Autoantibodies targeting type I interferons: Prevalence, mechanisms of induction, and association with viral disease susceptibility

Abstract

The type I IFN (IFN‐I) system is essential to limit severe viral disease in humans. Thus, IFN‐I deficiencies are associated with serious life‐threatening infections. Remarkably, some rare individuals with chronic autoimmune diseases develop neutralizing autoantibodies (autoAbs) against IFN‐Is thereby compromising their own innate antiviral defenses. Furthermore, the prevalence of anti‐IFN‐I autoAbs in apparently healthy individuals increases with age, such that ∼4% of those over 70 years old are affected. Here, I review the literature on factors that may predispose individuals to develop anti‐IFN‐I autoAbs, such as reduced self‐tolerance caused by defects in the genes AIRE, NFKB2, and FOXP3 (among others), or by generally impaired thymus function, including thymic involution in the elderly. In addition, I discuss the hypothesis that predisposed individuals develop anti‐IFN‐I autoAbs following “autoimmunization” with IFN‐Is generated during some acute viral infections, systemic inflammatory events, or chronic IFN‐I exposure. Finally, I highlight the enhanced susceptibility that individuals with anti‐IFN‐I autoAbs appear to have towards viral diseases such as severe COVID‐19, influenza, or herpes (e.g., varicella‐zoster virus, herpes simplex virus, cytomegalovirus), as well as adverse reactions to live‐attenuated vaccines. Understanding the mechanisms underlying development and consequences of anti‐IFN‐I autoAbs will be key to implementing effective prophylactic and therapeutic measures.

Longitudinal Analysis Over Decades Reveals the Development and Immune Implications of Type I Interferon Autoantibodies in an Aging Population

“…Based on previous hypotheses (Hale, 2023), and the data presented so far in this manuscript, we postulate that anti-IFN-I autoAbs develop following exposure to unusually high levels of IFN-I (possibly driven by severe infection) in the context of diminished self-tolerance. Towards validating this concept, we followed-up on the case of individual P7, who developed neutralizing anti-IFNα autoAbs in their mid-50s, and maintained them lifelong ever since (>12 years) (Fig.…”

“…Compared to samples taken from before anti-IFN-I autoAbs were detectable, we observed a clear temporal correlation between induction of neutralizing anti-IFNα2 autoAbs and a reduction of baseline ISG levels in patient PBMCs. It is logical to assume that the appearance and maintenance of these neutralizing autoAbs led to this functional impairment of innate antiviral immunity, thus contributing to an increased susceptibility to severe viral infections as previously reported (reviewed in (Bastard et al, 2024a;Hale, 2023)). The consequences of harboring other neutralizing anti-IFN-I autoAbs (e.g.…”

“…Deficiencies in the human type I interferon (IFN-I) system leave individuals susceptible to a range of severe viral diseases typically caused by pathogens to which they lack pre-existing humoral immunity (reviewed in (Duncan et al, 2021; Meyts and Casanova, 2021; Stertz and Hale, 2021)). While life-threatening viral diseases linked directly to genetic defects in the IFN-I system are extremely rare (and mainly manifest themselves in the very young) (Duncan et al, 2021), it has recently become apparent from cross-sectional studies that a functional defect caused by autoantibodies (autoAbs) targeting IFN-I cytokines is not particularly rare in elderly populations (reviewed in (Bastard et al, 2024a; Hale, 2023)). Specifically, the prevalence of autoAbs neutralizing the IFN-I cytokines IFNα and/or IFNω increases sharply with age in otherwise healthy individuals, such that a conservative estimate of prevalence in those >70 years old is about eight times higher (1.4%) than that in younger individuals (0.17%) (Bastard et al, 2021).…”

“…Multiple distinct host genetic defects converging on disruption of central T-cell tolerance in the thymus have been shown to underlie the development of anti-IFN-I autoAbs in several patient cohorts (reviewed in (Bastard et al, 2024a; Hale, 2023)). The best characterized examples of these defects include mutations in the AIRE gene, which encodes an autoimmune regulator that normally ensures negative selection of autoreactive T-cells (Meager et al, 2006; Meyer et al, 2016), and mutations in the NFKB2, MAP3K14 (NIK) and RELB genes, that encode components of the alternative NF-κB pathway and regulate AIRE expression (Bodansky et al, 2022; Le Voyer et al, 2023; Ramakrishnan et al, 2018; Sjogren et al, 2022).…”

“…The best characterized examples of these defects include mutations in the AIRE gene, which encodes an autoimmune regulator that normally ensures negative selection of autoreactive T-cells (Meager et al, 2006; Meyer et al, 2016), and mutations in the NFKB2, MAP3K14 (NIK) and RELB genes, that encode components of the alternative NF-κB pathway and regulate AIRE expression (Bodansky et al, 2022; Le Voyer et al, 2023; Ramakrishnan et al, 2018; Sjogren et al, 2022). Patients with these genetic defects exhibit thymic abnormalities and reduced self-tolerance, and typically develop anti-IFN-I autoAbs in early childhood (Le Voyer et al, 2023; Meager et al, 2006), which has been speculated to occur following an infection event triggering ‘immunization’ with endogenous IFN-I (Hale, 2023). However, the role of genetics and other pre-disposing factors in contributing to the increased prevalence of anti-IFN-I autoAbs in elderly populations is little understood, and it still remains to be resolved at the individual level at what point in life these autoAbs develop, their longevity, and their impact on an individual’s innate antiviral defenses.…”