The interferon (IFN) system can be defined as the IFN genes and proteins, the inducers of IFN production, the IFN producing cells, as well as target cells affected by IFN. There are three different types of IFN (I–III), and type I IFN is the largest family consisting of more than 15 different proteins. The type I IFNs are our main defense against viral infections and production can be triggered by ligation of several different sensors of nucleic acid. Most cells can produce small amounts of type I IFN, but the principal type I IFN-producing cell is the plasmacytoid dendritic cell (pDC).

There are several observations suggesting an important role for the IFN system in the etiopathogenesis of SLE, but also other autoimmune diseases. Among these are the reported development of SLE during treatment with IFN-α, a prominent increase in the expression of IFN regulated genes (an IFN signature) in SLE, the existence of endogenous, or self derived, IFN inducers in SLE patients and a genetic association between SLE and gene variants within the type I IFN signaling pathway.

Several studies have shown that type I IFN seems to be the most important IFN for inducing the IFN signature, but it’s clear that type II and type III IFNs also can contribute. Furthermore, patients with SLE have epigenetic changes in type I IFN regulated genes, which are hypomethylated. Thus, there are strong evidences that activation of the IFN system, and particular the type I IFNs, is a key event in the SLE disease process.

The type I IFN system is closely connected to a number of other cytokine and chemokine pathways, which all can contribute to both the IFN signature and type I IFN effects. Important type I IFN effects are maturation and differentiation of dendritic cells, activation of T and B cells with enhanced antibody production and induction of increased expression of autoantigens. Consequently, type I IFNs can act as an immune adjuvant and promote an autoimmune process. Furthermore, the regulation of the type I IFN system is abnormal in SLE and negative feedback mechanisms are impaired, causing a positive feed-forward loop, which sustain the autoimmune reaction. Many different therapeutic targets exist within the IFN system and several studies have recently been published showing beneficial effects of blocking or down-regulating the activated type I IFN system in SLE. However, not all patients with SLE improve during IFN inhibition and obviously; better stratification of patients and more precise treatments are needed in the heterogeneous group of SLE patients. This can be done by integrating clinical phenotype with genetic setup, gene expression profile and analysis of activated pro inflammatory pathways.