title: Dendritic cells regulate natural killer cell activation and epithelial injury in experimental biliary atresia.
abstract: Biliary atresia is the most common cholangiopathy of childhood. During infancy, an idiopathic activation of the neonatal immune system targets the biliary epithelium, obstructs bile ducts, and disrupts the anatomic continuity between the liver and the intestine. Here, we use a model of virus-induced biliary atresia in newborn mice to trace the initiating pathogenic disease mechanisms to resident plasmacytoid (pDCs) and conventional (cDCs) dendritic cells. We found pDCs to be the most abundant DC population in the livers of newborn mice, and we observed pDCs in the livers of infants at the time of diagnosis. In the livers of newborn mice, cDCs spontaneously overexpressed the costimulatory molecule CD80 soon after birth, and pDCs produced the cytokine interleukin-15 (IL-15) in response to a virus insult. Both subtypes of primed DCs were required for the proliferation of T lymphocytes and the activation of natural killer cells. Disruption of this cellular network by depletion of pDCs or blockade of IL-15 signaling in mice in vivo prevented epithelial injury, maintained anatomic continuity of the bile duct, and promoted long-term survival. These findings identify cellular triggers of biliary injury and have implications for future therapies to block the progression of biliary atresia and liver disease.
authors.affiliation: Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3039, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Saxena
authors.forename: Pranavkumar
authors.initials: P
authors.lastname: Shivakumar
authors.forename: Gregg
authors.initials: G
authors.lastname: Sabla
authors.forename: Reena
authors.initials: R
authors.lastname: Mourya
authors.forename: Claire
authors.initials: C
authors.lastname: Chougnet
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bezerra
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018122:B7-1 Antigen / Q000378:metabolism; D001656:Biliary Atresia / Q000150:complications / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D049109:Cell Proliferation; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007223:Infant; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D053647:Receptors, Interleukin-15 / Q000276:immunology; D012401:Rotavirus / Q000276:immunology; D012400:Rotavirus Infections / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D018122:B7-1 Antigen; D019409:Interleukin-15; D053647:Receptors, Interleukin-15