title: Activation-Associated Accelerated Apoptosis of Memory B Cells in Critically Ill Patients With Sepsis.
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.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  Critical care units.
  
  
  METHODS
  Adult sepsis patients without any documented immune comorbidity.
  
  
  METHODS
  None.
  
  
  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.
authors.affiliation: 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.
authors.forename: Manu
authors.initials: M
authors.lastname: Shankar-Hari
authors.forename: David
authors.initials: D
authors.lastname: Fear
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
authors.forename: Tracey
authors.initials: T
authors.lastname: Mare
authors.forename: Richard
authors.initials: R
authors.lastname: Beale
authors.forename: Chad
authors.initials: C
authors.lastname: Swanson
authors.forename: Mervyn
authors.initials: M
authors.lastname: Singer
authors.forename: Jo
authors.initials: J
authors.lastname: Spencer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D016638:Critical Illness; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006785:Hospitals, University; D006801:Humans; D007362:Intensive Care Units; D008231:Lymphopenia / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger; D018805:Sepsis / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D046888:Tissue Array Analysis
chemical_list: D017304:Annexin A5; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases