A Multifaceted Interplay Among Hemophagocytosis, Interleukin-18, and Type I Interferon Distinguishes Still Disease From Other Autoinflammatory Diseases

IF 9.9 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2026-08-25 Epub Date: 2026-04-08 DOI:10.1002/art.70102

Yvonne M. Mueller PhD, Charlotte Girard MD, PhD, Harmen J. G. van de Werken PhD, Stefan J. Erkeland PhD, Dwin G. B. Grashof MSc, Laurie Vaillant PhD, Renske J. H. den Dekker MSc, Iris van Zuijen MSc, Sharon Veenbergen PhD, Fanny Coffin PhD, Eric Bindels PhD, Yvan Jamilloux MD, Katerina Laskari MD, Vassili Soumelis MD, PhD, Bruno Fautrel MD, PhD, Cem Gabay MD, PhD, Peter D. Katsikis MD, PhD

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引用次数: 0

Abstract

Objective

The unknown pathophysiology and the lack of specific features for systemic juvenile idiopathic arthritis and adult-onset Still disease (collectively known as Still disease; SD) delay diagnosis and appropriate treatment. The goal of this study was to identify features and mechanisms that distinguish SD from other systemic autoinflammatory diseases (SAID).

Methods

Using the SomaScan assay and RNA sequencing (RNA-Seq), we determined the plasma proteomes and immune cell microRNA (miRNA) and RNA transcriptomes of 372 patients with SAID, respectively. Proteomic findings were validated by enzyme-linked immunosorbent assays. SD (n = 72) and non-SD SAIDs (n = 300) were compared to identify distinguishing features of SD. We performed integrated and unbiased analyses of all data sets using weighted gene correlation network analysis to identify feature modules that characterize SD and stratify patients.

Results

Elevated plasma heme oxygenase 1 (HO-1) and interleukin-18 (IL-18) strongly correlate and characterize SD but do not associate with general inflammation. SD was characterized by ferroptosis in plasma, type I interferon (IFN) signaling in monocyte transcriptomes, and elevated natural killer cell miRNA-146a-5p, which is an IL-18 induced miRNA. Finally, we identified feature modules that distinguish SD from other SAIDs and stratified patients with SD into two distinct subgroups not attributable to disease activity or inflammation but hemophagocytosis.

Conclusion

This unprecedented large omics data set of SAIDs revealed that complex interactions among hemophagocytosis, IL-18, and type I IFN signaling characterize SD. Furthermore, two distinct subgroups in patients with SD were distinguished by the degree of hemophagocytic activity. Finally, the large proteomics and RNA-Seq data sets generated in this study can serve as an invaluable resource for the further investigation of SD and other SAIDs.

Abstract Image

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血球吞噬、IL-18和I型IFN之间的多方面相互作用将Still病与其他自身炎症性疾病区分开来。

目的：系统性青少年特发性关节炎和成人发病的Still病（统称Still病/SD）的病理生理学未知和缺乏特异性特征延迟了诊断和适当治疗。本研究的目的是确定区分SD与其他系统性自身炎症性疾病（SAID）的特征和机制。方法：采用SomaScan法测定372例SAID患者血浆蛋白质组，RNAseq法测定免疫细胞miRNA和RNA转录组。酶联免疫吸附试验证实了蛋白质组学的发现。将SD （n=72）和非SD （n=300）进行比较，以确定SD的显著特征。我们使用加权基因相关网络分析（WGCNA）对所有数据集进行了综合和无偏分析，以确定表征SD和分层患者的特征模块。结果：血浆血红素加氧酶1 （HO-1）和IL-18升高与SD密切相关，但与一般炎症无关。SD的特征是血浆铁下垂，单核细胞转录组中I型IFN信号传导，NK细胞miRNA-146a-5p （IL-18诱导的miRNA）升高。最后，我们确定了区分SD与其他said的特征模块，并将SD患者分为两个不同的亚组，这两个亚组不是由于疾病活动或炎症，而是由于噬血细胞现象。结论：这一前所未有的大型SAIDs组学数据揭示了噬血细胞作用、IL-18和I型IFN信号传导之间的复杂相互作用是SD的特征。此外，在SD患者中，两个不同的亚组可以通过噬血细胞活性的程度来区分。最后，本研究生成的大型蛋白质组学和RNAseq数据集可以作为进一步研究SD和其他said的宝贵资源。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.