The innate immune system in SLE: type I interferons and dendritic cells

Abstract

Patients with systemic lupus erythematosus (SLE) have an increased expression of type I interferon (IFN) regulated genes because of a continuous production of IFN-alpha. The cellular and molecular background to this IFN-alpha production has started to be elucidated during the last years, as well as the consequences for the innate and adaptive immune systems. Plasmacytoid dendritic cells (pDC) activated by immune complexes containing nucleic acids secrete type I IFN in SLE. Type I IFN causes differentiation of monocytes to myeloid-derived dendritic cell (mDC) and activation of autoreactive T and B cells. A new therapeutic option in patients with SLE is, therefore, inhibition of IFN-alpha, and recent data from a phase I clinical trial suggests that administration of neutralizing monoclonal antibodies against anti-IFN-alpha can ameliorate disease activity.

Figure 1

Schematic view of the etiopathogenesis of SLE. Viral infections induce type I interferon (IFN) production by plasmacytoid dendritic cells (pDC) and the release of autoantigens, which in susceptible individuals can break tolerance and cause production of autoantibodies against DNA and/or RNA containing autoantigens. These autoantigens together with autoantibodies will form immune complexes that can act as endogenous IFN inducers, which cause a continuous IFN-α production. Type I IFN will induce maturation of monocytes (Mo) into dendritic cells (DC), and activate B cells. IFN-induced mDCs activate both CD4 and CD8 T cells. All these events can explain the development of an autoimmune reaction as described in the text. Autoreactive B cells are also directly activated by immune complexes, which further increase the autoantibody production and sustain the autoimmune process. T-cell receptor (TCR).