Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies.
J Exp Med
; 221(9)2024 09 02.
Article
in En
| MEDLINE
| ID: mdl-39017930
ABSTRACT
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, â¼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset â¼63 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, IFNß, 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autoantibodies
/
Interferon Type I
/
Antibodies, Neutralizing
/
COVID-19
Limits:
Adult
/
Aged
/
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
J Exp Med
Year:
2024
Document type:
Article