the effects of transferring immune cells from these mice to athymic mice. RESULTS: Enteric defensins were detected in extra-intestinal tissues of patients with APECED, especially in medullary thymic epithelial cells. Some patients with APECED lacked Paneth cells and were seropositive for defensin-specific autoantibodies; the presence of autoantibodies correlated with frequent diarrhea. Aire(-/-) mice developed defensin-specific T cells. Adoptive transfer of these T cells to athymic mice resulted in T-cell infiltration of the gut, loss of Paneth cells, microbial dysbiosis, and the induction of T-helper 17 cell-mediated autoimmune responses resembling those observed in patients with APECED. CONCLUSIONS: In patients with APECED, loss of AIRE appears to cause an autoimmune response against enteric defensins and loss of Paneth cells. Aire(-/-) mice developed defensin-specific T cells that cause intestinal defects similar to those observed in patients with APECED. These findings provide a mechanism by which loss of AIRE-mediated immune tolerance leads to intestinal disorders in patients with APECED.