Immune dysregulation in mania: A proof-of-concept platelet proteomics study

Aims: Bipolar disorder (BD) is a major psychiatric condition with a multifaceted and largely unknown pathophysiology. Mania, the defining feature of BD, remains underinvestigated. Proteomics offers a powerful, data-driven, unbiased approach to uncover biological alterations. Blood platelets provide a stable and comprehensive reflection of the body's internal milieu. This proof-of-concept study explores platelet proteomic alterations in mania. Methods: High-resolution proteomic profiling was performed on platelet samples from hospitalized patients with severe mania (n = 11) and 1:1 age- and sex-matched healthy controls (n = 11) using liquid chromatography–tandem mass spectrometry. Platelet proteins were quantified, differentially expressed proteins identified, and functional enrichment analyses conducted to characterize associated biological pathways. Key proteomic predictions were validated by enzyme-linked immunosorbent assay (ELISA) in platelet and plasma samples. Results: Proteomic analysis revealed that mania is associated with proteins primarily enriched in immune activation while lacking those enriched in cell homeostasis. Among shared proteins, mania exhibited a prominent cluster of downregulated proteins, primarily converging on immune-related pathways. The most robust alteration involved deficits in MHC Class I-mediated antigen processing. Key immune regulatory hubs – transforming growth factor (TGF)-β and interleukin-4 (IL-4) – were identified, with the association of increased TGF-β levels with mania validated by ELISA. Conclusions: This study highlights platelet proteomics as a valuable tool for investigating biological alterations in psychiatric disorders. Our findings indicate deficits in MHC Class I-related pathways and immune alterations consistent with chronic low-grade inflammation, suggesting potential roles for latent viral and autoimmune-related mechanisms in BD. These results support and refine the concept of immune dysregulation in mania and BD.