Sepsis is life-threatening organ dysfunction due to dysregulated host responses to infection. Current knowledge of human B-cell alterations in sepsis is sparse. We tested the hypothesis that B-cell loss in sepsis involves distinct subpopulations of B cells and investigated mechanisms of B-cell depletion.Design:
Prospective cohort study.Setting:
Critical care units.Patients:
Adult sepsis patients without any documented immune comorbidity.Interventions:
None.Measurements and Main Results:
B-cell subsets were quantified by flow cytometry; annexin-V status identified apoptotic cells and phosphorylation of intracellular kinases identified activation status of B-cell subsets. B cell–specific survival ligand concentrations were measured. Gene expression in purified B cells was measured by microarray. Differences in messenger RNA abundance between sepsis and healthy controls were compared. Lymphopenia present in 74.2% of patients on admission day was associated with lower absolute B-cell counts (median [interquartile range], 0.133 [0.093–0.277] 109 cells/L) and selective depletion of memory B cells despite normal B cell survival ligand concentrations. Greater apoptotic depletion of class-switched and IgM memory cells was associated with phosphorylation of extracellular signal-regulated kinases, implying externally driven lymphocyte stress and activation-associated cell death. This inference is supported by gene expression profiles highlighting mitochondrial dysfunction and cell death pathways, with enriched intrinsic and extrinsic pathway apoptosis genes.Conclusions:
Depletion of the memory B-cell compartment contributes to the immunosuppression induced by sepsis. Therapies targeted at reversing this immune memory depletion warrant further investigation.