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URL: https://pubmed.ncbi.nlm.nih.gov/32972996/

⇱ Autoantibodies against type I IFNs in patients with life-threatening COVID-19 - PubMed

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Abstract

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

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Figures

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Neutralizing auto-Abs to type I IFNs underlie life-threatening COVID-19 pneumonia.
We tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19 by impairing the binding of type I IFNs to their receptor and the activation of the downstream responsive pathway. Neutralizing auto-Abs are represented in red, and type I IFNs are represented in blue. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. ISGs, IFN-stimulated genes; TLR, Toll-like receptor; IFNAR, IFN-α/β receptor; pSTAT, phosphorylated signal transducers and activators of transcription; IRF, interferon regulatory factor.
👁 Fig. 1
Fig. 1. Neutralizing auto-Abs against IFN-α2 and/or IFN-ω in patients with life-threatening COVID-19.
(A) Multiplex particle-based assay for auto-Abs against IFN-α2 and IFN-ω in patients with life-threatening COVID-19 (N = 782), in patients with asymptomatic or mild SARS-CoV-2 infection (N = 443), and in healthy controls not infected with SARS-CoV-2 (N = 1160). (B) Anti–IFN-ω Ig isotypes in 23 patients with life-threatening COVID-19 and auto-Abs to type I IFNs. (C) Representative fluorescence-activated cell sorting (FACS) plots depicting IFN-α2– or IFN-ω–induced pSTAT1 in healthy control cells (gated on CD14+ monocytes) in the presence of 10% healthy control or anti–IFN-α2 or anti–IFN-ω auto-Abs–containing patient plasma (top panel) or an IgG-depleted plasma fraction (bottom panel). Max, maximum; neg, negative; pos, positive; NS, not stimulated. (D) Plot of anti–IFN-α2 auto-Ab levels against their neutralization capacity. The stimulation index (stimulated over unstimulated condition) for the plasma from each patient was normalized against that of healthy control plasma from the same experiment. Spearman’s rank correlation coefficient = −0.6805; P < 0.0001. (E) Median inhibitory concentration (IC50) curves representing IFN-α2– and IFN-ω–induced pSTAT1 levels in healthy donor cells in the presence of serial dilutions of patient plasma. The stimulation index (stimulated over unstimulated condition) for patient plasma was normalized against that of 10% healthy control plasma. IFN-α2: IC50 = 0.016%, R2 = 0.985; IFN-ω: IC50 = 0.0353%, R2 = 0.926. R2, coefficient of determination. (F) Neutralizing effect on CXLC10 induction, after stimulation with IFN-α2, IFN-β, or IFN-γ, in the presence of plasma from healthy controls (N = 4), patients with life-threatening COVID-19 and auto-Abs against IFN-α2 (N = 8), and APS-1 patients (N = 2).
👁 Fig. 2
Fig. 2. Auto-Abs against the different type I IFN subtypes.
(A) ELISA for auto-Abs against the 13 different IFN-α subtypes, IFN-ω, IFN-β, IFN-κ, and IFN-ε in patients with life-threatening COVID-19 and auto-Abs against IFN-α2 (N = 22), APS-1 patients (N = 2), and healthy controls (N = 2). (B) LIPS for the 12 different IFN-α subtypes tested in patients with auto-Abs against IFN-α2 (N = 22) and healthy controls (N = 2). (C) Neighbor-joining phylogenetic tree of the 17 human type I IFN proteins. Horizontal branches are drawn to scale (bottom left, number of substitutions per site). Thinner, intermediate, and thicker internal branches have bootstrap support of <50, ≥50, and >80%, respectively. The bootstrap value for the branch separating IFN-ω from all IFN-α subtypes is 100%.
👁 Fig. 3
Fig. 3. Enhanced SARS-CoV-2 replication, despite the presence of IFN-α2, in the presence of plasma from patients with auto-Abs against IFN-α2 and low in vivo levels of IFN-α.
(A) SARS-CoV-2 replication—measured 24 hours (left) and 48 hours (right) after infection—in Huh7.5 cells treated with IFN-α2 in the presence of plasma from patients with life-threatening COVID-19 and neutralizing auto-Abs against IFN-α2 (N = 8); a commercial anti–IFN-α2 antibody; or control plasma (N = 2). (B) IFN-α levels in the plasma or serum of patients with neutralizing auto-Abs (N = 41), healthy controls (N = 5), COVID-19 patients without auto-Abs (N = 21), and patients with life-threatening COVID-19 and loss-of-function (LOF) variants (N = 10), as assessed by Simoa ELISA. (C) z-scores for type I IFN gene responses in whole blood of COVID-19 patients with (N = 8) or without (N = 51) neutralizing auto-Abs, or healthy uninfected controls (N = 22). The median ± interquartile range is shown. z-scores were significantly lower for patients with neutralizing auto-Abs compared with patients without auto-Abs (Mann-Whitney test, P = 0.01).
👁 Fig. 4
Fig. 4. Demographic and ethnic information about the patients and controls.
(A) Gender distribution in patients with life-threatening COVID-19 and auto-Abs to type I IFNs, patients with life-threatening COVID-19 and without auto-Abs to type I IFNs, and individuals with asymptomatic or mild SARS-CoV-2. (B) Age distribution in patients with life-threatening COVID-19 and auto-Abs to type I IFNs, patients with life-threatening COVID-19 and without auto-Abs to type I IFNs, and individuals with asymptomatic or mild SARS-CoV-2. yo, years old. (C) PCA on 49 patients with life-threatening COVID-19 and auto-Abs against type I IFNs. EUR, Europeans; AFR, Africans; EAS, East-Asians.

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