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. 2023 May 20;43(6):1093–1103. doi: 10.1007/s10875-023-01512-9

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Autoantibodies neutralizing type I interferons are present in the broncho-alveolar lavage of ~ 10% of patients with life-threatening COVID-19. (A) Gyros (high-throughput automated ELISA) results for auto-Abs against IFN-α2 and/or IFN-ω in the plasma of patients with life-threatening COVID-19 (N = 95). The dotted line indicates the threshold for positivity, defined as a type I IFN auto-Ab level exceeding 100. (B) Results for the neutralization of IFN-α2, IFN-ω (100 pg/mL or 10 ng/mL) or IFN-β (10 ng/mL) in the presence of a 1:10 dilution of plasma from patients with life-threatening COVID-19 (N = 95). The relative luciferase activity (RLA) ratio (ISRE dual luciferase activity, with normalization against Renilla luciferase activity) is shown, after stimulation with IFN-α2, IFN-ω, or IFN-β, with normalization against the RLA obtained without stimulation in the presence of a 1:10 dilution of plasma. The dotted line indicates the threshold for neutralization, defined as an RLA ratio of no more than 3. (C) Gyros results for auto-Abs against IFN-α2 and IFN-ω in the plasma of a patient known to have high titers of auto-Abs neutralizing IFN-α2 and IFN-ω (“Positive” plasma), in the bronchoalveolar lavage (BAL) of patients with life-threatening COVID-19 (N = 254), and in PBS supplemented with 0.05% Tween (PBS-T) as a negative control. The dotted line indicates the threshold for positivity, defined as a type I IFN auto-Ab level above 1. (D) Results for the neutralization of IFN-α2, IFN-ω (100 pg/mL), or IFN-β (10 ng/mL) in the presence of a 1:5 dilution of BAL from patients with life-threatening COVID-19 (N = 415) and individuals without interstitial lung disease (“Uninfected controls” – N = 27). Relative luciferase activity (RLA) ratio (ISRE dual luciferase activity, with normalization against Renilla luciferase activity) is shown after stimulation with IFN-α2, IFN-ω, or IFN-β, with normalization against the RLA without stimulation in the presence of a 1:5 dilution of BAL. The dotted line indicates the threshold for neutralization, defined as an RLA ratio of no more than 3. (E) Plot showing the RLA ratio after stimulation with IFN-α2 or IFN-ω or IFN-β, in the presence of a 1:10 dilution of plasma or a 1:5 dilution of BAL from patients with life-threatening COVID-19 (N = 95). The dotted lines indicate the threshold for neutralization, defined as an RLA ratio of no more than 3. Patients with neutralizing auto-Abs in both BAL and plasma are shown in the bottom left corner, whereas the patients in the bottom right corner had neutralizing auto-Abs only in plasma. (F-G) Principal component analysis (PCA) (F), and volcano plot representation (G) of the concentrations of 59 biomarkers in BAL from patients with life-threatening COVID-19 pneumonia with (N = 11) or without (N = 117) auto-Abs against type I IFNs. PCA was performed with the FactoMineR package. Wilcoxon tests were performed to compare the concentrations of biomarkers in BAL between patients with and without auto-Abs against type I IFNs, with a p-value < 0.05 considered significant