慢性乙型肝炎患者肝组织中黑色素瘤缺乏因子2表达与病变程度的相关性
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摘要
目的初步探讨DNA识别受体之一黑色素瘤缺乏因子2(AIM-2)在慢性乙型肝炎患者肝脏组织中表达分布及其与肝组织病变程度的相关性。方法利用免疫组织化学方法对54例CHB患者肝组织活检标本、19例慢加急性肝功能衰竭(HBV-ACLF)肝移植术后病肝组织标本及20例健康供体肝脏组织标本进行AIM-2检测,利用Image-Pro-Plus 6.0软件测定AIM-2积分吸光度值。肝脏组织炎症程度分为G1~4和纤维化程度分为S0~4,并进行HAI评分。两组间比较采用独立样本的秩和检验,多组间比较用Kruskal-Wallis检验分析,各组数据间相关性分析采用Spearman相关分析。结果 AIM-2表达定位于肝实质细胞的胞质内。正常肝组织中极少表达,HBV相关患肝组织中表达显著增多。患者肝脏组织AIM-2积分吸光度值中位数在HBV-ACLF组为19 772.48,显著高于CHB组的4 996.88(Z=5.008,P<0.001);CHB组显著高于健康对照组的2 296.49(Z=-3.028,P=0.002);患肝组织AIM-2表达水平与肝脏炎症HAI评分正相关(r=0.707,P<0.0001)。结论 AIM-2在正常肝组织极少表达;但在慢性乙型肝炎患者肝组织表达显著增加,且随肝脏炎症的加重而表达增强,提示AIM-2可能在慢性乙型肝炎肝脏损伤机制中发挥重要作用。
Objective To investigate the expression of absent in melanoma 2(AIM-2) in liver of patients with chronic hepatitis B, and to evaluate the correlation between the expression level of AIM-2 and the degree of liver damage. Methods AIM2 were detected in 73 liver specimens including 54 from common CHB patients, 19 from patients with acute-on-chronic liver failure(HBV-ACLF), and 20 from healthy controls by immunohistochemical staining. Semi-quantitative of the integral absorbance were conducted by the software Image-Pro-Plus 6.0. The correlation between the AIM-2 levels and the degree of liver damage were analyzed, respectively. Results AIM-2 expression was exclusive to the hepatic cellular cytoplasm in the liver tissue of patients with HBV. The median integral absorbance of AIM-2 in CHB patients was 4 996.88, which was significantly higher than that in healthy controls of 2296.49(Z =-3.028, P = 0.002), but was less than that in HBV-ACLF patients with 19 772.48(Z =-5.008, P < 0.001). The integral absorbance of AIM-2 in CHB patients was also positive correlated with the score of histological activity index(HAI) in liver(r = 0.707, P < 0.0001). Conclusions AIM-2 rarely expressed in healthy liver, but significantly upregulation were found in patients with chronic hepatitis B especially in patients with acute-on-chronic liver failure, indicating that AIM-2 may contribute to the pathogeneses of liver damage in chronic hepatitis B and liver failure.
Objective To investigate the expression of absent in melanoma 2(AIM-2) in liver of patients with chronic hepatitis B, and to evaluate the correlation between the expression level of AIM-2 and the degree of liver damage. Methods AIM2 were detected in 73 liver specimens including 54 from common CHB patients, 19 from patients with acute-on-chronic liver failure(HBV-ACLF), and 20 from healthy controls by immunohistochemical staining. Semi-quantitative of the integral absorbance were conducted by the software Image-Pro-Plus 6.0. The correlation between the AIM-2 levels and the degree of liver damage were analyzed, respectively. Results AIM-2 expression was exclusive to the hepatic cellular cytoplasm in the liver tissue of patients with HBV. The median integral absorbance of AIM-2 in CHB patients was 4 996.88, which was significantly higher than that in healthy controls of 2296.49(Z =-3.028, P = 0.002), but was less than that in HBV-ACLF patients with 19 772.48(Z =-5.008, P < 0.001). The integral absorbance of AIM-2 in CHB patients was also positive correlated with the score of histological activity index(HAI) in liver(r = 0.707, P < 0.0001). Conclusions AIM-2 rarely expressed in healthy liver, but significantly upregulation were found in patients with chronic hepatitis B especially in patients with acute-on-chronic liver failure, indicating that AIM-2 may contribute to the pathogeneses of liver damage in chronic hepatitis B and liver failure.
引文
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12 Reinholz M,Kawakami Y,Salzer S,et al.HPV16 activates the AIM2 inflammasome in keratinocytes[J].Arch Dermatol Res,2013,305(8):723-732.
