Nihira Hiroshi, Nakajima Daisuke, Izawa Kazushi, Kawashima Yusuke, Shibata Hirofumi, Konno Ryo, Higashiguchi Motoko, Miyamoto Takayuki, Nishitani-Isa Masahiko, Hiejima Eitaro, Honda Yoshitaka, Matsubayashi Tadashi, Ishihara Takashi, Yashiro Masato, Iwata Naomi, Ohwada Yoko, Tomotaki Seiichi, Kawai Masahiko, Murakami Kosaku, Ohnishi Hidenori, Ishimura Masataka, Okada Satoshi, Yamashita Motoi, Morio Tomohiro, Hoshino Akihiro, Kanegane Hirokazu, Imai Kohsuke, Nakamura Yasuko, Nonoyama Shigeaki, Uchiyama Toru, Onodera Masafumi, Ishikawa Takashi, Kawai Toshinao, Takita Junko, Nishikomori Ryuta, Ohara Osamu, Yasumi Takahiro
Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan; Department of Pediatrics, Kyoto Okamoto Memorial Hospital, Kuse, Japan.
Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan.
J Allergy Clin Immunol. 2025 May 2. doi: 10.1016/j.jaci.2025.04.025.
Type I interferonopathy is characterized by aberrant upregulation of type I interferon signaling. The mRNA interferon signature is a useful marker for activation of the interferon pathway and for diagnosis of type I interferonopathy; however, early diagnosis is challenging.
This study sought to identify the proteomic interferon signature in dried blood spot (DBS) samples. The aim was to evaluate the usefulness of the interferon signature for neonatal screening and to gain insight into presymptomatic state of neonates with inborn errors of immunity (IEIs).
DBS samples from healthy newborns/adults, patients with type I interferonopathy or other IEIs as well as from neonates with viral infections, including some samples obtained during the presymptomatic neonatal period, were examined by nontargeted proteome analyses. Expression of interferon-stimulated genes (ISGs) was evaluated and a DBS-interferon signature was defined. Differential expression/pathway analysis was also performed.
The ISG products IFIT5, ISG15, and OAS2 were detected. Expression of IFIT5 and ISG15 was upregulated significantly in individuals with type I interferonopathy. We defined the sum of the z scores for these as the DBS-interferon signature, and found that patients with IEIs other than type I interferonopathy, such as chronic granulomatous disease (CGD), also showed significant elevation. Additionally, neonatal samples of type I interferonopathy and CGD patients showed high interferon signatures. Pathway analysis of neonatal CGD samples revealed upregulation of systemic lupus erythematosus-like pathways.
Upregulation of the interferon pathway exists already at birth-not only in neonates with type I interferonopathy but also in other IEIs, including CGD.
I型干扰素病的特征是I型干扰素信号异常上调。mRNA干扰素特征是干扰素途径激活和I型干扰素病诊断的有用标志物；然而，早期诊断具有挑战性。
本研究旨在鉴定干血斑（DBS）样本中的蛋白质组干扰素特征。目的是评估干扰素特征在新生儿筛查中的有用性，并深入了解患有先天性免疫缺陷（IEIs）的新生儿的症状前状态。
通过非靶向蛋白质组分析检查来自健康新生儿/成人、I型干扰素病患者或其他IEIs患者以及病毒感染新生儿（包括一些在症状前新生儿期获得的样本）的DBS样本。评估干扰素刺激基因（ISGs）的表达并定义DBS干扰素特征。还进行了差异表达/途径分析。
检测到ISG产物IFIT5、ISG15和OAS2。IFIT5和ISG15的表达在I型干扰素病患者中显著上调。我们将这些的z分数总和定义为DBS干扰素特征，并发现除I型干扰素病以外的IEIs患者，如慢性肉芽肿病（CGD），也显示出显著升高。此外，I型干扰素病和CGD患者的新生儿样本显示出高干扰素特征。新生儿CGD样本的途径分析显示系统性红斑狼疮样途径上调。
干扰素途径的上调在出生时就已存在——不仅在I型干扰素病的新生儿中，而且在包括CGD在内的其他IEIs中也是如此。
