可溶性CD40在肝脏疾病中的表达及其临床意义
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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
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
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
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
引文
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1. Schonbeck U. and P Libby.. The CD40/CD40L receptor/ligand dyad. Cell Mol Life Sci, 2001; 58(1): 4-43
2. van Kooten C., Gaillard C., Galizzi JP., et al. B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40. Eur. J. Immunol. 1994; 24(4): 787-792
3. Bjorck P., Braesch-Andersen S, and Paulie S. Antibodies to distinct epitopes on the CD40 molecule co-operate in stimulation and can be used for the detection of soluble CD40. Immunology. 1994; 83(3): 430-437
4. Contin C., Pitard V., Delmas Y., et al. Potential role of soluble CD40 in the humoral immune response impairment of uraemic patients. Immunology. 2003; 110(1): 131-140
5. Schwabe RF., Engelmann H., Hess S., et al. Soluble CD40 in the serum of healthy donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients. Clin Exp Immunol. 1999; 117(1): 153-158
6. Schmilovitz-Weiss H., Belinki A., Pappo O., et al. Role of circulating soluble CD40 as an apoptotic marker in liver disease. Apoptosis. 2004; 9(2): 205-210
7. Hock BD., McKenzie JL., Patton NW., et al. Circulating levels and clinical significance of soluble CD40 in patients with hematologic malignancies. Cancer. 2006; 106(10): 2148-2157
8. Sugimoto K.,Shiraki K.,Ito T., et al. Expression of functional CD40 in human hepatocellular carcinoma. Hepatology. 1999; 30(4): 920-926
9. Holub M., Zakeri SM., Lichtenberger C., et al. Heterogeneous expression and regulation of CD40 in human hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2003; 15(2): 119-126
10. Afford SC., Randhawa S., Eliopoulos AG., et al. CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med.1999; 189(2): 441-446
11. Leifeld L., Trautwein C., Dumuolin FL., et al. Enhanced expression of CD80 (BT-1), CD86(B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure. Am J Pathol. 1999; 154(6): 1711- 1720
12．病毒性肝炎防治方案．中华传染病杂志，2001；19(1)：56-62
13．中国抗癌协会肝癌专业委员会．原发性肝癌的临床诊断与分期标准．中华肝脏病杂志．2001；9(6)：324
14. Zhou ZH., Wang JF., Wang YD., et al. An agonist anti-human CD40 monoclonal antibody that induces dendritic cell formation and maturation and inhibits proliferation of a myeloma cell line. Hybridoma. 1999; 18(6): 471-478
15. Zhuang Y., Huang J., Zhou Z., et al. A novel blocking monoclonal antibody recognizing a distinct epitope of human CD40 molecule. Tissue Antigens.2005; 65(1): 81-87
16. Levine SJ. Mechanisms of soluble cytokine receptor generation. J Immunol. 2004; 173(9): 5343-5348
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20. Zhou F., Ajuebor MN., Beck PL., et al. CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis. Hepatology. 2005; 42(2): 372-380
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22. Jablonska E., Kiersnowska-Rogowska B., Rogowski F., et al. TNF family molecules in the serum of patients with B-cell chronic lymphocytic leukemia (B-CLL). Leuk Lymphoma. 2005; 46(9): 1307-1312
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24. Holler N., Kataoka T., Bodmer JL., et al. Development of improved soluble inhibitors of FasL and CD40L based on oligomerized receptors. J Immunol Methods. 2000; 237(1-2): 159-173
25. Johar D., Roth JC., Bay GH., et al. Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer. Rocz Akad Med Bialymst, 2004; 49: 31-39
