【作者】 刘慧；

【导师】 张学光；

【作者基本信息】 苏州大学 ， 免疫学， 2006， 硕士

【摘要】 CD40是属于肿瘤坏死因子受体(TNFR)超家族的Ⅰ型跨膜糖蛋白，表达在B细胞、单核／巨噬细胞、树突状细胞(DCs)等多种类型细胞上，它与其配体CD40L(CD154)结合后在免疫应答、免疫调节以及炎症反应等生理、病理过程中发挥重要作用。可溶性CD40(sCD40)与膜型CD40(mCD40)在体内呈现共存现象，具有与CD40L结合的生物学活性，参与免疫应答的调节，可能是mCD40-CD40L相互作用的天然拮抗剂。正常人血清低表达sCD40分子，业已发现肾脏病、肝脏病、阿尔茨海默病、血液病等多种疾病患者血清sCD40水平明显升高，且显示与临床病理或疾病进程相关。体外实验显示活化B细胞能够释放sCD40，但是sCD40是否还有其他细胞来源以及sCD40的产生机制和临床意义尚待进一步研究。 本研究第一部分系统分析了各种肝脏疾病患者血清中sCD40的表达及其与临床生化指标和病程发展的相关性。实验结果显示，sCD40在各种肝病患者(急性肝炎、重型肝炎、肝硬化和原发性肝癌)血清较健康人异常升高(P＜0.001)，而且其水平与患者年龄呈弱负性相关。急性肝炎患者血清sCD40浓度与丙氨酸氨基转移酶(ALT)、天门冬酸氨基转移酶(AST)水平显著正相关(r=0.59，p＜0.001：r=0.34，p＜0.01)，随着肝功能恢复正常、病情好转，其血清sCD40水平逐渐下降：急性肝炎男性较女性患者血清sCD40显著升高(P=0.026)，提示性激素可能影响sCD40的产生。重型肝炎死亡患者sCD40浓度显著高于存活患者(P=0.022)，而且并发肝性脑病患者显著升高(P=0.018)，由此提示重型肝炎患者发病初期血清sCD40浓度越高，随病情进展患者并发肝性脑病和死亡的危险性越大，患者血清中持续存在高水平的sCD40，提示预后不良。 业已有研究显示B细胞释放的sCD40是由TNF-α转换酶(TACE，ADAM17)或其他金属蛋白酶(MP)水解mCD40所致。课题第二部分进一步探讨了肝癌患者更多还原

【Abstract】 CD40, a type I transmembrane glycoprotein, belongs to the tumor necrosis factor receptor (TNFR) superfamily, and is expressed on a wide range of cells such as B cells, monocytes/macrophages, dendritic cells (DCs) .The interaction of CD40 with its ligand CD40L(CD 154),expressed predominantly on activated T cells,mast cells and basophils,is critical in the regulation of immune response and expression of inflammatory mediators,such as cytokines,chemokines and adhesion molecules.The soluble form of CD40(sCD40),which co-exists with the membrane-anchored form(mCD40) in vivo,is able to bind membrane CD40L and viewed as a natural antagonist of mCD40-CD40L interaction. Low levels of circulating sCD40 have been detected in the blood of normal donors and elevated levels of sCD40 have been reported in patients with renal failure,liver diseases,Alzheimer disease and hematologic malignancies, and its clinical signifances have been demonstrated, such as its values in diagnosis and prognosis of disease. Although it has been showed that activated B cells release sCD40 in vitro, the ability of other cell types to release sCD40 and its mechanisms of generation in vivo has not been established.In the current study we investigated circulating levels and clinical signifcance of sCD40 in patients with liver disease,and demonstrated the mechanisms of sCD40 generation in hepatocellular carcinoma(HCC).Soluble CD40 was measured with an enzyme-linked immunosorbent assay(ELISA).Compared with the low levels of sCD40 in the sera of normal controls,the sera levels of sCD40 were significantly higher in patients with different types of liver disease,including acute hepatitis,hepatitis gravis,hepatocirrhosis and primary carcinoma of the liver,and has negative correlation更多还原