本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2312665

摘要内容如下：

背景

自身免疫性多内分泌综合征1型（APS-1）是一种由自身免疫调节因子（AIRE）缺陷引起的危及生命的常染色体隐性遗传综合征。在APS-1中，自身反应性T细胞逃避胸腺阴性选择，浸润器官并驱动自身免疫损伤。控制APS-1中T细胞介导的损伤的效应机制仍然知之甚少。

方法

我们研究了APS-1是否可以归类为干扰素-γ介导的疾病。我们首先评估了参与前瞻性自然史研究的APS-1患者，并评估了血液和组织中的mRNA和蛋白表达。然后，我们使用AIRE-/-IFNg-/-小鼠和用Janus激酶（JAK）抑制剂ruxolitinib治疗的AIRE-/-小鼠检测了干扰素-γ的致病作用。基于我们的研究结果，我们使用鲁索利替尼治疗了5例APS-1患者，并评估了临床、免疫学、组织学、转录和自身抗体反应。

结果

APS-1患者的血液和所有受自身免疫影响的组织中的干扰素-γ反应增强。AIRE-/-小鼠通过T细胞选择性地增加干扰素-γ的产生，并在多个器官中增强干扰素-γ、磷酸化信号转导子和转录激活子1（pSTAT1）和CXCL9信号。在AIRE-/-小鼠中，IFNg消融或ruxolitinib诱导的JAK-STAT阻断使干扰素-γ反应正常化，并避免了器官中的T细胞浸润和损伤。Ruxolitinib治疗5例APS-1患者后，T细胞衍生的干扰素-γ水平下降，干扰素-γ和CXCL9水平恢复正常，脱发、口腔念珠菌病、指甲营养不良、胃炎、肠炎、关节炎、干燥综合征、荨麻疹和甲状腺炎得到缓解。在这些患者中未发现鲁索利替尼的严重不良反应。

结论

我们的研究结果表明，由AIRE缺乏引起的APS-1，其特征是过度的多器官干扰素-γ介导的反应。ruxolitinib对5名患者的JAK抑制作用显示出有希望的结果。（由国家过敏和传染病研究所和其他机构资助。）。

英文原文如下：

Abstracts

BACKGROUND  Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood.

METHODS  We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses.

RESULTS  Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients.

CONCLUSIONS  Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

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