Cytokine-Producing B Cells Promote Immune-Mediated Bile Duct Injury in Murine Biliary Atresia

Hepatology. 2018 Nov;68(5):1890-1904. doi: 10.1002/hep.30051. Epub 2018 Jul 10.


Biliary atresia (BA) is a neonatal T cell-mediated, inflammatory, sclerosing cholangiopathy. In the rhesus rotavirus (RRV)-induced neonatal mouse model of BA (murine BA), mice lacking B cells do not develop BA, and the lack of B cells is associated with loss of T-cell and macrophage activation. The aim of this study was to determine the mechanism of B cell-mediated immune activation (antigen presentation versus cytokine production) in murine BA. Normal neonatal B cells in the liver are predominantly at pro-B and pre-B cellular development. However, BA mice exhibit a significant increase in the number and activation status of mature liver B cells. Adoptively transferred B cells into RRV-infected, B cell-deficient mice were able to reinstate T-cell and macrophage infiltration and biliary injury. Nonetheless, neonatal liver B cells were incompetent at antigen presentation to T cells. Moreover, 3-83 immunoglobulin transgenic mice, in which B cells only present an irrelevant antigen, developed BA, indicating a B-cell antigen-independent mechanism. B cells from BA mice produced a variety of innate and adaptive immune cytokines associated with immune activation. In vitro trans-well studies revealed that BA B cells secreted cytokines that activated T cells based on increased expression of T-cell activation marker cluster of differentiation 69. Conclusion: Neonatal liver B cells are highly activated in murine BA and contribute to immune activation through production of numerous cytokines involved in innate and adaptive immunity; this work provides increased knowledge on the capacity of neonatal B cells to contribute to an inflammatory disease through cytokine-mediated mechanisms, and future studies should focus on targeting B cells as a therapeutic intervention in human BA.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity / immunology
  • Adolescent
  • Animals
  • Animals, Newborn
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • Bile Ducts / immunology
  • Bile Ducts / pathology*
  • Biliary Atresia / immunology*
  • Cell Culture Techniques
  • Child
  • Child, Preschool
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Liver / immunology
  • Liver / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Sequence Analysis, RNA
  • Spleen / immunology


  • Cytokines