自身免疫性肝炎患者肝组织程序性死亡受体1表达及其临床意义探讨
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摘要
目的观察自身免疫性肝炎(AIH)患者肝组织程序性死亡受体1(PD-1)表达情况及其临床意义。方法 2015年5月～2017年4月我院收治的AIH患者68例(活动期48例,缓解期20例),在超声引导下使用BARD一次性全自动活检枪行肝穿刺活检术取得肝组织。另选择同期肝血管瘤患者13例,经手术取得肝组织。采用ABC法检测肝组织PD-1表达。比较肝组织PD-1表达情况并采用Pearson相关分析其与血生化学和血清学指标的相关性。结果 48例活动期AIH患者血清TBIL、AST、ALT、ALP和GGT水平分别为(72.1±48.9)μmol/L、(243.1±170.4) U/L、(345.3±217.7) U/L、(154.3±94.6) U/L和(86.5±43.5) U/L,显著高于20例缓解期患者【分别为(14.8±4.2)μmol/L、(28.3±8.7) U/L、(27.6±8.8) U/L、(73.3±51.3) U/L和(71.3±27.3) U/L,P<0.05】;活动期患者血清GLO和Ig G水平分别为(34.3±11.3) g/L和(23.2±7.5) g/L,显著高于缓解期【分别为(30.7±10.2)g/L和(11.7±4.6) g/L,P<0.05】;68例AIH患者肝组织PD-1表达阳性率为(13.61±6.87)%,显著高于对照组的(2.25±0.68)%(P<0.05),而48例活动期患者肝组织PD-1表达阳性率为(16.56±7.81)%,显著高于缓解期组的(6.56±3.21)%(P<0.05);48例活动期患者肝组织界面性肝炎为93.75%,淋巴细胞浸润为89.58%,单管破坏性炎症为6.25%,而20例缓解期患者无界面性肝炎、淋巴细胞浸润或单管破坏性炎症表现;活动期AIH患者肝组织PD-1表达阳性率与血清TBIL (r=0.996,P<0.001)、AST(r=0.989,P<0.001)、ALT(r=0.995,P<0.001)、ALP(r=0.998,P<0.001)、GGT(r=0.995,P<0.001)、GLO(r=0.996,P<0.001)和Ig G(r=0.997,P<0.001)均呈正相关,在缓解期AIH患者,肝组织PD-1表达阳性率与血清TBIL (r=0.999,P<0.001)、AST(r=0.999,P<0.001)、ALT(r=0.999,P<0.001)、ALP(r=0.999,P<0.001)、GGT(r=0.999,P<0.001)和Ig G(r=0.999,P<0.001)呈正相关(P<0.001)。结论 AIH患者肝组织PD-1表达增强,与肝组织炎症活动度密切相关,其参与肝损伤的作用机制还需要进一步探讨。
Objective To investigate the expression of programmed death receptor 1(PD-1) in liver tissue of patients with autoimmune hepatitis(AIH) and its clinical implications. Methods 68 patients with AIH(48 active and 20 at remission) were admitted to our hospital between May 2015 and April 2017,and liver biopsies were performed. 13 patients with hepatic hemangioma were included and their liver tissues were obtained by surgery for control. The expression of PD-1 in liver tissues was detected by immunochemical staining. The correlation between the positive expression of PD-1 in liver tissues and serum liver function indexes in patients with AIH was analyzed. Results Serum bilirubin,AST, ALT,ALP and GGT levels in 48 patients with active AIH were(72.1±48.9) μmol/L,(243.1±170.4) U/L,(345.3±217.7) U/L,(154.3±94.6) U/L and(86.5±43.5) U/L,much higher than(14.8±4.2) μmol/L,(28.3±8.7) U/L,(27.6±8.8) U/L,(73.3±51.3) U/L and(71.3±27.3) U/L in20 patients at remission(all P<0.05),and serum globulin and IgG levels were(34.3±11.3) g/L and(23.2±7.5)g/L,much higher than(30.7±10.2) g/L and(11.7±4.6)g/L in patients at remission(P<0.05);the positive rate of PD-1 expression in liver tissues of 68 patients with AIH was(13.61 ±6.87)%,significantly higher than(2.25±0.68)% in patients with hepatic hemangioma(P<0.05),and the positive rate in 48 patients with active AIH was(16.56±7.81) %,significantly higher than(6.56±3.21)% in patients at remission(P<0.05);the incidences of interfacial inflammation,lymphocyte invasion and single tube destructive inflammation in 48 patients with active AIH were 93.75%,89.58% and 6.25%;the PD-1 expressions in liver tissues of patients with active AIH were positively correlated to serum