title: Recruitment mechanisms of primary and malignant B cells to the human liver.
abstract: B cells are present within chronically inflamed liver tissue and recent evidence implicates them in the progression of liver disease. In addition, a large proportion of hepatic lymphomas are of B-cell origin. The molecular signals that regulate normal and malignant B-cell recruitment into peripheral tissue from blood are poorly understood, leading us to study human B-cell migration through hepatic sinusoidal endothelial cells in flow-based adhesion assays. In such assays, human blood-derived B cells were captured from shear flow without a previous rolling phase and underwent firm adhesion mediated by vascular cell adhesion molecule-1 (VCAM-1). Unlike T cells, which displayed vigorous crawling behavior on the endothelium, B cells remained static before a proportion underwent transendothelial migration mediated by a combination of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion protein-1, common lymphatic endothelial and vascular endothelial receptor-1/stabilin-1, and the chemokine receptors, CXCR3 and CXCR4. B-cell lymphoma cell lines and primary malignant B cells from patients with chronic lymphocytic leukemia and marginal zone B cell lymphoma also underwent integrin-mediated firm adhesion involving ICAM-1 and/or VCAM-1 and demonstrated ICAM-1-dependent shape-change and crawling behavior. Unlike primary lymphocytes, the malignant cells did not undergo transendothelial migration, which could explain why lymphomas are frequently characterized by the intravascular accumulation of malignant cells in the hepatic sinusoids.
  
  
  CONCLUSIONS
  Our findings demonstrate that distinct combinations of signals promote B-cell recruitment to the liver, suggesting the possibility of novel targets to modulate liver inflammation in disease. Certain features of lymphocyte homing are maintained in lymphoma recruitment to the liver, suggesting that therapeutic targets for lymphocyte recruitment may also prevent hepatic lymphoma dissemination.
authors.affiliation: Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom. s.shetty@bham.ac.uk
authors.forename: Shishir
authors.initials: S
authors.lastname: Shetty
authors.forename: Tony
authors.initials: T
authors.lastname: Bruns
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Weston
authors.forename: Zania
authors.initials: Z
authors.lastname: Stamataki
authors.forename: Ye H
authors.initials: YH
authors.lastname: Oo
authors.forename: Heather M
authors.initials: HM
authors.lastname: Long
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.forename: Paul
authors.initials: P
authors.lastname: Moss
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hubscher
authors.forename: Patricia F
authors.initials: PF
authors.lastname: Lalor
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured / Q000166:cytology* / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D022781:Hepatocytes / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000166:cytology / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000473:pathology; D008297:Male; D012016:Reference Values; D012494:Sampling Studies