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Cytokine‐Producing B Cells Promote Immune‐Mediated Bile Duct Injury in Murine Biliary Atresia
Author(s) -
Bednarek Joseph,
Traxinger Brianna,
Brigham Dania,
Roach Jonathan,
Orlicky David,
Wang Dong,
Pelanda Roberta,
Mack Cara L.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30051
Subject(s) - biology , immune system , cd40 , cytokine , immunology , t cell , b cell , antigen presentation , acquired immune system , b 1 cell , antigen , antigen presenting cell , cytotoxic t cell , antibody , in vitro , biochemistry
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.