AUTHOR=Miyamoto Takayuki , Honda Yoshitaka , Izawa Kazushi , Kanazawa Nobuo , Kadowaki Saori , Ohnishi Hidenori , Fujimoto Masakazu , Kambe Naotomo , Kase Naoya , Shiba Takeshi , Nakagishi Yasuo , Akizuki Shuji , Murakami Kosaku , Bamba Masahiro , Nishida Yutaka , Inui Ayano , Fujisawa Tomoo , Nishida Daisuke , Iwata Naomi , Otsubo Yoshikazu , Ishimori Shingo , Nishikori Momoko , Tanizawa Kiminobu , Nakamura Tomoyuki , Ueda Takeshi , Ohwada Yoko , Tsuyusaki Yu , Shimizu Masaki , Ebato Takasuke , Iwao Kousho , Kubo Akiharu , Kawai Toshinao , Matsubayashi Tadashi , Miyazaki Tatsuhiko , Kanayama Tomohiro , Nishitani-Isa Masahiko , Nihira Hiroshi , Abe Junya , Tanaka Takayuki , Hiejima Eitaro , Okada Satoshi , Ohara Osamu , Saito Megumu K. , Takita Junko , Nishikomori Ryuta , Yasumi Takahiro TITLE=Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.905960 DOI=10.3389/fimmu.2022.905960 ISSN=1664-3224 ABSTRACT=Purpose

Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature.

Methods

The type I IFN signature was measured in patients’ whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature.

Results

A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling.

Conclusions

Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.