Tim-3/galectin-9通路在乙肝相关性急性肝衰竭患者单核细胞功能失活中的作用研究

The immune dysfunction stage has been associated with poor outcomes of patients with HBV related acute liver failure (HBV-ALF). Functional de-activation of monocytes play a important role in immune dysfunction. However, little is known about the molecular mechanisms underlying monocyte dysfunction. Recent evidence suggested a novel molecular-Tim-3 might regulate the function of monocytes. We previously found Tim-3 was expressed at much lower level in patients with HBV-ALF than chronic Hepatitis B (CHB) patients and health controls. These results indicated the inhibition of Tim-3/ galectin-9 might be related with monocyte dysfunction. However, it is unknown which aspect of monocyte functionality (such as antigen presentation, phagocytosis, cytokine production and so on) was affected by this pathway and the exact mechanism underlying this regulation. Thus, we isolated monocytes from HBV-ALF patients and performed in vitro experiments to investigated the molecular mechanisms underlying functional de-activation of monocytes. It would provide insight into the pathogenesis of HBV- ALF and pave way to novel strategies for prognostification and treatment.

慢乙肝急性肝衰竭（HBV-ALF）后期的免疫抑制状态与其预后密切相关，而单核细胞功能失活在免疫抑制过程中扮演了重要的角色，但其功能失活的分子机制尚不明确。研究显示Tim-3/ galectin-9通路作为新发现的免疫调控通路很可能参与了对单核细胞的功能调控。我们在前期研究中发现与健康对照组和慢乙肝组相比，HBV-ALF患者CD14+的单核细胞TIM-3表达明显降低，且与HLA-DR表达呈正相关，提示TIM-3/ galectin-9通路可能与HBV-ALF患者单核细胞功能失活有关，但是在这一过程中该通路对单核细胞抗原提呈、吞噬、细胞因子分泌等免疫功能的具体影响和调控过程中所涉及的信号通路等关键问题都处于研究的空白领域。我们拟对HBV-ALF患者单核细胞进行分离和检测并结合体外细胞功能实验，深入研究患者单核细胞功能失活的分子机制，为明确HVB-ALF的免疫病理机制和治疗提供新的思路。

终末期重症肝病患者易发生细菌感染(其中以革兰氏阴性杆菌为主)，严重细菌感染(合并肾功能不全、低血压等器官衰竭)的风险显著高于一般人群。项目组基于临床研究结果，探讨其可能机制，发现患者的单核细胞在内毒素刺激后分泌的炎症细胞因子水平远高于代偿期肝硬化及健康人群，是导致患者细菌感染重症化的重要机制。项目组通过流式细胞术检测进一步发现相对于代偿期肝硬化及健康人群，终末期重症肝病患者单核细胞表面Tim-3分子表达明显降低，而通过体内及体外实验表明患者体内的内毒素血症是导致单核细胞Tim-3分子表达下降的原因。通过体外实验表明Tim-3分子表达下降与单核细胞对内毒素的敏感性密切相关，阻断Tim-3分子可明显增加单核细胞在内毒素刺激后分泌的细胞因子水平。进一步研究发现Tim-3通路可能通过作用于p38 MAPK与TLR-4/LPS信号通路产生交互作用。该研究揭示了终末期重症肝病患者单核细胞功能异常的新机制，为患者细菌感染重症化的治疗提供新的靶点。

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