Mild COVID-19 despite autoantibodies against type I IFNs in autoimmune polyendocrine syndrome type 1

Abstract

Autoantibodies to interferon (IFN)-α and IFN-ω (type-I-IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with Autoimmune-Polyendocrine-Syndrome Type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type-I-IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied six patients with APS-1 between April 1st, 2020 and April 1st, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies to IFN-αand IFN-ω. The patients ́ sera ability to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFNneutralization assays. We describe four patients with APS-1 and pre-existing high titers of neutralizing autoantibodies to IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnoea, oxygen requirement or high temperature. All infected patients with APS-1 shared female sex and age younger than 26 years. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

“…These data suggest that the presence of neutralizing autoantibodies to type-I IFNs and the inflammation-prone lung tissue of APECED patients may heighten their risk for life-threatening COVID-19 complications ( 11 , 84 , 101 ). Of interest, another recent study reported four APECED patients who developed mild COVID-19 infection despite the presence of neutralizing autoantibodies to type-I IFNs, consistent with a model of incomplete clinical penetrance ( 102 ). These patients were <26-year-old, female, and did not have pre-existing autoimmune pneumonitis ( 102 ).…”

“…Of interest, another recent study reported four APECED patients who developed mild COVID-19 infection despite the presence of neutralizing autoantibodies to type-I IFNs, consistent with a model of incomplete clinical penetrance ( 102 ). These patients were <26-year-old, female, and did not have pre-existing autoimmune pneumonitis ( 102 ). Collectively, these reports indicate that APECED patients, particularly adults and/or those with underlying pneumonitis, can be at risk for severe COVID-19.…”

SARS-CoV-2 Spike Protein-Directed Monoclonal Antibodies May Ameliorate COVID-19 Complications in APECED Patients

“…Another recent study reported that 4 APECED patients with neutralizing autoantibodies to type-I IFNs developed mild COVID-19; all 4 patients were females with ages younger than 26 years old, without underlying autoimmune pneumonitis (29). Currently, therapies for COVID-19 in patients with rare genetic disorders are extrapolated from randomized controlled trials (RCTs) in the general population and published experience is limited.…”

Human autoantibodies underlying infectious diseases

“…In a large study of 22 APS-1 patients, most ( n = 19, 86%) suffered from severe or critical COVID-19 and four patients died; the others had mild or asymptomatic infections, possibly due to prior or early medical interventions ( Bastard et al, 2021c ). Another group recently described four younger APS-1 patients with neutralizing auto-Abs, who developed only mild or moderate COVID-19 ( Meisel et al, 2021 ). Overall, patients with APS-1, particularly those over the age of 25 yr, are at very high risk of developing severe or critical COVID-19 pneumonia.…”