bilirubin(r=0.996,P<0.001),AST(r=0.989,P<0.001),ALT(r=0.995,P<0.001),ALP(r=0.998,P<0.001),GGT(r=0.995,P<0.001),GLO(r=0.996,P<0.001) and IgG levels(r=0.997,P<0.001),and they were positively correlated to serum bilirubin(r=0.999,P<0.001),AST(r=0.999,P<0.001),ALT(r=0.999,P<0.001),ALP(r=0.999,P<0.001),GGT(r=0.999,P<0.001) and IgG levels(r=0.999,P<0.001) in patients at remission. Conclusion The expression of PD-1 in liver tissues of patients with AIH is strongly intensified and positively correlated to hepatic activity index,and the mechanism by which it take part in the pathogenesis of AIH needs further investigation.
Objective To investigate the expression of programmed death receptor 1(PD-1) in liver tissue of patients with autoimmune hepatitis(AIH) and its clinical implications. Methods 68 patients with AIH(48 active and 20 at remission) were admitted to our hospital between May 2015 and April 2017,and liver biopsies were performed. 13 patients with hepatic hemangioma were included and their liver tissues were obtained by surgery for control. The expression of PD-1 in liver tissues was detected by immunochemical staining. The correlation between the positive expression of PD-1 in liver tissues and serum liver function indexes in patients with AIH was analyzed. Results Serum bilirubin,AST, ALT,ALP and GGT levels in 48 patients with active AIH were(72.1±48.9) μmol/L,(243.1±170.4) U/L,(345.3±217.7) U/L,(154.3±94.6) U/L and(86.5±43.5) U/L,much higher than(14.8±4.2) μmol/L,(28.3±8.7) U/L,(27.6±8.8) U/L,(73.3±51.3) U/L and(71.3±27.3) U/L in20 patients at remission(all P<0.05),and serum globulin and IgG levels were(34.3±11.3) g/L and(23.2±7.5)g/L,much higher than(30.7±10.2) g/L and(11.7±4.6)g/L in patients at remission(P<0.05);the positive rate of PD-1 expression in liver tissues of 68 patients with AIH was(13.61 ±6.87)%,significantly higher than(2.25±0.68)% in patients with hepatic hemangioma(P<0.05),and the positive rate in 48 patients with active AIH was(16.56±7.81) %,significantly higher than(6.56±3.21)% in patients at remission(P<0.05);the incidences of interfacial inflammation,lymphocyte invasion and single tube destructive inflammation in 48 patients with active AIH were 93.75%,89.58% and 6.25%;the PD-1 expressions in liver tissues of patients with active AIH were positively correlated to serum bilirubin(r=0.996,P<0.001),AST(r=0.989,P<0.001),ALT(r=0.995,P<0.001),ALP(r=0.998,P<0.001),GGT(r=0.995,P<0.001),GLO(r=0.996,P<0.001) and IgG levels(r=0.997,P<0.001),and they were positively correlated to serum bilirubin(r=0.999,P<0.001),AST(r=0.999,P<0.001),ALT(r=0.999,P<0.001),ALP(r=0.999,P<0.001),GGT(r=0.999,P<0.001) and IgG levels(r=0.999,P<0.001) in patients at remission. Conclusion The expression of PD-1 in liver tissues of patients with AIH is strongly intensified and positively correlated to hepatic activity index,and the mechanism by which it take part in the pathogenesis of AIH needs further investigation.
