Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies.

Fernbach, Sonja; Mair, Nina K; Abela, Irene A; Groen, Kevin; Kuratli, Roger; Lork, Marie; Thorball, Christian W; Bernasconi, Enos; Filippidis, Paraskevas; Leuzinger, Karoline; Notter, Julia; Rauch, Andri; Hirsch, Hans H; Huber, Michael; Günthard, Huldrych F; Fellay, Jacques; Kouyos, Roger D; Hale, Benjamin G (2024). Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies. Journal of experimental medicine, 221(9) Rockefeller University Press 10.1084/jem.20240365

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Autoantibodies 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.

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