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.

Background SARS-CoV-2 vaccination is recommended in patients with inborn errors of immunity (IEI); however, little is known about immunogenicity and safety in these patients. Objectives To evaluate the impact of genetic diagnosis, age, and treatment on antibody response to COVID-19 vaccine and related adverse event (AE) in a cohort of patients with IEI. Methods Plasma was collected from twenty-two healthcare worker (HCW) controls, 81 IEI patients and 2 thymoma pre-immunization, 1 to 6 days prior to the second dose of mRNA vaccine and at a median of 30 days after completion of the immunization schedule with either mRNA vaccine or a single dose of Johnson & Johnson’s Janssen vaccine. Anti-Spike (S) and anti-Nucleocapsid (N) antibody titers were measured using a luciferase immunoprecipitation systems (LIPS) method. T and B cell counts and use of immunosuppressive drugs were extracted from medical records. Vaccine-associated AE were collected after each dose. Results Positive anti-S antibodies were detected in 27/46 (58.7%) of the patients after one dose of mRNA vaccine and in 63 of 74 (85.1%) fully immunized patients. A lower rate of seroconversion (7/11, 63.6%) was observed in patients APECED. Previous use of rituximab and baseline counts of <1,000 CD3 + T cells/μL and <100 CD19 + B cells/μL were associated with lower anti-S IgG levels. No significant adverse events were reported. Conclusion Vaccinating IEI patients is safe, but immunogenicity is impacted by certain therapies and gene defects. These data may guide counseling IEI patients on prevention of SARS-CoV-2 infection and need for subsequent boosts.

Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)– and signal transducer and activator of transcription 1 (STAT1)–dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)–STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell–dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans.