SLE is characterised by an activation of the interferon (IFN) system, which leads to an increased expression of IFN-regulated genes. The reasons behind the IFN signature in SLE are (1) the existence of endogenous IFN inducers, (2) activation of several IFN-producing cell types, (3) production of many different IFNs, (4) a genetic setup promoting IFN production and (5) deficient negative feedback mechanisms. The consequences for the immune system is a continuous stimulation to an immune response, and for the patient a number of different organ manifestations leading to typical symptoms for SLE. In the current review, we will present the existing knowledge of the IFN system and pathway activation in SLE. We will also discuss how this information can contribute to our understanding of both the aetiopathogenesis and some organ manifestations of the disease. We will put forward some issues that are unresolved and should be clarified in order to make a proper stratification of patients with SLE, which seems important when selecting a therapy aiming to downregulate the IFN system.

ObjectivesSystemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.MethodsDNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.ResultsWe identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.ConclusionsOur results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

These results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.

Several systemic autoimmune diseases display a prominent IFN signature. This is caused by a continuous IFN-α production by plasmacytoid dendritic cells (pDCs), which are activated by immune complexes (ICs) containing nucleic acid. The IFN-α production by pDCs stimulated with RNA-containing IC (RNA-IC) consisting of anti-RNP autoantibodies and U1 small nuclear ribonucleoprotein particles was recently shown to be inhibited by monocytes, but enhanced by NK cells. The inhibitory effect of monocytes was mediated by TNF-α, PGE2, and reactive oxygen species, but the mechanisms for the NK cell-mediated increase in IFN-α production remained unclear. In this study, we investigated the mechanisms whereby NK cells increase the RNA-IC–induced IFN-α production by pDCs. Furthermore, NK cells from patients with systemic lupus erythematosus (SLE) were evaluated for their capacity to promote IFN-α production. We found that CD56dim NK cells could increase IFN-α production >1000-fold after RNA-IC activation, whereas CD56bright NK cells required costimulation by IL-12 and IL-18 to promote IFN-α production. NK cells produced MIP-1α, MIP-1β, RANTES, IFN-γ, and TNF-α via RNA-IC–mediated FcγRIIIA activation. The IFN-α production in pDCs was promoted by NK cells via MIP-1β secretion and LFA-mediated cell–cell contact. Moreover, NK cells from SLE patients displayed a reduced capacity to promote the RNA-IC–induced IFN-α production, which could be restored by exogenous IL-12 and IL-18. Thus, different molecular mechanisms can mediate the NK cell-dependent increase in IFN-α production by RNA-IC–stimulated pDCs, and our study suggests that the possibility to therapeutically target the NK–pDC axis in IFN-α–driven autoimmune diseases such as SLE should be investigated.

ObjectivesTo investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).MethodsPatients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.ResultsSLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10–86 and OR 7.48 (6.73 to 8.32), p=2.2×10–304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10–5), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10–2), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10–5), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10–3), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10–2), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10–3), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10–2), anti-β2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10–3) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10–2) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10–2), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10–2), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10–7), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10–3) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10–2) in high to low quartile comparison.ConclusionsA high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.