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

## TL;DR

This study shows that the loss of immune tolerance to type I interferons occurs before autoantibody development and leads to lifelong susceptibility to infections.

## Contribution

The study reveals that age-related loss of self-tolerance precedes anti-IFN-I autoantibody development and increases infection risk.

## Key findings

- Anti-IFN-I autoantibodies persist lifelong and increase in titer over decades.
- Neutralizing anti-IFNα autoantibodies correlate with reduced IFN-stimulated gene levels and severe COVID-19.
- Pre-existing autoreactivity and prior viral infections are linked to anti-IFN-I autoantibody emergence.

## Abstract

Rare autoantibodies neutralizing type I IFNs can underlie viral disease severity. Here, the authors dissect immunological and age-related factors associated with anti-IFN-I autoantibody development in individuals over a 35-year period and further reveal the lifelong infection susceptibility that results.

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.