IFI6 is associated with interferon activation and complement-associated immune responses in primary Sjögren's disease

Primary Sjögren's disease (pSjD) is a systemic autoimmune disease characterized by chronic immune-mediated inflammation of exocrine glands and a prominent type I interferon (IFN-I) signature. However, the molecular mechanisms linking interferon signaling with downstream immune and inflammatory pathways in pSjD remain incompletely understood. In this study, we performed an integrative analysis combining public transcriptomic datasets, immune infiltration analysis, single-cell RNA sequencing, and experimental validation to investigate the potential involvement of interferon alpha-inducible protein 6 (IFI6) in pSjD. Differential expression and network analyses identified IFI6 as an upregulated interferon-stimulated gene associated with immune-related pathways. Immune infiltration analysis showed that IFI6 expression was associated with activated dendritic cells and CD4⁺ memory T cells. Single-cell RNA sequencing further indicated preferential expression of IFI6 in dendritic cell subsets. Clinical validation revealed increased serum IFI6 levels in patients with pSjD, which were negatively associated with salivary flow rate. In addition, immunoprecipitation coupled with proteomic analysis identified complement-related proteins within IFI6-associated complexes, and enrichment analysis suggested the involvement of complement activation pathways. Overall, these findings indicate that IFI6 expression is associated with interferon-related immune activation and complement-associated inflammatory pathways in pSjD. IFI6 may serve as a potential biomarker reflecting interferon-related immune activation and is associated with reduced salivary flow rate in pSjD, although further studies are required to clarify its precise functional role.