Type I interferons (IFN-Is) are critical antiviral cytokines that restrict viral replication and limit viral disease. A remarkable recent discovery is that human autoantibodies (autoAbs) neutralizing the activities of IFN-Is phenocopy inborn errors of immunity and markedly exacerbate susceptibility to life-threatening infections. Development of these pathogenic autoAbs in humans is strongly linked to genetic and nongenetic factors affecting thymic function, and they are estimated to be present in >100 million people worldwide with a prevalence that increases with age. Here, we review major advances from the last few years that have improved our mechanistic understanding of human IFN-I autoAb development and function, as well as their association with a significant proportion of different severe viral diseases. In particular, we highlight how neutralizing IFN-I autoAbs can persist in individuals for decades, compromising IFN-I-mediated defenses, and underlying subsequent critical infections with diverse pathogens, including SARS-CoV-2, West Nile virus, tick-borne encephalitis virus, seasonal influenza viruses, herpesviruses, and rare zoonoses caused by MERS-CoV, flaviviruses, and avian H5N1 influenza A virus. Furthermore, we discuss how neutralizing IFN-I autoAbs facilitate severe adverse events with live-attenuated viral vaccines, such as the yellow fever or chikungunya virus vaccines, and suggest how implementation of IFN-I autoAb diagnostics in at-risk populations may be clinically beneficial with current prophylactic or therapeutic options. Finally, in the context of new experimental insights into how autoAbs block the ability of IFN-Is to engage with the IFNAR1/IFNAR2 receptors, we detail future opportunities to design advanced novel therapeutic strategies that might specifically mitigate IFN-I autoAb pathogenic effects.
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