IL-21与酒精性肝病免疫致病机制及疾病进展的关系研究

。It is important to find immunological factors that can predict the disease progression and clinical outcome of human alcoholic liver disease. Interleukin-21 (IL-21) was identified as a member of the type I cytokine family in 2000, and regulates central functions of immunity. Recent studies demonstrated that the IL-21 was responsible for the immune pathological progression of liver injury and HBV clearance in mice. However, there is no report on the role of IL-21 in human alcoholic liver disease. Our recent study found that IL-21-positive cells were enriched in the livers in the patients with alcoholic hepatitis. Analysis of IL-21-positive cells documented that livers from patients with alcoholic hepatitis exhibited more IL-21-positive cells infiltration than did livers from healthy subjects. In addition, we found IL-21 receptor (IL-21R) was highly expressed by hepatic neutrophil and hepatic stellate cells. As such, we hypothesize that hepatocyte necrosis or dynamic change of hepatic microenvironment initiate immune cells to release a lot of IL-21, which, in turn, activates hepatic neutrophil and hepatic stellate cells and then lead to liver damage and fibrosis during disease progressio.Recently, we design studies to test the hypothesis through cross- sectional study and longitudinal study. Our findings may provide novel evidences for the immunopathogenesis in alcoholic liver disease, identify the potential role of IL-21 in predicting disease progression and facilitate the rational development of immunotherapeutic strategies for limiting or blocking liver damage and fibrosis.

阐明酒精性肝病疾病进展的免疫学因子对于临床治疗具有重要意义。IL-21是2000年鉴定出的"γ链家族"新成员，近年来的研究提示：IL-21与肝脏疾病的发生密切相关。小鼠模型发现，成年鼠肝内IL-21水平是HBV被清除的关键原因。我们前期的研究显示：酒精性肝炎患者肝内多种免疫细胞可产生IL-21，且表达水平较健康人显著增加；肝内中性粒细胞和肝星状细胞高表达IL-21受体（IL-21R）。但IL-21与酒精性肝病免疫致病机制及疾病进展的关系，目前还不清楚。因此，我们假设酒精性肝病进展过程中，肝细胞坏死或肝内微环境改变是诱导IL-21大量产生的重要原因，后者进一步激活肝内中性粒细胞和肝星状细胞，导致肝脏的损伤和肝纤维化的发生、发展。目前我们正扩大病例证实上述假设。总之，本研究有利于阐明IL-21在酒精性肝病疾病进展中的免疫致病机制，并为今后针对IL-21设计新的抗酒精性肝病治疗靶点提出理论依据。

阐明酒精性肝病疾病进展的免疫学因子对于临床治疗具有重要意义。IL-21 是 2000 年鉴定出的"γ链家族"新成员，近年来的研究提示：IL-21与肝脏疾病的发生密切相关。小鼠模型发现，成年鼠肝内IL-21水平是HBV被清除的关键原因。我们前期的研究显示：酒精性肝炎患者肝内多种免疫细胞可分泌IL-21，且表达水平较健康人显著增加；同时肝内中性粒细胞和肝星状细胞可高表达IL-21 受体（IL-21R）。但IL-21与酒精性肝病免疫致病机制及疾病进展的关系，目前还不清楚。因此，我们假设酒精性肝病进展过程中，肝细胞坏死或肝内微环境改变是诱导IL-21大量产生的重要原因，后者进一步激活肝内中性粒细胞和肝星状细胞，导致肝脏的损伤和肝纤维化的发生、发展。本项目首先研究了IL-21是否与酒精性肝病患者疾病进展相关及探索其可能的机制。我们入组了68例酒精性肝病患者，同时入组了20例健康对照进行对比研究。结果发现：1）酒精性肝病患者血浆IL-21水平较健康人明显升高；2）体外实验发现：IL-21可明显促进肝星状细胞系LX-2细胞活化。与此同时，我们对酒精性肝病的临床进行了深入研究。1）提出了新的酒精性肝炎临床诊断标准：对目前国内外AH的临床诊断标准进行了分析，并提出相对明确和较易运用的一些临床诊断AH的建议；2）对住院的酒精性肝病患者临床特点进行分析：住院的酒精性肝病患者占住院肝病患者的比例在不断上升，须重视对男性人群和疾病的早期干预；3）对130例酒精性肝衰竭患者临床特点与预后进行分析：酒精性肝衰竭的常见诱发因素为感染和短期过量饮酒，凝血功能、肾功能和脑功能障碍是预后不良的重要预测因素；4）对酒精性肝硬化与乙肝、丙肝肝硬化及自身免疫性肝硬化患者临床特点进行对比分析：酒精性肝硬化在我国的发病率不断升高，且与乙型肝炎、丙型肝炎肝硬化和自身免疫性肝硬化相比有其独特的临床特点。