Uddin, Mohammed J2021-08-042021-08-042020204-2020.95https://repository.mbru.ac.ae/handle/1/406Introduction: Three risk factors for life-threatening coronavirus disease 2019 (COVID-19) pneumonia have been identified— being male, being elderly, or having other medical conditions—but these risk factors cannot explain why critical disease remains relatively rare in any given epidemiological group. Given the rising toll of the COVID-19 pandemic in terms ofmorbidity andmortality, understanding the causes and mechanisms of life-threatening COVID-19 is crucial. Rationale: B cell autoimmune infectious phenocopies of three inborn errors of cytokine immunity exist, in which neutralizing autoantibodies (auto-Abs) against interferon-g (IFN-g) (mycobacterial disease), interleukin-6 (IL-6) (staphylococcal disease), and IL-17A and IL-17F (mucocutaneous candidiasis) mimic the clinical phenotypes of germline mutations of the genes that encode the corresponding cytokines or receptors. Human inborn errors of type I IFNs underlie severe viral respiratory diseases. Neutralizing auto-Abs against type I IFNs, which have been found in patients with a few underlying noninfectious conditions, have not been unequivocally shown to underlie severe viral infections. While searching for inborn errors of type I IFN immunity in patients with life-threatening COVID-19 pneumonia, we also tested the hypothesis that neutralizing auto-Abs against type I IFNs may underlie critical COVID-19. We searched for auto-Abs against type I IFNs in 987 patients hospitalized for life-threatening COVID- 19 pneumonia, 663 asymptomatic or mildly affected individuals infected with SARSCoV- 2, and 1227 healthy controls from whom samples were collected before the COVID- 19 pandemic. Results: At least 101 of 987 patients (10.2%) with life-threatening COVID-19 pneumonia had neutralizing immunoglobulin G (IgG) auto-Abs against IFN-w (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three individual type I IFNs. These auto-Abs neutralize high concentrations of the corresponding type I IFNs, including their ability to block SARSCoV- 2 infection in vitro. Moreover, all of the patients tested had low or undetectable serum IFN-a levels during acute disease. These auto- Abs were present before infection in the patients tested and were absent from 663 individualswith asymptomatic ormild SARSCoV- 2 infection (P < 10−16). They were present in only 4 of 1227 (0.33%) healthy individuals (P < 10−16) before the pandemic. The patients with auto-Abs were 25 to 87 years old (half were over 65) and of various ancestries. Notably, 95 of the 101 patients with auto-Abs were men (94%). Conclusion: ABcell autoimmunephenocopy 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%ofmen. In these patients, adaptive autoimmunity impairs innate and intrinsic antiviral immunity. These findings provide a first explanation for the excess of men among patients with life threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-b).enCOVID-19SARS-CoV-2AutoantibodiesArticle