Additionally, controversy exists about the pathogenic role of ISG15, since the overexpression of ISG15 in NETs of SLE patients could be both a consequence of the overstimulation by the IFNα/β signature, and a signal from NETs involved in the production of IFNγ by lymphocyte subpopulations [13, 57]. This evidence concerns the gene ISG15 and systemic lupus erythematosus.