Transcriptomic Characterization of a Monocyte Antigen-Presentation-Low Immunoparalysis State in Sepsis

Sepsis immunoparalysis is commonly monitored with monocyte HLA-DR, but whether a composite antigen-presentation-low transcriptomic state adds mechanistic information beyond existing endotypes remains uncertain. We integrated public bulk cohorts (GSE65682, GSE57065, and GSE54514) with single-cell datasets (GSE167363 and GSE279452) to define a directional immunoparalysis score combining low antigen-presentation/HLA-II and costimulatory response with high emergency-myeloid and inhibitory-tolerance programs. In GSE65682, the score was associated with 28-day mortality ( n = 479; adjusted OR = 1.32, 95% CI: 1.01–1.72; p = 0.0396), although discrimination was modest (AUC = 0.568, 95% CI: 0.506–0.628). The score overlapped with MARS endotypes, was highest in MARS2, and remained associated after age, sex, and MARS adjustment (OR = 1.39, 95% CI: 1.00–1.92; p = 0.048). GSE57065 supported disease-state elevation, whereas GSE54514 and APACHE II analyses defined negative predictive boundaries. Single-cell analyses localized the signal to antigen-presenting and pro-inflammatory monocytes, classical monocytes, and dendritic cells. The proposed transcript panel is hypothesis-generating for prospective immune-state monitoring, not a validated clinical decision tool.