Abstract / Summary
Abstract Background Major depressive disorder (MDD) and its most severe phenotype, major dysmood disorder (MDMD), are distinguished by the activation of the immune-inflammatory response system, T cell activation, and a relative T regulatory cell suppression. While traditional models rely on dyadic protein associations, multi-protein coordination and emergent system dynamics remain largely uncharacterized in MDMD immune architectures. Objectives To investigate the self-organizing properties and higher-order structural organization of the MDMD immune interactome, identifying central coordinating nodes, functional bottlenecks, and enriched emergent biological processes. Results Network topological evaluation identified a core backbone of primary coordinating hubs: tumor necrosis factor-α (TNF), interleukin (IL)6, CXCL12, CXCL10, CCL5, CD4, CD8A, HLA-DR, and FOXP3. Functional overrepresentation revealed that the network self-organizes around systemic defense responses and viral-mediated processes involving viral protein interactions with cytokines and their receptors. Chemokine signaling cascades and TNF/NF-κB pathways constituted primary feedback circuits. Molecular complex detection extracted a tightly coordinated higher-order module centered on RELA-regulated viral protein–cytokine interactions, reflecting group-level functional interdependence rather than isolated dyadic interactions. Conclusions Acute immune-inflammatory activation in MDMD behaves as an emergent, self-organized state driven by higher-order viral-associated pathway modules. These findings indicate that viral-immune interactions may serve as critical structural drivers that organize systemic T cell activation and chronic inflammatory recurrence, providing a systems-level framework for MDD pathogenesis.