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TAFRO 亚型特发性多中心 Castleman 病中与 mTOR 激活相关的 I 型 IFN 反应。

Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease.

机构信息

Department of Medicine and.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

出版信息

JCI Insight. 2020 May 7;5(9):135031. doi: 10.1172/jci.insight.135031.

Abstract

The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness involving episodic disease flares of thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) and progressive multiple organ dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD-TAFRO patients and that an mTOR inhibitor is effective in a small cohort of patients. However, the upstream mechanisms, cell types, and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD-TAFRO through cellular and transcriptomic studies. Using paired iMCD-TAFRO PBMC samples collected during flare and remission, we identified T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD-TAFRO flare. These changes were associated with increased Type I IFN (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes. Finally, we found that IFN-β stimulation of monocytes and T cells from iMCD-TAFRO patient remission samples induced increased mTOR activation compared with healthy donors, and this was abrogated with either mTORC1 or JAK1/2 inhibition. The data presented here support a potentially novel role for IFN-I signaling as a driver of increased mTOR signaling in iMCD-TAFRO.

摘要

特发性多中心 Castleman 病(iMCD-TAFRO)的 TAFRO 临床亚型是一种罕见的血液学疾病,涉及血小板减少症、全身性水肿、发热、网状纤维骨髓纤维化、肾功能不全和器官肿大(TAFRO)以及进行性多器官功能障碍的周期性疾病发作。我们之前表明,mTOR 信号通路在 iMCD-TAFRO 患者的淋巴结中升高,并且 mTOR 抑制剂在一小部分患者中有效。然而,疾病发病机制中涉及的上游机制、细胞类型和介质仍然未知。在这里,我们通过细胞和转录组学研究开发了一种针对 iMCD-TAFRO 中候选细胞驱动因素和机制的靶向方法。使用在疾病发作和缓解期间收集的配对 iMCD-TAFRO PBMC 样本,我们在 iMCD-TAFRO 发作期间鉴定了 T 细胞激活和 NK 细胞和单核细胞亚群频率的改变。这些变化与 CD8+T 细胞、NK 细胞和单核细胞中 I 型干扰素(IFN-I)反应基因谱的增加有关。最后,我们发现与健康供体相比,IFN-β刺激来自 iMCD-TAFRO 患者缓解样本的单核细胞和 T 细胞会诱导 mTOR 激活增加,而用 mTORC1 或 JAK1/2 抑制剂阻断该作用。这里呈现的数据支持 IFN-I 信号作为 iMCD-TAFRO 中增加的 mTOR 信号的驱动因素的潜在新作用。

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