Systemic lupus erythematosus (SLE) is a complex autoimmune disease which affects 
multiple organs. The type I interferon (IFN) gene signature and circulating 
autoantibodies are hallmarks of SLE. Plasmacytoid dendritic cells (pDCs) are 
considered the main producers of type I IFN and production is modulated by 
multiple other immune cell types. In SLE, essentially every immune cell type is 
dysregulated and aberrant deregulation is thought to be due, in part, to direct 
or indirect exposure to IFN. Genetic variants within or around the transcription 
factor interferon regulatory factor 5 (IRF5) associate with SLE risk. Elevated 
IFNα activity was detected in the sera of SLE patients carrying IRF5 risk 
polymorphisms who were positive for either anti-RNA binding protein (anti-RBP) 
or anti-double-stranded DNA (anti-dsDNA) autoantibodies. Neutrophils are also an 
important source of type I IFNs and are found in abundance in human blood. 
Neutrophil extracellular traps (NETs) are considered a potential source of 
antigenic trigger in SLE that can lead to type I IFN gene induction, as well as 
increased autoantibody production. In this review, we will focus on immune cell 
types that produce type I IFNs and/or are affected by type I IFN in SLE. In 
addition, we will discuss potential inducers of endogenous type I IFN production 
in SLE. Last, we will postulate how the different immune cell populations may be 
affected by an IRF5-SLE risk haplotype.