Longitudinal Analysis Over Decades Reveals the Development and Immune Implications of Type I Interferon Autoantibodies in an Aging Population

ABSTRACT Pre-existing autoantibodies (autoAbs) neutralizing type I interferons (IFN-Is: IFNα, IFNβ, IFNω) have recently been described as significant contributors to the severity of viral infectious diseases. Here, we explore the development and consequences of anti-IFN-I autoAbs at high-resolution using retrospective samples and data from 1876 well-treated individuals >65 years of age enrolled in the Swiss HIV Cohort Study, a nationwide, longitudinal cohort with up to 35 years of follow-up. Approximately 1.9% of individuals developed anti-IFN-I autoAbs, with a median onset age of ∼63 years (range 45-80). Once developed, anti-IFN-I autoAbs persisted for life, and generally increased in titer over years. Most individuals developed distinct neutralizing and non-neutralizing anti-IFN-I autoAb repertoires at discrete times that selectively targeted various combinations of IFNα, IFNβ, and IFNω. Longitudinal analyses further revealed that emergence of neutralizing anti-IFNα autoAbs correlated with reduced IFN-stimulated gene (ISG) levels, indicating impairment of innate immunity. Patient data review suggested that prior recorded viral infections and autoimmune history influence the likelihood of mounting anti-IFN-I autoAbs. Indeed, systematic measurements in biobanked samples revealed significant enrichment of pre-existing autoreactivity against clinically relevant autoantigens in individuals who later developed anti-IFN-I autoAbs. In this context, we describe lifelong neutralizing anti-IFNα autoAbs (and impaired innate immunity), that manifested in an individual following IFNα therapy, and who was retrospectively found to have had pre-existing autoreactivity to β2-glycoprotein-I before IFNα treatment. Our decades-spanning longitudinal analyses illuminate the development and immune implications of anti-IFN-I autoAbs in an aging population, and support a ‘two-hit’ hypothesis whereby loss of self-tolerance prior to immune-triggering with endogenous or exogenous IFN-I may pose a risk for developing late-onset, lifelong IFN-I functional deficiency.