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

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

Fernbach, Sonja
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Mair, Nina K.
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Abela, Irene A.
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July 17, 2024
Journal Of Experimental Medicine

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, similar to 1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset similar to 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 IFN alpha, IFN beta, and IFN omega. Emergence of neutralizing anti-IFN alpha 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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