Human autoantibodies neutralizing type I IFNs: From 1981 to 2023

Abstract

SummaryHuman autoantibodies (auto‐Abs) neutralizing type I IFNs were first discovered in a woman with disseminated shingles and were described by Ion Gresser from 1981 to 1984. They have since been found in patients with diverse conditions and are even used as a diagnostic criterion in patients with autoimmune polyendocrinopathy syndrome type 1 (APS‐1). However, their apparent lack of association with viral diseases, including shingles, led to wide acceptance of the conclusion that they had no pathological consequences. This perception began to change in 2020, when they were found to underlie about 15% of cases of critical COVID‐19 pneumonia. They have since been shown to underlie other severe viral diseases, including 5%, 20%, and 40% of cases of critical influenza pneumonia, critical MERS pneumonia, and West Nile virus encephalitis, respectively. They also seem to be associated with shingles in various settings. These auto‐Abs are present in all age groups of the general population, but their frequency increases with age to reach at least 5% in the elderly. We estimate that at least 100 million people worldwide carry auto‐Abs neutralizing type I IFNs. Here, we briefly review the history of the study of these auto‐Abs, focusing particularly on their known causes and consequences.

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

“…Compared with samples taken 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, which is likely due to neutralization of the low levels of constitutively secreted tonic IFN-I that prime innate antiviral defenses ( Flagg et al, 2023 ; Gough et al, 2012 ). 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., against IFNβ or IFNω) could not be readily discerned in our subcohort due to the relatively low numbers of positive individuals identified, although a recent report suggests that neutralization of IFNα may have greater pathogenic consequences than neutralization of IFNω ( Bastard et al, 2024b ).…”

“…In this regard, the availability of longitudinal biobanked plasma and PBMC samples, together with high-resolution tracking of anti-IFN-I autoAb induction (such as presented here), could prove invaluable to retrospectively assess thymus-related immunosenescence in specific individuals by assaying historic thymic output (e.g., by quantifying T cell receptor excision circles, or TRECs [ Mitchell et al, 2010 ]) and correlating this directly with the subsequent likelihood of anti-IFN-I autoAb induction. Given the apparent severe consequences of anti-IFN-I autoAbs for infection susceptibility (reviewed in Bastard et al [2024a] ; Hale [2023] ), in the future there may be a clear clinical role for performing diagnostic autoimmune (e.g., ANA test and others) or TREC quantifications to help predict an individual’s risk of developing this form of IFN system deficiency.…”

“…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 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 rare in the elderly (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 apparently 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 ).…”

“…Furthermore, the presence of neutralizing anti-IFN-I autoAbs in individuals has been associated with an increased susceptibility to severe infections caused by several viral pathogens, including SARS-CoV-2 ( Akbil et al, 2022 ; Bastard et al, 2020 , 2024b ; Busnadiego et al, 2022 ; Chauvineau-Grenier et al, 2022 ; Credle et al, 2022 ; Eto et al, 2022 ; Frasca et al, 2022 ; Goncalves et al, 2021 ; Manry et al, 2022 ; Mathian et al, 2022 ; Scordio et al, 2022 ; Solanich et al, 2021 ; Troya et al, 2021 ; Wang et al, 2021 ), MERS-CoV ( Alotaibi et al, 2023 ), influenza A virus ( Zhang et al, 2022 ), West Nile virus ( Gervais et al, 2023 ; Lin et al, 2023 ), and various herpesviruses ( Bayat et al, 2015 ; Burbelo et al, 2010 ; Busnadiego et al, 2022 ; Hetemaki et al, 2021 ; Mathian et al, 2022 ; Mogensen et al, 1981 ; Pozzetto et al, 1984 ). Given that >100 million people worldwide have been estimated to harbor neutralizing anti-IFN-I autoAbs ( Bastard et al, 2024a ) and are therefore at increased risk of severe infectious disease outcomes, it is critical to understand factors associated with their development and pathogenic mechanisms to inform future mitigation strategies.…”

“…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 the negative selection of autoreactive T cells ( Meager et al, 2006 ; Meyer et al, 2016 ), and mutations in the NFKB2 , MAP3K14 (NIK), and RELB genes, which 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 ).…”