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1. Levine SJ. Mechanisms of soluble cytokine receptor generation. J Immunol. 2004; 173(9): 5343-5348
2. Contin C., Pitard V., Itai T., et al. Membrane-anchored CD40 is processed by the tumor necrosis factor-alpha-converting enzyme. Implications for CD40 signaling. J Biol Chem. 2003; 278(35): 32801-32809
3. Tone M., Tone Y., Fairchild PJ., et al. Regulation of CD40 function by its isoforms generated through alternative splicing. Proc Natl Acad Sci. 2001 ;98(4): 1751-1756
4. Zhou ZH.,Wang JF.,Wang YD.,et al. An agonist anti-human CD40 monoclonal antibody that induces dendritic cell formation and maturation and inhibits proliferation of a myeloma cell line. Hybridoma. 1999; 18(6): 471-478
5. Zhuang Y., Huang J.,Zhou Z., et al. A novel blocking monoclonal antibody recognizing a distinct epitope of human CD40 molecule. Tissue Antigens.2005;65(1):81-87
6. Solomon KA., Pesti N., Wu, G., et al. Cutting edge: a dominant negative form of TNF-alpha converting enzyme inhibits pro TNF and TNFRII secretion. J. Immunol. 1999; 163(8): 4105-4108
7. Hansen HP., Dietrich S., Kisseleva T., et al. CD30 shedding from Karpas 299 lymphoma cells is mediated by TNF-alpha-converting enzyme. J. Immunol. 2000; 165(12):6703-6709
8. Holler N., Kataoka T., Bodmer JL., et al. Development of improved soluble inhibitors of FasL and CD40L based on oligomerized receptors. J Immunol Methods. 2000;237(1-2):159-173
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3. Holub M.,Zakeri SM.,Lichtenberger C., et al. Heterogeneous expression and regulation of CD40 in human hepatocellular carcinoma.Eur J Gastroenterol Hepatol.2003,15: 119-126.
4. Afford SC.,Randhawa S.,Eliopoulos AG., et al.CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med. 1999, 189: 441-446.
5. Gaweco AS., Wiesner RH.,Yong S., et al. CD40L (CD154) expression in human liver allografts during chronic ductopenic rejection. Liver Transpl Surg. 1999,5: 1-7.
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8. Kimura K., Kakimi K., Wieland S.,et al. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. J Immunol. 2002, 169: 5188-5195.
9. Leifeld L.,Trautwein C,,Dumuolin FL.,et al. Enhanced expression of CD80 (B7-1), CD86 (B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure.Am J Pathol. 1999, 154: 1711-1720.
10. Zhou F.,Ajuebor MN.,Beck PL.,et al.CD154-CD40 Interactions drive hepatocyte apoptosis in murine fulminant hepatitis. Hepatology. 2005, 42: 372-380
11. Adachi M.,Higushi H.,Miura S., et al. Blocking of CD40/CD40L and CD28/B7 interaction prevents the concanavalin A-induced liver injury in BALB/c mouse through the inhibition of interleukin 12 production. Hepatology. 1998,324A
12. van Kooten C.,Gaillard C.,Galizzi JP., et al. B cell regulate expression of D40 ligand on activated T cells by lowering mRNA level and through the release of soluble CD40.Eur J Immunol. 1994,24: 787-792
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14. Contin C.,Pitard .V,Itai T., et al. Membrane-anchored CD40 Is Processed by the Tumor Necrosis Factor-α-converting Enzyme. J Biol Chem. 2003,278: 32801-32809
15. Ding X.,Yang LY.,Huang GW., et al. ADAM17 mRNA expression and pathological features of hepatocellular carcinoma. World J Gastroenterol. 2004,10: 2735-2739
16. Schmitz V.,Barajas M.,Wang L., et al. Adenovirus-mediated CD40 ligand gene therapy in a rat model of orthotopic hepatocellular carcinoma.Hepatology. 2001,34: 72-81.
