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Critical care medicine · May 2017
Observational StudyActivation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis.
- Manu Shankar-Hari, David Fear, Paul Lavender, Tracey Mare, Richard Beale, Chad Swanson, Mervyn Singer, and Jo Spencer.
- 1Peter Gorer Department of Immunobiology, Programme of Infection and Immunity, King's College London, London, United Kingdom. 2Division of Asthma, Allergy and Lung Biology, King's College London, London, United Kingdom. 3Department of Intensive Care Medicine, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom. 4MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, Guy's Hospital, London, United Kingdom. 5Department of Infectious diseases, Programme of Infection and Immunity, King's College London, London, United Kingdom. 6Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom.
- Crit. Care Med. 2017 May 1; 45 (5): 875-882.
ObjectiveSepsis 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.DesignProspective cohort study.SettingCritical care units.PatientsAdult sepsis patients without any documented immune comorbidity.InterventionsNone.Measurements And Main ResultsB-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.ConclusionsDepletion 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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