Type I interferon in the pathogenesis of systemic lupus erythematosus

Abstract

Type I interferon (IFN) is a primary pathogenic factor in systemic lupus erythematosus (SLE). Gain-of-function genetic variants in the type I IFN pathway have been associated with risk of disease. Common polygenic as well as rare monogenic influences on type I IFN have been demonstrated, supporting a complex genetic basis for high IFN in many SLE patients. Both SLE-associated autoantibodies and high type I IFN can be observed in the pre-disease state. Patients with SLE and evidence of high type I IFN have more active disease and a greater propensity to nephritis and other severe manifestations. Despite the well-established association between type I IFN and SLE, the specific triggers of type I IFN production, the mechanisms by which IFNs help perpetuate the cycle of autoreactive cells and autoantibody production are not completely clear. This review provides an updated overview of type I IFN in SLE pathogenesis, clinical manifestations, and current therapeutic strategies targeting this pathway.

Figure 1

Schematic diagram of various ways the type I IFN pathway is modulated in SLE. Nucleic acid containing immune complexes formed by SLE-associated autoantibodies are taken up by plasmacytoid dendritic cells. Genetic variants in IRF5 and IRF7 can result in greater type I IFN production, particularly in those patients with autoantibodies. Type I IFN then signals through the IFNAR receptor, and polymorphisms such as the SLE-associated STAT4 allele result in augmented signaling downstream of the receptor. Polymorphisms in regulatory molecules, such as ILT3, can result in defective function and decreased ability to negatively regulate inflammatory pathways. In many patients, this multifactorial process leads to persistent dysregulation of the IFN pathway at multiple locations.

Figure 2

Diagram of genetic influences on type I IFN in SLE patients. The X and Y axes represent relative values for effect size and frequency in the population respectively. Common polymorphisms individually exert a modest influence on type I IFN, but when paired with the appropriate gene-gene or gene-environment interaction, would exert a moderate effect on type I IFN. The need for additional factors that assort independently de facto decreases the frequency in the general population. Lastly, some extremely rare monogenic variations have been reported that have a large effect upon the type I IFN pathway and typically lead to the interferonopathy category of diseases, which share some features with SLE.