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

TY - JOUR

T1 - Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis

AU - Shankar-Hari, Manu

AU - Fear, David

AU - Lavender, Paul

AU - Mare, Tracey

AU - Beale, Richard

AU - Swanson, Chad

AU - Singer, Mervyn

AU - Spencer, Jo

N1 - Export Date: 22 June 2017 CODEN: CCMDC

PY - 2017/5

Y1 - 2017/5

N2 - 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.

AB - 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.

KW - Aged

KW - Aged, 80 and over

KW - Annexin A5

KW - Apoptosis

KW - B-Lymphocyte Subsets

KW - B-Lymphocytes

KW - Critical Illness

KW - Enzyme-Linked Immunosorbent Assay

KW - Extracellular Signal-Regulated MAP Kinases

KW - Female

KW - Gene Expression

KW - Hospitals, University

KW - Humans

KW - Intensive Care Units

KW - Lymphopenia

KW - Male

KW - Middle Aged

KW - Prospective Studies

KW - RNA, Messenger

KW - Sepsis

KW - Tissue Array Analysis

KW - Journal Article

KW - Observational Study

UR - http://www.scopus.com/inward/record.url?scp=85015240972&partnerID=8YFLogxK

U2 - 10.1097/CCM.0000000000002380

DO - 10.1097/CCM.0000000000002380

M3 - Article

C2 - 28296810

SN - 0090-3493

VL - 45

SP - 875

EP - 882

JO - Critical Care Medicine

JF - Critical Care Medicine

IS - 5

ER -