A high burden of SLE risk genes is associated with persistent activation of the interferon system in patients with lupus.
Comment on: Single-cell RNA-seq reveals a persistent interferon signature in immune cells from systemic lupus erythematosus patients with high versus low polygenic risk scores despite antimalarial treatment. J Autoimmun. 2026 May 12:161:103575. doi: 10.1016. Commented by: Lars Rönnblom, Department of Medical Sciences, Uppsala University, Sweden. Genome-wide association studies have identified more than 300 loci associated to increased risk for SLE. For the majority of the gene variants in these loci the functional consequences in the SLE disease process are unknown. However, a large proportion of identified risk genes are connected to the interferon signaling pathway and contribute to the interferon signature in SLE. Calculating a polygenic risk score (PRS) is a method to quantify the cumulative genetic burden in a single patient and studies have shown that patients with a high PRS have a more severe disease phenotype with increased organ damage and reduced survival, compared to individuals with a low PRS. Antimalarial therapy is a well-established treatment of SLE and have shown efficacy in a large proportion of patients. The therapeutic effect is partly mediated by down regulation of the activated interferon system, which is connected to clinical response. However, despite therapeutic concentrations of hydroxychloroquine, many patients still have flares and accumulation of organ damage. The main objective of the present study was therefore to clarify if antimalarial treatment has different effects in patients with a high or a low PRS. SLE patients in remission with a high or a low PRS were compared in gene expression profile at single cell level on peripheral blood mononuclear cells. A total of 6 healthy controls and 16 matched patients treated with similar antimalarial doses, but no corticosteroids, were investigated. On average, 9636 cells were analyzed from each donor and 2724 genes detected per cell. Despite similar clinical picture, patients with a high PRS had a prominent interferon signature across multiple immune cell types, compared to patients with a low PRS who had a weak expression of interferon stimulated genes only in monocytes. Pathway analysis revealed that the interferon signaling pathway in plasmacytoid dendritic cells was strongly enriched in patients with a high PRS., but not in patients with a low PRS. In summary, the PRS seems to dictates SLE patients’ molecular immune profile, even when the clinical presentation appears identical. Furthermore, antimalarial treatment alone is insufficient to suppress the activation of the interferon system in patients with a high PRS, even during remission, which suggests that genetic stratification can be of value to control sub-clinical and potential harmful disease activity. At the same time, a group of patients with SLE and a low PRS, may have sufficient control of the disease with only hydroxychloroquine treatment.
