Research ArticleBiliary Atresia

Dendritic Cells Regulate Natural Killer Cell Activation and Epithelial Injury in Experimental Biliary Atresia

Science Translational Medicine  28 Sep 2011:
Vol. 3, Issue 102, pp. 102ra94
DOI: 10.1126/scitranslmed.3002069

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Unblocking the Road to Treating Biliary Atresia

Biliary atresia is the most common cause of liver cirrhosis in young children. With onset of symptoms in the first few weeks of life, the disease is triggered by activation of the neonatal immune system, which targets the epithelial cells that line the bile ducts. Immune system activation is followed rapidly by fibrosis and obstruction of the bile duct lumen. Cessation of bile flow from the liver to the intestines produces jaundice and clay-colored stools within a few weeks of birth. The most effective treatment to restore bile flow is surgical intervention to remove the damaged bile duct and to create a new conduit using a segment of the small intestine. Despite surgery and improved bile flow, liver disease progresses to end-stage cirrhosis in most children. The development of new therapies to block progression to cirrhosis has been hampered by our limited knowledge of the earliest events underpinning biliary atresia pathogenesis. To identify the early triggers of this disease, Saxena et al. used a neonatal mouse model in which biliary atresia is induced by infection with rotavirus. Because dendritic cells (DCs) are known to be important for priming innate and adaptive immunity, Saxena and colleagues first examined liver DCs in early mouse postnatal life and after rotavirus infection. They found spontaneous expression of the activation marker CD80 in a subtype of DCs called conventional DCs (cDCs) and discovered that the rotavirus preferentially infected plasmacytoid DCs (pDCs) in early postnatal life. A potential role for DCs in the pathogenesis of the human disease was suggested by gene expression and immunostaining of liver biopsies from infants diagnosed with biliary atresia. These analyses showed an increased number of activated pDCs in the portal tracts, which contain small bile duct branches that collect bile for drainage into the intestine. To directly explore whether pDCs are involved in bile duct injury, the investigators used cocultures of DCs, T lymphocytes, and natural killer (NK) cells to demonstrate that pDCs produce the cytokine interleukin-15 (IL-15) and that both DC subtypes are required for the proliferation of T lymphocytes and the activation of NK cells. Notably, disruption of this cellular network by depletion of pDCs or blockade of IL-15 signaling in neonatal mice infected with rotavirus prevented injury to bile duct epithelial cells, maintained anatomic continuity of bile ducts, and promoted long-term survival of the animals. These findings identify DCs as cellular triggers of biliary injury. The presence of activated DCs in the livers of human infants at the time of diagnosis with biliary atresia points to DCs and IL-15 as potential therapeutic targets that could be blocked to halt the progression of liver disease in these infants.