Investigating the association between interferons and flares of systemic lupus erythematosus at a single cell level

Abstract

Elevated levels of interferons (IFN) are a hallmark of Systemic Lupus Erythematosus (SLE) and are linked to disease flares, but the precise mechanisms underlying this remain unclear. We examined the association between IFN-stimulated proteins (ISPs) and immune changes in flaring and quiescent SLE patients at single-cell resolution. Using CyTOF, six ISPs were measured in PBMC populations from 18 healthy controls, 24 quiescent SLE patients, and 46 recently flaring SLE patients. Individual ISPs and a composite ISP score were assessed. Analysis of 29 immune populations revealed that mean ISP levels correlated with peripheral blood IFN-stimulated gene (ISG) expression and were higher in flaring than quiescent patients. Despite this correlation, ISP expression was heterogeneous between and within cell subsets. To identify factors contributing to this heterogeneity, we compared the top ISP-expressing cells with the remaining cells in each subject. High ISP-expressing cells had increased trafficking marker expression with distinct expression patterns suggesting that cells may have transited different tissues. Except for β7, these molecules were not induced by IFN in-vitro . Longitudinal analysis revealed that ISP expression gradually decreased in T and activated innate immune populations with flare resolution, whereas that in B cell populations remained stable with the baseline levels predicting sustained or recurrent disease activity one year later. Although mean ISP expression in most cell populations correlated with global ISG expression, there is heterogeneity between and within immune populations in SLE, likely reflecting variable IFN exposure as cells traffic through inflamed sites within the body.