背景:1型自身免疫性多内分泌综合征(APS-1)是一种危及生命的综合征,自身免疫调节因子(AIRE)缺乏引起的常染色体隐性综合征。在APS-1中,自身反应性T细胞逃避胸腺阴性选择,渗入器官,驱动自身免疫性损伤。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:我们检查了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和蛋白质表达。然后,我们使用用Janus激酶(JAK)抑制剂ruxolitinib治疗的Aire-/-Ifng-/-小鼠和Aire-/-小鼠检查了干扰素-γ的致病作用。根据我们的发现,我们使用鲁索利替尼治疗5例APS-1患者,并进行临床评估,免疫学,组织学,转录,和自身抗体反应。
结果:APS-1患者在血液和所有检查的自身免疫受累组织中干扰素-γ反应增强。Aire-/-小鼠有选择性增加T细胞产生的干扰素-γ和增强的干扰素-γ,磷酸化信号转导和转录激活因子1(pSTAT1),和CXCL9在多个器官中的信号。在Aire-/-小鼠中Ing消融或鲁索替尼诱导的JAK-STAT阻断使干扰素-γ反应正常化,并避免了T细胞浸润和器官损伤。鲁索利替尼治疗5例APS-1患者导致T细胞来源的干扰素-γ水平降低,正常的干扰素-γ和CXCL9水平,和脱发的缓解,口腔念珠菌病,指甲营养不良,胃炎,肠炎,关节炎,干燥样综合征,荨麻疹,和甲状腺炎.在这些患者中没有发现鲁索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,其特点是过度,多器官干扰素-γ介导的反应。在5名患者中用鲁索替尼抑制JAK显示了有希望的结果。(由国家过敏和传染病研究所等资助。).
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.).