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48．庄羽美，黄建安，朱华亭，等．可溶性CD40酶联检测试剂盒的研制及其检测的临床意义．中国免疫学杂志．2004；20(8)：563-566
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1. Schonbeck U. and P Libby.. The CD40/CD40L receptor/ligand dyad. Cell Mol Life Sci, 2001; 58(1): 4-43
2. van Kooten C., Gaillard C., Galizzi JP., et al. B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40. Eur. J. Immunol. 1994; 24(4): 787-792
3. Bjorck P., Braesch-Andersen S, and Paulie S. Antibodies to distinct epitopes on the CD40 molecule co-operate in stimulation and can be used for the detection of soluble CD40. Immunology. 1994; 83(3): 430-437
4. Contin C., Pitard V., Delmas Y., et al. Potential role of soluble CD40 in the humoral immune response impairment of uraemic patients. Immunology. 2003; 110(1): 131-140
5. Schwabe RF., Engelmann H., Hess S., et al. Soluble CD40 in the serum of healthy donors, patients with chronic renal failure, haemodialysis and chronic ambulatory peritoneal dialysis (CAPD) patients. Clin Exp Immunol. 1999; 117(1): 153-158
6. Schmilovitz-Weiss H., Belinki A., Pappo O., et al. Role of circulating soluble CD40 as an apoptotic marker in liver disease. Apoptosis. 2004; 9(2): 205-210
7. Hock BD., McKenzie JL., Patton NW., et al. Circulating levels and clinical significance of soluble CD40 in patients with hematologic malignancies. Cancer. 2006; 106(10): 2148-2157
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9. Holub M., Zakeri SM., Lichtenberger C., et al. Heterogeneous expression and regulation of CD40 in human hepatocellular carcinoma. Eur J Gastroenterol Hepatol. 2003; 15(2): 119-126
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11. Leifeld L., Trautwein C., Dumuolin FL., et al. Enhanced expression of CD80 (BT-1), CD86(B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure. Am J Pathol. 1999; 154(6): 1711- 1720
12．病毒性肝炎防治方案．中华传染病杂志，2001；19(1)：56-62
13．中国抗癌协会肝癌专业委员会．原发性肝癌的临床诊断与分期标准．中华肝脏病杂志．2001；9(6)：324
14. Zhou ZH., Wang JF., Wang YD., et al. An agonist anti-human CD40 monoclonal antibody that induces dendritic cell formation and maturation and inhibits proliferation of a myeloma cell line. Hybridoma. 1999; 18(6): 471-478
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20. Zhou F., Ajuebor MN., Beck PL., et al. CD154-CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis. Hepatology. 2005; 42(2): 372-380
21．曾雪涛．肿瘤免疫．见：陈慰峰主编．医学免疫学．第3版．北京：人民卫生出社，2002．231-232
22. Jablonska E., Kiersnowska-Rogowska B., Rogowski F., et al. TNF family molecules in the serum of patients with B-cell chronic lymphocytic leukemia (B-CLL). Leuk Lymphoma. 2005; 46(9): 1307-1312
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26．王静艳，穆桂玲，刘沛，等．乙型重型肝炎基因变异与免疫异常的关系．中华传染病杂志，2001；19(2)：73-76
1. Levine SJ. Mechanisms of soluble cytokine receptor generation. J Immunol. 2004; 173(9): 5343-5348
2. Contin C., Pitard V., Itai T., et al. Membrane-anchored CD40 is processed by the tumor necrosis factor-alpha-converting enzyme. Implications for CD40 signaling. J Biol Chem. 2003; 278(35): 32801-32809
3. Tone M., Tone Y., Fairchild PJ., et al. Regulation of CD40 function by its isoforms generated through alternative splicing. Proc Natl Acad Sci. 2001 ;98(4): 1751-1756
4. Zhou ZH.,Wang JF.,Wang YD.,et al. An agonist anti-human CD40 monoclonal antibody that induces dendritic cell formation and maturation and inhibits proliferation of a myeloma cell line. Hybridoma. 1999; 18(6): 471-478
5. Zhuang Y., Huang J.,Zhou Z., et al. A novel blocking monoclonal antibody recognizing a distinct epitope of human CD40 molecule. Tissue Antigens.2005;65(1):81-87
6. Solomon KA., Pesti N., Wu, G., et al. Cutting edge: a dominant negative form of TNF-alpha converting enzyme inhibits pro TNF and TNFRII secretion. J. Immunol. 1999; 163(8): 4105-4108
7. Hansen HP., Dietrich S., Kisseleva T., et al. CD30 shedding from Karpas 299 lymphoma cells is mediated by TNF-alpha-converting enzyme. J. Immunol. 2000; 165(12):6703-6709
8. Holler N., Kataoka T., Bodmer JL., et al. Development of improved soluble inhibitors of FasL and CD40L based on oligomerized receptors. J Immunol Methods. 2000;237(1-2):159-173
1. Cruickshank SM.,Southgate J.,Selby PJ., et al. Expression and cytokine regulation of immune recognition elements by normal human biliary epithelial and established liver cell lines in vitro.J Hepatol. 1998,29:550-558.
