For example, USP18 and ISG15 are negative feedback regulators of IFNAR-JAK-STAT signaling, and their deficiency in humans drives severe autoimmune disease (Zhang et al., 2015; Meuwissen et al., 2016; Bogunovic et al., 2012; Martin-Fernandez et al., 2020; Malakhova et al., 2006). This evidence concerns the gene ISG15 and autoimmune disease.