Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies. Journal of Experimental Medicine
Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. In this work, the authors traced 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.
In summary, this study provides a comprehensive longitudinal exploration of the age-related development and specificities of anti-IFN-I autoAbs. This work identified prior loss of tolerance and infection-related factors as influencers of anti-IFN-I autoAb induction and thereby supports the hypothesis that at least two-hits probably underlie this process. These findings have implications for diagnosing those who may be predisposed to developing anti-IFN-I autoAbs and the lifelong IFN-I functional deficiency and severe infection susceptibility that results. Broader knowledge in this area should contribute to the development of targeted strategies to mitigate severe viral disease susceptibility.