CD71+幼红细胞的免疫抑制作用及其参与胆道闭锁的发病机制

Biliary atresia (BA) is the main indication for pediatric liver transplantation. The pathogenesis is largely unknown. It is known that possibility of RRV to induce BA phenotype decreases dramatically with time in one week after birth, accomplished by the significant decrease of CD71+erythroblasts in the liver within first week of life. It has been frequently shown that BA is associated with dysfunction of immune response in liver and around bile ducts. The most recent researches provide evidence that CD71+erythroblasts have immune suppressive functions in neonatal period. Our primitive results show that early depletion of CD71+erythroblasts prior to RRV infection could significantly improve BA phenotype. And the number of CD71+erythroblasts can quickly come up after depletion, exceeding the un-depleted group. The population of CD71+erythroblasts was negatively correlated with effector cells responsible for bile duct injury at all time points tested. Therefore, we speculated that, at earlier time after birth, liver is overpopulated by CD71+erythroblasts, which suppresses anti-virus immune cells activation to clear off the virus; at later time point after birth, CD71+erythroblasts decrease dramatically, being incapable of suppressing over-activation of pro-inflammatory response, leading to massive immune cells infiltration into the portal area and obstruction of extrahepatic bile ducts.

胆道闭锁（BA）是儿童终末期肝病和肝移植的首要病因，发病机制不完全明确。已有的研究证实，肝内、外胆管免疫功能异常是BA炎症进展的重要原因。动物模型中新生鼠对轮状病毒（RRV）易感性在出生一周内随日龄逐渐下降，而初生小鼠肝脏可检测大量CD71+幼红细胞，随后逐渐减少，第7天几乎消失。说明RRV的易感性下降与CD71+幼红细胞数量下降存在时间一致性。 最新研究和我们前期干预实验发现，新生儿体内CD71+幼红细胞具有免疫抑制功能。病毒感染鼠早期用特异抗体清除肝脏CD71+幼红细胞，可显著改善BA表型；而后CD71+幼红细胞迅速回升，使肝组织中促炎细胞显著减少。据此我们推测：出生早期，肝脏组织中存在大量CD71+幼红细胞，抑制免疫细胞激活，不能有效清除病毒；出生后期，肝组织CD71+幼红细胞迅速减少，不能有效抑制免疫系统的过度激活，导致胆管上皮细胞损伤和大量炎性细胞浸润，从而诱发BA。