The Goldilocks Zone of Type I IFNs: Lessons from Human Genetics

Type I IFNs (IFN-Is) are powerful cytokines. They provide remarkable protection against viral infections, but their indiscriminate production causes severe self-inflicted damage that can be lethal, particularly in early development. In humans, inappropriately high IFN-I levels caused by defects in the regulatory mechanisms that control IFN-I production and response result in clinical conditions known as type I interferonopathies. In essence, type I interferonopathies define the upper limit of safe, IFN-related inflammation in vivo. Conversely, the loss of IFN-I responsiveness increases susceptibility to viral infections, but, surprisingly, most affected individuals survive despite these inborn errors of immunity. These findings suggest that too much IFN-I early in life is toxic, but that insensitivity to IFN-I is perhaps not the death sentence it was initially thought to be. Human genetic analyses have suggested that seemingly insignificant levels of IFN-regulated gene activity may be sufficient for most of the antiviral defenses used by humans in natura.