Structural integrity with functional plasticity: what type I IFN receptor polymorphisms reveal

The type I IFNs activate an array of signaling pathways, which are initiated after IFNs bind their cognate receptors, IFNα/β receptor (IFNAR)1 and IFNAR2. These signals contribute to many aspects of human health including defense against pathogens, cancer immunosurveillance, and regulation of inflammation. How these cytokines interact with their receptors influences the quality of these signals. As such, the integrity of receptor structure is pivotal to maintaining human health and the response to immune stimuli. This review brings together genome wide association studies and clinical reports describing the association of nonsynonymous IFNAR1 and IFNAR2 polymorphisms with clinical disease, including altered susceptibility to viral and bacterial pathogens, autoimmune diseases, cancer, and adverse reactions to live‐attenuated vaccines. We describe the amino acid substitutions or truncations induced by these polymorphisms and, using the knowledge of IFNAR conformational changes, IFNAR‐IFN interfaces and overall structure‐function relationship of the signaling complexes, we hypothesize the effect of these polymorphisms on receptor structure. That these predicted changes to IFNAR structure are associated with clinical manifestations of human disease, highlights the importance of IFNAR structural integrity to maintaining functional quality of these receptor‐mediated responses. Type I IFNs are pivotal to innate immune responses and ultimately, to human health. Understanding the consequences of altered structure on the actions of these clinically significant cell receptors provides important information on the roles of IFNARs in health and disease.