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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies predominantly to nuclear material. Many aspects of disease pathology are mediated by the deposition of nucleic acid containing immune complexes, which also induce the type 1interferon response, a characteristic feature of SLE. Notably, SLE is remarkably heterogeneous, with a variety of organs involved in different individuals, who also show variation in disease severity related to their ancestries. Here, we probed one potential contribution to disease heterogeneity as well as a possible source of immunoreactive nucleic acids by exploring the expression of human endogenous retroviruses (HERVs). We investigated the expression of HERVs in SLE and their potential relationship to SLE features and the expression of biochemical pathways, including the interferon gene signature (IGS). Towards this goal, we analyzed available and new RNA-Seq data from two independent whole blood studies using Telescope. We identified 481 locus specific HERV encoding regions that are differentially expressed between case and control individuals with only 14% overlap of differentially expressed HERVs between these two datasets. We identified significant differences between differentially expressed HERVs and non-differentially expressed HERVs between the two datasets. We also characterized the host differentially expressed genes and tested their association with the differentially expressed HERVs. We found that differentially expressed HERVs were significantly more physically proximal to host differentially expressed genes than non-differentially expressed HERVs. Finally, we capitalized on locus specific resolution of HERV mapping to identify key molecular pathways impacted by differential HERV expression in people with SLE. 

IL-10 is elevated in the autoimmune disease systemic lupus erythematosus (SLE). Here, we show that conventional dendritic cells (cDCs) from predisease lupus-prone B6.NZM Sle1/Sle2/Sle3 triple congenic (TCSle) mice produce more IL-10 than wild-type congenic cDCs upon TLR stimulation, and this overproduction is prevented by blocking the type I IFN receptor (IFNAR) with specific Abs. Priming wild-type cDCs with type I IFN mimics the IL-10 overproduction of TCSle cDCs. The MAPK ERK is more phosphorylated in lupus cDCs, partially contributing to IL-10 overproduction. Moreover, we found that TCSle cDCs express higher levels of IL-27 upon TLR7/TLR9 stimulation, and IFNAR blockade reduced IL-27 levels in TCSle cDCs. These results suggest that dysregulated type I IFNs in cDCs contribute to the increased IL-10 and IL-27 in SLE. Since IL-27 neutralization did not inhibit TLR-induced IL-10 production, we propose that type I IFNs enhanced IL-10 in TCSle cDCs independently from IL-27. Moreover, RNA sequencing analysis of a cohort of SLE patients reveals higher gene expression of these cytokines in SLE patients expressing a high IFN signature. Since IL-27 and IL-10 have both pro- and anti-inflammatory effects, our results also suggest that these cytokines can be modulated by the therapeutic IFN blockade in trials in SLE patients and have complex effects on the autoimmune response.