2. Sugimoto K.,Shiraki K.,Ito T., et al.Expression of functional CD40 in human hepatocellular carcinoma,Hepatology. 1999,30: 920-926.
3. Holub M.,Zakeri SM.,Lichtenberger C., et al. Heterogeneous expression and regulation of CD40 in human hepatocellular carcinoma.Eur J Gastroenterol Hepatol.2003,15: 119-126.
4. Afford SC.,Randhawa S.,Eliopoulos AG., et al.CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection. J Exp Med. 1999, 189: 441-446.
5. Gaweco AS., Wiesner RH.,Yong S., et al. CD40L (CD154) expression in human liver allografts during chronic ductopenic rejection. Liver Transpl Surg. 1999,5: 1-7.
6. Burgio VL.,Ballardini G.,Artini M.,et al.Expression of co-stimulatory molecules by Kupffer cells in chronic hepatitis of hepatitis C etiology. Hepatology. 1998, 7: 1600-1606.
7. Kunitani H., Shimizu Y., Murata H.,et al.Phenotypic analysis of circulating and intrahepatic dendritic cell subsets in patients with chronic liver diseases.J Hepatol.2002,36: 734-741
8. Kimura K., Kakimi K., Wieland S.,et al. Activated intrahepatic antigen-presenting cells inhibit hepatitis B virus replication in the liver of transgenic mice. J Immunol. 2002, 169: 5188-5195.
9. Leifeld L.,Trautwein C,,Dumuolin FL.,et al. Enhanced expression of CD80 (B7-1), CD86 (B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure.Am J Pathol. 1999, 154: 1711-1720.
10. Zhou F.,Ajuebor MN.,Beck PL.,et al.CD154-CD40 Interactions drive hepatocyte apoptosis in murine fulminant hepatitis. Hepatology. 2005, 42: 372-380
11. Adachi M.,Higushi H.,Miura S., et al. Blocking of CD40/CD40L and CD28/B7 interaction prevents the concanavalin A-induced liver injury in BALB/c mouse through the inhibition of interleukin 12 production. Hepatology. 1998,324A
12. van Kooten C.,Gaillard C.,Galizzi JP., et al. B cell regulate expression of D40 ligand on activated T cells by lowering mRNA level and through the release of soluble CD40.Eur J Immunol. 1994,24: 787-792
13. Schmilovitz-Weiss H.,Belinki A., Pappo O., et al. Role of circulating soluble CD40 as an apoptotic marker in liver disease.Apoptosis 2004,9: 205-210
14. Contin C.,Pitard .V,Itai T., et al. Membrane-anchored CD40 Is Processed by the Tumor Necrosis Factor-α-converting Enzyme. J Biol Chem. 2003,278: 32801-32809
15. Ding X.,Yang LY.,Huang GW., et al. ADAM17 mRNA expression and pathological features of hepatocellular carcinoma. World J Gastroenterol. 2004,10: 2735-2739
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