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. 2025 Aug;156(2):473-479.e1.
doi: 10.1016/j.jaci.2025.04.025. Epub 2025 May 2.

Dried blood spot proteome identifies subclinical interferon signature in neonates with type I interferonopathy

Hiroshi Nihira  1 , Daisuke Nakajima  2 , Kazushi Izawa  3 , Yusuke Kawashima  4 , Hirofumi Shibata  5 , Ryo Konno  2 , Motoko Higashiguchi  5 , Takayuki Miyamoto  5 , Masahiko Nishitani-Isa  5 , Eitaro Hiejima  5 , Yoshitaka Honda  5 , Tadashi Matsubayashi  6 , Takashi Ishihara  7 , Masato Yashiro  8 , Naomi Iwata  9 , Yoko Ohwada  10 , Seiichi Tomotaki  5 , Masahiko Kawai  11 , Kosaku Murakami  12 , Hidenori Ohnishi  13 , Masataka Ishimura  14 , Satoshi Okada  15 , Motoi Yamashita  16 , Tomohiro Morio  17 , Akihiro Hoshino  18 , Hirokazu Kanegane  18 , Kohsuke Imai  19 , Yasuko Nakamura  19 , Shigeaki Nonoyama  19 , Toru Uchiyama  20 , Masafumi Onodera  20 , Takashi Ishikawa  21 , Toshinao Kawai  21 , Junko Takita  5 , Ryuta Nishikomori  22 , Osamu Ohara  2 , Takahiro Yasumi  23
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Free article

Dried blood spot proteome identifies subclinical interferon signature in neonates with type I interferonopathy

Hiroshi Nihira et al. J Allergy Clin Immunol. 2025 Aug.
Free article

Abstract

Background: 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.

Objective: 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).

Methods: 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.

Results: 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.

Conclusion: Upregulation of the interferon pathway exists already at birth-not only in neonates with type I interferonopathy but also in other IEIs, including CGD.

Keywords: CGD; Inborn errors of immunity; WAS; dried blood spot; interferonopathy; neonate; newborn; proteome; signature.

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Conflict of interest statement

Disclosure statement Supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (grants 19K17328, 21K07795, 22K07867, 22K15939, and 24K18855); by Health and Labour Sciences Research Grant JPMH23FC1016; by the Agency for Medical Research and Development (grant JP24ek0109586); and by the “Research on Measures for Intractable Diseases” project from the Japanese Ministry of Health, Labor, and Welfare (grant 23809798). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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