Revisiting down syndrome through the lens of interferonopathy and innate immune dysregulation

Down syndrome (DS), caused by trisomy 21, has long been viewed primarily as a neurodevelopmental disorder. However, increasing evidence indicates that it is also associated with pervasive immune dysregulation, including chronic inflammation and heightened susceptibility to autoimmunity. Here, we revisit DS from the perspective of innate immunity and suggest that it shares key features with interferon-driven, autoinflammation-like conditions. Drawing on recent multi-omics studies, we outline a mechanistic framework linking chromosome 21 gene dosage to systemic immune activation. Increased expression of interferon receptors lowers the threshold for signaling and drives persistent activation of interferon-stimulated genes (ISGs). In parallel, reduced METTL3-dependent m⁶A modification may stabilize pro-inflammatory transcripts and enhance innate immune sensing. These changes occur alongside chromatin accessibility remodeling enriched for AP-1-associated elements, consistent with a transcriptionally primed state that amplifies inflammatory gene expression. Together, these processes form a feed-forward network involving interferon signaling, transcriptional activation, and cytokine production, providing a basis for the basal inflammatory state in DS and its high burden of immune-mediated comorbidities. This framework also highlights potential therapeutic opportunities, including JAK-STAT inhibition and cytokine-targeted approaches, which may help restore immune homeostasis and inform future translational studies.