Journal
CRITICAL CARE MEDICINE
Volume 45, Issue 5, Pages 875-882Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000002380
Keywords
apoptosis; B cells; immune memory; immunosuppression; sepsis
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Funding
- ICU research funds at Guy's and St Thomas' NHS Foundation Trust
- National Institute for Health Research Biomedical Research Centre at King's Health Partners, London, United Kingdom
- National Institute for Health Research Clinician Scientist Award [NIHR-CS-2016-16-011]
- Research Councils UK (RCUK)
- GlaxoSmithKline
- U.K. NIHR Senior Investigator Fellowship
- U.K. Medical Research Council [MR/M019756/1DE]
- BBSRC [BB/H019634/1] Funding Source: UKRI
- MRC [MR/M019756/1] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre, MRC-Asthma UK Centre] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/H019634/1] Funding Source: researchfish
- Medical Research Council [G1000758, G1000758B, MR/M019756/1] Funding Source: researchfish
- National Institute for Health Research [16/33/01, CS-2016-16-011] Funding Source: researchfish
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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] 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.
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