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.
