Giraud Matthieu, Taubert Richard, Vandiedonck Claire, Ke Xiayi, Lévi-Strauss Matthieu, Pagani Franco, Baralle Francisco E, Eymard Bruno, Tranchant Christine, Gajdos Philippe, Vincent Angela, Willcox Nick, Beeson David, Kyewski Bruno, Garchon Henri-Jean
Inserm, U580, 75015 Paris, France.
Nature. 2007 Aug 23;448(7156):934-7. doi: 10.1038/nature06066. Epub 2007 Aug 8.
Promiscuous expression of tissue-restricted auto-antigens in the thymus imposes T-cell tolerance and provides protection from autoimmune diseases. Promiscuous expression of a set of self-antigens occurs in medullary thymic epithelial cells and is partly controlled by the autoimmune regulator (AIRE), a nuclear protein for which loss-of-function mutations cause the type 1 autoimmune polyendocrine syndrome. However, additional factors must be involved in the regulation of this promiscuous expression. Here we describe a mechanism controlling thymic transcription of a prototypic tissue-restricted human auto-antigen gene, CHRNA1. This gene encodes the alpha-subunit of the muscle acetylcholine receptor, which is the main target of pathogenic auto-antibodies in autoimmune myasthenia gravis. On re-sequencing the CHRNA1 gene, we identified a functional bi-allelic variant in the promoter that is associated with early onset of disease in two independent human populations (France and United Kingdom). We show that this variant prevents binding of interferon regulatory factor 8 (IRF8) and abrogates CHRNA1 promoter activity in thymic epithelial cells in vitro. Notably, both the CHRNA1 promoter variant and AIRE modulate CHRNA1 messenger RNA levels in human medullary thymic epithelial cells ex vivo and also in a transactivation assay. These findings reveal a critical function of AIRE and the interferon signalling pathway in regulating quantitative expression of this auto-antigen in the thymus, suggesting that together they set the threshold for self-tolerance versus autoimmunity.
组织限制性自身抗原在胸腺中的杂乱表达可诱导T细胞耐受，并预防自身免疫性疾病。一组自身抗原的杂乱表达发生在髓质胸腺上皮细胞中，部分受自身免疫调节因子（AIRE）控制，AIRE是一种核蛋白，其功能丧失突变会导致1型自身免疫性多内分泌综合征。然而，这种杂乱表达的调控必定还涉及其他因素。在此，我们描述了一种控制原型组织限制性人类自身抗原基因CHRNA1胸腺转录的机制。该基因编码肌肉乙酰胆碱受体的α亚基，而肌肉乙酰胆碱受体是自身免疫性重症肌无力中致病性自身抗体的主要靶标。在对CHRNA1基因进行重新测序时，我们在启动子中鉴定出一个功能性双等位基因变体，该变体与两个独立人群（法国和英国）的疾病早发相关。我们发现，该变体可阻止干扰素调节因子8（IRF8）的结合，并在体外胸腺上皮细胞中消除CHRNA1启动子活性。值得注意的是，CHRNA1启动子变体和AIRE均可在体外人髓质胸腺上皮细胞以及反式激活试验中调节CHRNA1信使核糖核酸水平。这些发现揭示了AIRE和干扰素信号通路在调节胸腺中这种自身抗原定量表达方面的关键作用，表明它们共同设定了自身耐受与自身免疫的阈值。
