Reduced Expression of FOXP3 and Regulatory T-Cell Function in Severe Forms of Early-onset Autoimmune Enteropathy
Reduced Expression of FOXP3 and Regulatory T-Cell Function in Severe Forms of Early-onset Autoimmune Enteropathy
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DOI：
10.1053/j.gastro.2010.06.006
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发表时间：
2010-09-01
期刊：
影响因子：
29.4
通讯作者：
Ruemmele, Frank M.
中科院分区：
文献类型：
--
作者：
Moes, Nicolette;Rieux-Laucat, Frederic;Ruemmele, Frank M.
背景与目的：对自身免疫性肠病（AIE）的早期发病形式的病理生理学知之甚少。AIE与FOXP 3的突变有关，FOXP 3是一种控制调节性T细胞发育和功能的转录因子。我们通过临床、遗传和功能免疫学研究分析了新生儿或出生后早期AIE的分子基础。方法：对出生后5个月内发病的9例男孩和2例女孩AIE的胃肠病学和免疫学特征进行分析。在外周血单核细胞中对FOXP 3和IL 2 RA进行基因分型。FOXP 3信使RNA和蛋白质表达采用逆转录聚合酶链反应、流式细胞术和CD 4（+）T细胞的共聚焦免疫荧光进行分析。在共培养系统中测定调节性T细胞功能（CD 4（+）CD 25（+））。结果：肠外自身免疫相关的AIE严重且危及生命;所有患者均需要全肠外营养。7名患者的调节性T细胞功能改变，FOXP 3突变导致FOXP 3蛋白表达丢失或减少; 2名婴儿的调节性T细胞活性降低，FOXP 3蛋白水平降低，尽管我们没有检测到FOXP 3编码区，poly-A位点或启动子区的突变（称为FOXP 3依赖性AIE）。两名患者有正常数量的调节性T细胞，表达正常水平的FOXP 3蛋白和正常的调节活性，在体外共培养试验（称为FOXP 3-独立AIE）。结论：大多数AIE病例与调节性T细胞功能的改变有关;一些，但不是全部，病例有影响FOXP 3表达水平的突变。AIE的发病机制尚需进一步研究。
BACKGROUND & AIMS: Little is known about the pathophysiology of early onset forms of autoimmune enteropathy (AIE). AIE has been associated with mutations in FOXP3-a transcription factor that controls regulatory T-cell development and function. We analyzed the molecular basis of neonatal or early postnatal AIE using clinical, genetic, and functional immunological studies. METHODS: Gastroenterological and immunological features were analyzed in 9 boys and 2 girls with AIE that began within the first 5 months of life. FOXP3 and IL2RA were genotyped in peripheral blood monocytes. FOXP3 messenger RNA and protein expression were analyzed using reverse-transcription polymerase chain reaction, flow cytometry, and confocal immunofluorescence of CD4(+) T cells. Regulatory T-cell function (CD4(+)CD25(+)) was assayed in coculture systems. RESULTS: AIE associated with extraintestinal autoimmunity was severe and life-threatening; all patients required total parenteral nutrition. Regulatory T cells from 7 patients had altered function and FOXP3 mutations that resulted in lost or reduced FOXP3 protein expression; 2 infants had reduced regulatory T-cell activity and reduced levels of FOXP3 protein, although we did not detect mutations in FOXP3 coding region, poly-A site, or promoter region (called FOXP3-dependent AIE). Two patients had a normal number of regulatory T cells that expressed normal levels of FOXP3 protein and normal regulatory activity in in vitro coculture assays (called FOXP3-independent AIE). No mutations in IL2RA were found. CONCLUSIONS: Most cases of AIE are associated with alterations in regulatory T-cell function; some, but not all, cases have mutations that affect FOXP3 expression levels. Further studies are needed to identify mechanisms of AIE pathogenesis.