Integrated multi-omics analysis reveals shared IFN-γ-associated monocyte signatures in primary Sjögren's syndrome and Alzheimer's disease.

BACKGROUND: Primary Sjögren's syndrome (pSS) is epidemiologically associated with an increased risk of Alzheimer's disease (AD); however, the shared IFN-γ-related immune mechanisms underlying this association remain poorly understood. METHODS: Peripheral blood transcriptomic, single-cell transcriptomic, and epigenomic datasets from patients with AD and pSS were integrated and analyzed. These findings were further validated using peripheral blood samples from patients and in vitro IFN-γ stimulation experiments to systematically characterize the shared IFN-γ-related immune features. RESULTS: Integrated multi-omics analysis revealed shared IFN-γ-related immune signatures between pSS and AD, with transcriptional responses predominantly enriched in CD14+ and CD16+ monocytes. Among these, OAS3 was consistently upregulated in both monocyte subsets. Western blot analysis further confirmed elevated OAS3 protein expression in the peripheral blood of patients with pSS and AD. Integrated analysis of public multi-omics datasets together with in vitro IFN-γ stimulation experiments showed a time-associated increase in OAS3 expression following IFN-γ stimulation, which remained consistently induced even under low-dose stimulation. Although the IFN-γ-associated inflammatory transcriptional profiles differed between glucose and galactose culture conditions, OAS3 expression remained consistently induced under both metabolic conditions. ATAC-seq and CUT&Tag analyses showed that IFN-γ stimulation increased chromatin accessibility at the OAS3 promoter and enhanced H3K4me1 enrichment, a process that may be associated with activation of the JAK/STAT signaling pathway. Exploratory analysis of a publicly available OAS3-knockout THP-1 dataset revealed altered enrichment of immune- and neurodegeneration-related pathways. CONCLUSIONS: This study demonstrates that pSS and AD share IFN-γ-related immune-inflammatory features and identifies OAS3 as a candidate IFN-γ-responsive molecule that exhibits sustained responsiveness to IFN-γ stimulation. These findings provide new insights into the shared IFN-γ-associated immune features of pSS and AD and support the potential of OAS3 as a peripheral biomarker for future mechanistic and translational studies.