Suppression of Type I Interferon Signaling in Myeloid Cells by Autoantibodies in Severe COVID-19 Patients

• Published in: Journal of clinical immunology 2024-04, Vol.44 (4), p.104, Article 104
• Main Authors: Aoki, Ami, Iwamura, Chiaki, Kiuchi, Masahiro, Tsuji, Kaori, Sasaki, Atsushi, Hishiya, Takahisa, Hirasawa, Rui, Kokubo, Kota, Kuriyama, Sachiko, Onodera, Atsushi, Shimada, Tadanaga, Nagaoka, Tetsutaro, Ishikawa, Satoru, Kojima, Akira, Mito, Haruki, Hase, Ryota, Kasahara, Yasunori, Kuriyama, Naohide, Nakamura, Sukeyuki, Urushibara, Takashi, Kaneda, Satoru, Sakao, Seiichiro, Nishida, Osamu, Takahashi, Kazuhisa, Kimura, Motoko Y., Motohashi, Shinichiro, Igari, Hidetoshi, Ikehara, Yuzuru, Nakajima, Hiroshi, Suzuki, Takuji, Hanaoka, Hideki, Nakada, Taka-aki, Kikuchi, Toshiaki, Nakayama, Toshinori, Yokote, Koutaro, Hirahara, Kiyoshi
• Format: Article
• Language: English
• Subjects: Autoantibodies; Autoantibodies - blood; Autoantibodies - immunology; Biomedical and Life Sciences; Biomedicine; Coronaviruses; COVID-19; COVID-19 - immunology; Dendritic cells; Dendritic Cells - immunology; Epitope mapping; Female; Humans; Immunology; Infectious Diseases; Interferon; Interferon Type I - immunology; Interferon Type I - metabolism; Internal Medicine; Leukocytes (mononuclear); Male; Medical Microbiology; Monocytes; Myeloid cells; Myeloid Cells - immunology; Original; Original Article; Peripheral blood mononuclear cells; Risk factors; SARS-CoV-2 - immunology; Severe acute respiratory syndrome coronavirus 2; Severity of Illness Index; Signal Transduction - immunology
• ISSN: 0271-9142; 1573-2592; 1573-2592
• DOI: 10.1007/s10875-024-01708-7

Purpose Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. Methods We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. Results Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. Conclusion Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.