Cause and consequences of the activated type I interferon system in SLE

Abstract

Patients with systemic lupus erythematosus (SLE) have an increased expression of type I interferon (IFN)-regulated genes (an IFN signature), which is caused by an ongoing production of type I IFNs by plasmacytoid dendritic cells (pDCs). The reasons behind the continuous IFN production in SLE are the presence of self-derived IFN inducers and a lack of negative feed-back signals that downregulate the IFN response. In addition, several cells in the immune system promote the IFN production by pDCs and gene variants in the type I IFN signaling pathway contribute to the IFN signature. The type I IFNs act as an immune adjuvant and stimulate T cells, B cells, and monocytes, which all play an important role in the loss of tolerance and persistent autoimmune reaction in SLE. Consequently, new treatments aiming to inhibit the activated type I IFN system in SLE are now being developed and investigated in clinical trials.

Keywords: Etiopathogenesis; Immune regulation; Plasmacytoid dendritic cells; Systemic lupus erythematosus; Type I interferon.

Fig. 1

Type I interferon production is affected by interactions between plasmacytoid dendritic cells and other cell types. Plasmacytoid dendritic cells (pDCs) produce type I interferon (IFN) when stimulated with RNA containing immune complexes (RNA-IC). Activated monocytes/macrophages suppress the capacity of pDCs to produce type I IFN by releasing reactive oxygen species (ROS) and prostaglandin E2 (PGE2). In contrast, NK cells enhance the type I IFN production by activated pDCs via lymphocyte-associated antigen (LFA)-1 and secretion of MIP-1β. Also, the B cells and activated T cells increase the type I IFN production by RNA-IC-stimulated pDCs via a mechanisms involving CD31 molecule and soluble GM-CSF, respectively