Recruitment mechanisms of primary and malignant B cells to the human liver

Authors

  • Shishir Shetty,

    Corresponding author
    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
    • Center for Liver Research, 5th Floor IBR, School of Immunity and Infection, University of Birmingham, Birmingham, UK B15 2TT
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    • fax: +44121 4158701

  • Tony Bruns,

    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
    2. Department of Internal Medicine II, Division of Gastroenterology, Hepatology, and Infectious Diseases, Jena University Hospital, Jena, Germany
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    • These authors contributed equally to this study.

  • Christopher J. Weston,

    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
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  • Zania Stamataki,

    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
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  • Ye H. Oo,

    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
    2. National Institute for Health Research Biomedical Research Unit in Liver Disease, University Hospital Birmingham, Birmingham, United Kingdom
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  • Heather M. Long,

    1. School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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  • Gary M. Reynolds,

    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
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  • Guy Pratt,

    1. School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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  • Paul Moss,

    1. School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
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  • Sirpa Jalkanen,

    1. MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
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  • Stefan G. Hubscher,

    1. School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
    2. Department of Cellular Pathology, University Hospital Birmingham, Birmingham, United Kingdom
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  • Patricia F. Lalor,

    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
    2. National Institute for Health Research Biomedical Research Unit in Liver Disease, University Hospital Birmingham, Birmingham, United Kingdom
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  • David H. Adams

    1. Center for Liver Research, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
    2. National Institute for Health Research Biomedical Research Unit in Liver Disease, University Hospital Birmingham, Birmingham, United Kingdom
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  • Potential conflict of interest: Nothing to report.

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. Conclusion: 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. (HEPATOLOGY 2012)

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