Type I interferon (IFN) signalling is a key axis implicated in multiple autoimmune diseases, driving chronic immune dysregulation. While disease-specific interferon-stimulated gene (ISG) signatures have been studied extensively, the presence of a universal ISG signature across all autoimmune diseases remains unproven. Here, I perform a pan-disease comparative transcriptomic analysis to identify heterologous ISG overlaps—i.e., ISGs that are shared across subsets (pairs or triplets) of diseases, rather than across all.

I selected publicly available gene expression datasets for autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and primary Sjögren’s syndrome. Using standardized R workflows (e.g. limma), I identified differentially expressed genes for each disease (|log₂FC| > 1, adj. p < 0.05). These DEGs were intersected with a curated ISG reference catalog to isolate disease-specific ISG sets. I then performed pairwise and triple-wise overlap analyses to detect shared ISG signatures across disease combinations. Enrichment analyses (Gene Ontology, KEGG) elucidated the functional context of shared vs. unique ISG modules, and network-based visualization characterized hub genes and interconnections.

I found no ISG that is commonly differentially expressed across all autoimmune diseases studied. However, multiple ISGs are shared in subsets, e.g., between SLE and pSS, RA and MS, and in some cases trios such as pSS–RA–SLE. Overlapping ISG modules are enriched in antiviral defence, cytokine signalling, and JAK–STAT activation, whereas disease-unique ISGs map to pathways involving tissue remodelling, B-cell signalling, and metabolic processes. Network analysis identifies hub ISGs within overlapping modules that may serve as cross-disease regulatory nodes.

These results support a model in which autoimmune disorders share heterologous rather than universal interferon signatures. Overlapping ISG modules across disease subsets point toward convergent immune dysregulation, while unique ISGs may contribute to disease-specific pathology. The hub ISGs uncovered are promising candidates for cross-disease biomarker development or targeted therapy.