Gene expression profiling of dendritic cell tolerance dysfunction in women with systemic lupus erythematosus

Overview & Synopsis

Background: Dendritic cells (DCs) are central regulators of immune tolerance, and disturbances in their phenotype and function contribute to the breakdown of self-tolerance in systemic lupus erythematosus (SLE). Tolerogenic DCs (tolDCs), which suppress autoreactive responses and promote peripheral tolerance, are a promising therapeutic focus in autoimmune diseases. Methods: Here, we analyzed the transcriptional profiles of in vitro generated DCs derived from monocytes of individuals with SLE and healthy controls to identify disease-specific disruptions in tolerance associated pathways. Results: Interferon stimulated genes (ISGs) emerged as dominant markers across all cellular contexts, with monocytes exhibiting the most substantial enrichment; key ISGs (I FI27, IFI44L, USP18, IFI6 ) acted as central hubs in regulatory networks, underscoring their diagnostic and pathogenic significance. In tolDCs from SLE donors, lipid metabolism pathways were selectively altered, suggesting impaired synthesis of pro-resolving lipid mediators. Additionally, diminished IL10RA expression and dysregulated IRF4 activity in SLE moDCs indicated intrinsic defects in IL-10 mediated tolerogenic differentiation. Conclusion: Together, these findings suggest that interferon driven transcriptional rewiring, impaired IL-10 signaling, and aberrant lipid metabolic programming converge to compromise DCs tolerogenic capacity in SLE. This highlights key mechanistic pathways that could be targeted to restore immune tolerance and reduce chronic inflammation.