Ruyue Chen
Interferon-ω (IFN-ω) is a member of the human type I interferon family that has historically been overshadowed by IFN-α and IFN-β. Recent human "natural perturbations", most notably selective neutralization of IFN-ω by autoantibodies in life-threatening viral infections, have renewed interest in this comparatively understudied cytokine and indicate that its antiviral activity may not always be fully compensated in defined clinical settings. This renewed focus has prompted reassessment of its single-gene organization, distinct antigenicity, intermediate receptor-binding kinetics, cellular sources, and regulatory mechanisms. In parallel, thymus-centered tolerance disorders, including autoimmune regulator (AIRE) deficiency, additional inborn errors of immune tolerance, and acquired "sick thymus" states, establish anti-IFN-ω autoantibodies as a stable, high-penetrance immunophenotype linking tolerance failure to durable cytokine-directed autoimmunity. Beyond antiviral defense, multi-omic studies in lupus-spectrum disease suggest tissue- and compartment-specific IFN-ω signals within broader type I interferon programs, yet endogenous IFN-ω remains rarely quantified with ligand-level resolution. This Review integrates current knowledge of IFN-ω from molecular regulation to human disease. Further progress will require subtype-resolved measurement, direct comparison with other type I interferons under matched conditions, and human genetic studies testing whether rare IFNW1 variants contribute to severe viral disease.