Categorisation of monogenic disorders: Underlying a deficit of type I IFN activity / observed type I IFN signalling upregulation

The last 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions. Remarkably, only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases, albeit surprisingly few, with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps unexpectedly, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory disease.