Fernbach, SonjaSonjaFernbachMair, Nina KNina KMairAbela, Irene AIrene AAbelaGroen, KevinKevinGroenKuratli, RogerRogerKuratliLork, MarieMarieLorkThorball, Christian WChristian WThorballBernasconi, EnosEnosBernasconiFilippidis, ParaskevasParaskevasFilippidisLeuzinger, KarolineKarolineLeuzingerNotter, JuliaJuliaNotterRauch, AndriAndriRauch0000-0001-5297-6062Hirsch, Hans HHans HHirschHuber, MichaelMichaelHuberGünthard, Huldrych FHuldrych FGünthardFellay, JacquesJacquesFellayKouyos, Roger DRoger DKouyosHale, Benjamin GBenjamin GHale2024-10-262024-10-262024-09-02https://boris-portal.unibe.ch/handle/20.500.12422/179210Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.en600 - Technology::610 - Medicine & healtharticle10.48350/1990733901793010.1084/jem.20240365