E-T1IFNs · Elaboration of the type I interferonopathies

Type I interferons represent both key molecules in anti-viral defence and mediators of inflammatory disease, so that the induction, transmission and resolution of the interferon response are tightly regulated - balancing protection against infection versus the risk of immunopathology. Monogenic type I interferonopathies (T1IFNs), and related ‘complex’ phenotypes such as systemic lupus erythematosus and dermatomyositis, represent examples of a disturbance of the homeostatic control of this system, where a constitutive upregulation of type I interferon activity is considered directly relevant to pathology. Set against the absence of a routine assay in clinical medicine for the detection of upregulated type I interferon, the current application addresses major questions in the developing T1IFN field. Analogous to other screening strategies (e.g. using mouse ENU mutagenesis or yeast gene deletion series), we have established a pipeline for the systematic identification of human mutant states predisposing to upregulated type I interferon signalling. Such an approach will allow for the comprehensive definition of important themes in interferon biology, informing our understanding of anti-viral signalling and self-non-self discrimination. Furthermore, these studies will have direct translational benefit - since the identification of a phenotype as a T1IFN implies the possibility of therapy to reduce type I interferon levels and / or block interferon signalling.