Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Abstract

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

Figure S1.

Imaging of COVID-19 pneumonia in APS-1 patients. (A) Course of COVID-19 pneumonia in an APS-1 patient. Bilateral (left to right) ground-glass opacities are seen on initial chest CT 6 d after symptom onset (left upper panel). Persistence of bilateral ground-glass opacities with a worsening of radiographical signs in the left lung base on day 10 after symptom onset (right upper panel). Improvement of ground-glass opacities on days 16 (left lower panel) and 37 (right lower panel) after symptom onset. (B) Coronal chest CT angiogram demonstrating nonocclusive segmental pulmonary embolus to the distal pulmonary arterial branches of the right lower lobe. (C) Chest CT scan of an APS-1 patient showing bilateral alveolo-interstitial lesions of COVID-19 pneumonia.

Figure 1.

APS-1 patients have neutralizing auto-Abs against type I IFNs, the titers of which can be decreased by plasmapheresis. (A) Titers of auto-Ab titers against the 17 type I IFNs in APS-1 patients infected with SARS-CoV-2 (n = 8). (B) Neutralization of IFN-α2 by various dilutions of auto-Ab–containing serum from APS-1 patients with COVID-19 (n = 5). Relative luciferase activity is shown after stimulation with 10 ng/ml of IFN-α2. Results representative of two independent experiments are shown. ISRE, IFN stimulation response element; RLU, relative light units. (C) Plasmapheresis decreased the titers of type I IFN auto-Abs in one APS-1 patient (patient 17) with COVID-19 pneumonia. The titers of auto-Abs against IFN-α2 are shown for one of the APS-1 patients treated by plasmapheresis (PE). (D) Plasmapheresis (PE) decreased the titers of type I IFN auto-Abs in another APS-1 patient (patient 18) with COVID-19 pneumonia, treated with plasmapheresis, convalescent plasma, and IFN-β (as shown with arrows). The titers of auto-Abs against IFN-α2 are shown for the APS-1 patients treated by plasmapheresis in the upper panel. In the lower panel, ISG scores (evaluated by NanoString) show an increase after the initiation of treatments. ISG score cutoff for positivity is 2,758. RQ, relative quantitation.

Figure S2.

Analysis of lung-targeting auto-Abs against KCNRG and BPIFB1 in APS-1 patients with COVID-19. (A and B) Auto-Ab titers to KCNRG (A) and BPIFB1 (B) in APS-1 patients with COVID-19 (n = 8). Positive and negative control sample results are also shown.

Figure S3.

ISG score and neutrophil score at different time points in an APS-1 patient with severe COVID-19 treated with plasmapheresis, convalescent plasma, and IFN-β. (A and B) 24 ISGs are shown at each time point (A), and 6 neutrophil signature genes are shown (B). ISG score are higher during treatment, while the neutrophil score diminishes. PE, plasma exchange.