引文
[1]胡朝军,李永哲.重视自身免疫性肝病相关自身抗体的规范检测与合理应用.中华检验医学杂志,2014,37(2):81-83.
[2]Miyake Y,Yamamoto K,Matsushita H,et al.Multicenter validation study of anti-programmed cell death-1 antibody as a serological marker for type 1 autoimmune hepatitis.Hepatol Res,2015,44(13):1299-1307.
[3]Oba J,Nakahara T,Abe T,et al.Expression of programmed death receptor ligand 1 in melanoma may indicate tumor progression and poor patient survival.J Am Acad Dermatol,2014,70(5):954-956.
[4]Dirks J,Egli A,Sester U,et al.Blockade of programmed death receptor-1 signaling restores expression of mostly proinflammatory cytokines in anergic cytomegalovirus-specific T cells.Transpl Infect Dis,2013,15(1):79.
[5]Ye HO,Adams DH.Regulatory T cells and autoimmune hepatitis:defective cells or a hostile environment.J Hepatol,2012,57(1):6-8.
[6]Grant CR,Liberal R,Holder BS,et al.Dysfunctional CD39 POS,regulatory T cells and aberrant control of T-helper type 17cells in autoimmune hepatitis.Hepatology,2014,59(3):1007-1015.
[7]Jiang L,Wang L,Li PF,et al.Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma-like carcinoma.Onco Targets Ther,2015,8(2):1451.
[8]Grzywnowicz M,Karczmarczyk A,Skorka K,et al.Expression of programmed death 1 ligand in different compartments of chronic lymphocytic leukemia.Acta Haematol,2015,134(4):255-262.
[9]Solaymani-Mohammadi S,Lakhdari O,Minev I,et al.Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules.JLeukoc Biol,2016,99(3):475-482.
[10]董荣乔,周东方,韩冉,等.干扰素α对慢性丙型肝炎患者外周血T淋巴细胞表面程序性死亡受体-1表达的影响.中华肝脏病杂志,2013,21(12):899-902.
[11]邵鸣,肖玉珍.自身免疫性肝炎Ⅱ型1例.实用肝脏病杂志,2010,13(5):250-250.
[12]刘泽,蔡少平.中晚期自身免疫性肝炎-原发性胆汁性肝硬化重叠综合征的临床病理研究.实用肝脏病杂志,2008,10(1):18-19.
[13]Kremmler L,Blank CU.The clinical relevance of the programmed death-1(PD-1)receptor.Inter Praxis,2014,54(4):775-787.
[14]Alaghehbandan R,Stehlik J,Trpkov K,et al.Programmed death-1(PD-1)receptor/PD-1 ligand(PD-L1)expression in fumarate hydratase-deficient renal cell carcinoma.Ann Diagn Pathol,2017,29:17.
[15]Muenst S,Schaerli AR,Gao F,et al.Expression of programmed death ligand 1(PD-L1)is associated with poor prognosis in human breast cancer.Breast Cancer Res Treat,2014,146(1):15-24.
[16]Ishii H,Azuma K,Kawahara A,et al.Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer.J Thorac Oncol,2015,10(3):426-430.
[17]Seki T,Kiyosawa K,Inoko H,et al.Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients.Hepatology,2010,12(6):1300-1304.
[18]Richardson PD,James PD,Ryder SD.Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine.J Hepatol,2000,33(3):371-375.
[19]Kearl TJ,Jing W,Gershan JA,et al.Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma.J Immunol,2013,190(11):5620-5628.
[20]Cao D,Xu H,Guo G,et al.Intrahepatic expression of programmed death-1 and its ligands in patients with HBV-related acute-on-chronic liver failure.Inflammation,2013,36(1):110-120.
[21]Shao R,Fang Y,Yu H,et al.Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients:a prospective cohort study.Crit Care,2016,20(1):124.
[2]Miyake Y,Yamamoto K,Matsushita H,et al.Multicenter validation study of anti-programmed cell death-1 antibody as a serological marker for type 1 autoimmune hepatitis.Hepatol Res,2015,44(13):1299-1307.
