Autoantibodies Against Type I Interferons are a Prominent Feature in SARS-CoV-2 Fatal Disease and Hospitalization.

BACKGROUND

Autoantibodies have been implicated as key players in COVID-19 pathogenesis, with evidence of impacting disease severity and poor outcomes.

METHODS

We analyzed autoantibody profiles in 435 PCR-confirmed COVID-19 patients in Manaus, Brazil, comparing hospitalized (263) and nonhospitalized (172) individuals, and 37 healthy controls. Twenty autoantibodies and SARS-CoV-2-specific IgA/IgG antibodies were measured using multiplex Luminex® assays from plasma samples collected on days 1, 7, 14, and 28.

RESULTS

Hospitalized patients had significantly higher levels of autoantibodies targeting ACE2, MPO, IFNΩ, IFNα1, and IFNα2 at baseline, with 127 hospitalized patients positive for IFNα1, 161 for IFNα2 and 68 for IFNΩ. Longitudinal analysis revealed progressively increasing levels of anti-ACE2, B2G1, C1q, IFNα1, IFNα2, PADI4, PF4, and PR3 autoantibodies in hospitalized patients; however, the neutralizing capacity of IFNs were not investigated. Survival analysis showed that elevated type I IFN autoantibodies correlated with reduced survival (P = .023). Stronger correlations between autoantibodies and SARS-CoV-2 IgA/IgG were found in severe cases.

CONCLUSIONS

In this cohort, autoantibodies were linked to COVID-19 severity and mortality, indicating their potential as biomarkers for patient risk stratification and therapeutic targets. Further research is needed to explore their impact in long-term immune dysregulation and postacute sequelae in COVID-19 survivors.

LAY SUMMARY: COVID-19 affects people differently. Some recover quickly, while others become very sick or die. Scientists have found that some COVID-19 patients develop autoantibodies, or "self-attacking" antibodies. How and which autoantibodies were relevant in COVID-19 remains to be described. This study conducted in Manaus, Brazil, aimed to understand if these autoantibodies contributed to severe COVID-19 and poor survival outcomes. Manaus was one of the hardest-hit regions by the pandemic. We studied 435 COVID-19 patients (263 hospitalized, 172 nonhospitalized), and 37 healthy individuals. Blood samples were collected over 28 days and tested for 20 different autoantibodies and antibodies against the coronavirus using advanced laboratory assays. Hospitalized patients had notably higher levels of 2 specific autoantibodies. Those that block the body's natural antiviral proteins (type I interferons) and ACE2 (helps regulate systemic and local inflammation, and fluid homeostasis). These autoantibodies were strongly linked with severe illness and a higher risk of death, and increased over time. Patients with strong autoantibody responses also had higher levels of antibodies against the virus, suggesting a link between infection and immune self-attack. Autoantibodies were strongly linked to severe COVID-19 and death. Screening for them could help doctors identify high-risk patients early for effective treatment strategies.