Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis

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Abstract

OBJECTIVE: 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] 10 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.

Original languageEnglish
Pages (from-to)875-882
Number of pages8
JournalCritical Care Medicine
Volume45
Issue number5
Early online date31 May 2017
DOIs
Publication statusPublished - May 2017

Keywords

  • Aged
  • Aged, 80 and over
  • Annexin A5
  • Apoptosis
  • B-Lymphocyte Subsets
  • B-Lymphocytes
  • Critical Illness
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases
  • Female
  • Gene Expression
  • Hospitals, University
  • Humans
  • Intensive Care Units
  • Lymphopenia
  • Male
  • Middle Aged
  • Prospective Studies
  • RNA, Messenger
  • Sepsis
  • Tissue Array Analysis
  • Journal Article
  • Observational Study

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