Shankar-Hari, M;
Fear, D;
Lavender, P;
Mare, T;
Beale, R;
Swanson, C;
Singer, M;
(2017)
Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis.
Critical Care Medicine
, 45
(5)
pp. 875-882.
10.1097/CCM.0000000000002380.
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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] 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.
| Type: | Article |
|---|---|
| Title: | Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1097/CCM.0000000000002380 |
| Publisher version: | http://dx.doi.org/10.1097/CCM.0000000000002380 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Apoptosis, B cells, immune memory, immunosuppression, sepsis, GERMINAL CENTER, SEPTIC SHOCK, HOSPITAL READMISSION, ORGAN FAILURE, RISK-FACTORS, PLASMA-CELL, MORTALITY, RECEPTOR, INFECTION, INNATE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10043205 |
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