Dendritic cells regulate natural killer cell activation and epithelial injury in experimental biliary atresia.
Dendritic cells regulate natural killer cell activation and epithelial injury in experimental biliary atresia.
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DOI：
10.1126/scitranslmed.3002069
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发表时间：
2011-09-28
影响因子：
17.1
通讯作者：
Bezerra JA
中科院分区：
文献类型：
--
作者：
Saxena V;Shivakumar P;Sabla G;Mourya R;Chougnet C;Bezerra JA
胆道闭锁是儿童最常见的胆道疾病。在婴儿期，新生儿免疫系统的特发性激活以胆管上皮为目标，阻塞胆管，破坏肝脏和肠道之间的解剖连续性。在这里，我们使用病毒诱导的新生小鼠胆道闭锁模型来追踪常驻浆细胞样树突状细胞(PDCs)和常规树突状细胞(CDCs)的致病机制。我们发现pDC是新生小鼠肝脏中最丰富的DC细胞，我们在诊断时观察到婴儿肝脏中的pDC。在新生小鼠的肝脏中，CDC在出生后不久自发过度表达共刺激分子CD80，pDC在病毒攻击下产生细胞因子白介素15(IL-15)。T淋巴细胞的增殖和自然杀伤细胞的激活都需要两种亚型的DC。在小鼠体内，通过耗尽pDC或阻断IL-15信号来破坏这一细胞网络可以防止上皮损伤，维持胆管的解剖连续性，并促进长期生存。这些发现确定了胆道损伤的细胞触发因素，并对未来阻止胆道闭锁和肝病进展的治疗具有指导意义。
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.
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