[3]Oba J,Nakahara T,Abe T,et al.Expression of programmed death receptor ligand 1 in melanoma may indicate tumor progression and poor patient survival.J Am Acad Dermatol,2014,70(5):954-956.
[4]Dirks J,Egli A,Sester U,et al.Blockade of programmed death receptor-1 signaling restores expression of mostly proinflammatory cytokines in anergic cytomegalovirus-specific T cells.Transpl Infect Dis,2013,15(1):79.
[5]Ye HO,Adams DH.Regulatory T cells and autoimmune hepatitis:defective cells or a hostile environment.J Hepatol,2012,57(1):6-8.
[6]Grant CR,Liberal R,Holder BS,et al.Dysfunctional CD39 POS,regulatory T cells and aberrant control of T-helper type 17cells in autoimmune hepatitis.Hepatology,2014,59(3):1007-1015.
[7]Jiang L,Wang L,Li PF,et al.Positive expression of programmed death ligand-1 correlates with superior outcomes and might be a therapeutic target in primary pulmonary lymphoepithelioma-like carcinoma.Onco Targets Ther,2015,8(2):1451.
[8]Grzywnowicz M,Karczmarczyk A,Skorka K,et al.Expression of programmed death 1 ligand in different compartments of chronic lymphocytic leukemia.Acta Haematol,2015,134(4):255-262.
[9]Solaymani-Mohammadi S,Lakhdari O,Minev I,et al.Lack of the programmed death-1 receptor renders host susceptible to enteric microbial infection through impairing the production of the mucosal natural killer cell effector molecules.JLeukoc Biol,2016,99(3):475-482.
[10]董荣乔,周东方,韩冉,等.干扰素α对慢性丙型肝炎患者外周血T淋巴细胞表面程序性死亡受体-1表达的影响.中华肝脏病杂志,2013,21(12):899-902.
[11]邵鸣,肖玉珍.自身免疫性肝炎Ⅱ型1例.实用肝脏病杂志,2010,13(5):250-250.
[12]刘泽,蔡少平.中晚期自身免疫性肝炎-原发性胆汁性肝硬化重叠综合征的临床病理研究.实用肝脏病杂志,2008,10(1):18-19.
[13]Kremmler L,Blank CU.The clinical relevance of the programmed death-1(PD-1)receptor.Inter Praxis,2014,54(4):775-787.
[14]Alaghehbandan R,Stehlik J,Trpkov K,et al.Programmed death-1(PD-1)receptor/PD-1 ligand(PD-L1)expression in fumarate hydratase-deficient renal cell carcinoma.Ann Diagn Pathol,2017,29:17.
[15]Muenst S,Schaerli AR,Gao F,et al.Expression of programmed death ligand 1(PD-L1)is associated with poor prognosis in human breast cancer.Breast Cancer Res Treat,2014,146(1):15-24.
[16]Ishii H,Azuma K,Kawahara A,et al.Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer.J Thorac Oncol,2015,10(3):426-430.
[17]Seki T,Kiyosawa K,Inoko H,et al.Association of autoimmune hepatitis with HLA-Bw54 and DR4 in Japanese patients.Hepatology,2010,12(6):1300-1304.
[18]Richardson PD,James PD,Ryder SD.Mycophenolate mofetil for maintenance of remission in autoimmune hepatitis in patients resistant to or intolerant of azathioprine.J Hepatol,2000,33(3):371-375.
[19]Kearl TJ,Jing W,Gershan JA,et al.Programmed death receptor-1/programmed death receptor ligand-1 blockade after transient lymphodepletion to treat myeloma.J Immunol,2013,190(11):5620-5628.
[20]Cao D,Xu H,Guo G,et al.Intrahepatic expression of programmed death-1 and its ligands in patients with HBV-related acute-on-chronic liver failure.Inflammation,2013,36(1):110-120.
[21]Shao R,Fang Y,Yu H,et al.Monocyte programmed death ligand-1 expression after 3-4 days of sepsis is associated with risk stratification and mortality in septic patients:a prospective cohort study.Crit Care,2016,20(1):124.
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