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14 Cridland JA,Curley EZ,Wykes MN,et al.The mammalian PYHIN gene family:phylogeny,evolution and expression[J].BMC Evol Biol,2012,12:140.
15 DeYoung KL,Ray ME,Su YA,et al.Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma[J].Oncogene,1997,15(4):453-457.
16 中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2010年版)[J].中华传染病杂志,2011,29(2):65-80.
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18 中华医学会传染病与寄生虫病学分会,中华医学会肝病学分会.病毒性肝炎防治方案[J].中华传染病杂志,2001,19(1):56-62.
19 Schaff Z.The value of liver biopsy in chronic hepatitis[J].Orv Hetil,2011,152(22):856-858.
20 Choubey D,Walter S,Geng Y,et al.Cytoplasmic localization of the interferon-inducible protein that is encoded by the AIM2(absent in melanoma)gene from the 200-gene family[J].Febs Lett,2000,474(1):38-42.
21 Wu DL,Xu GH,Lu SM,et al.Correlation of AIM2 expression in peripheral blood mononuclear cells from humans with acute and chronic hepatitis B[J].Hum Immunol,2013,74(5):514-521.
22 Bieghs V,Trautwein C.The innate immune response during liver inflammation and metabolic disease[J].Trends Immunol,2013,34(9):446-452.
2 Bertoletti A,Ferrari C.Innate and adaptive immune responses in chronic hepatitis B virus infections:towards restoration of immune control of viral infection[J].Gut,2012,61(12):1754-1764.
3 Fernandes-Alnemri T,Yu JW,Datta P,et al.AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA[J].Nature,2009,458(7237):509-513.
4 Hornung V,Ablasser A,Charrel-Dennis M,et al.AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC[J].Nature,2009,458(7237):514-518.
5 Choubey D.Interferon-inducible Ifi200-family genes as modifiers of lupus susceptibility[J].Immunol Lett,2012,147(1-2):10-17.
6 Panchanathan R,Duan X,Arumugam M,et al.Cell type and gender-dependent differential regulation of the p202 and aim2proteins:implications for the regulation of innate immune responses in SLE[J].Mol Immunol,2011,49(1-2):273-280.
7 Choubey D,Panchanathan R.Interferon-inducible Ifi200-family genes in systemic lupus erythematosus[J].Immunol Lett,2008,119(1-2):32-41.
8 Kondo Y,Nagai K,Nakahata S,et al.Overexpression of the DNA sensor proteins,absent in melanoma 2 and interferon-inducible 16,contributes to tumorigenesis of oral squamous cell carcinoma with p53 inactivation[J].Cancer Sci,2012,103(4):782-790.
9 Lee J,Li L,Gretz N,et al.Absent in melanoma 2(AIM2)is an important mediator of interferon-dependent and-independent HLA-DRA and HLA-DRB gene expression in colorectal cancers[J].Oncogene,2012,31(10):1242-1253.
10 Kondo Y,Nagai K,Nakahata S,et al.Overexpression of the DNA sensor proteins,absent in melanoma 2 and interferon-inducible 16,contributes to tumorigenesis of oral squamous cell carcinoma with p53 inactivation[J].Cancer Sci,2012,103(4):782-790.
11 Yang Y,Zhou X,Kouadir M,et al.The AIM2 Inflammasome is involved in macrophage activation during infection with virulent Mycobacterium bovis strain[J].J Infect Dis,2013,208(11):1849-1858.
12 Reinholz M,Kawakami Y,Salzer S,et al.HPV16 activates the AIM2 inflammasome in keratinocytes[J].Arch Dermatol Res,2013,305(8):723-732.
13 Fernandes-Alnemri T,Yu JW,Juliana C,et al.The AIM2inflammasome is critical for innate immunity to Francisella tularensis[J].Nat Immunol,2010,11(5):385-393.
14 Cridland JA,Curley EZ,Wykes MN,et al.The mammalian PYHIN gene family:phylogeny,evolution and expression[J].BMC Evol Biol,2012,12:140.
15 DeYoung KL,Ray ME,Su YA,et al.Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma[J].Oncogene,1997,15(4):453-457.
16 中华医学会肝病学分会,中华医学会感染病学分会.慢性乙型肝炎防治指南(2010年版)[J].中华传染病杂志,2011,29(2):65-80.
17 刘青,王泰龄.慢加急性肝衰竭(ACLF)共识纪要:亚太肝病学会推荐(APASL)[J].临床肝胆病杂志,2010,26(1):13-18.
18 中华医学会传染病与寄生虫病学分会,中华医学会肝病学分会.病毒性肝炎防治方案[J].中华传染病杂志,2001,19(1):56-62.
19 Schaff Z.The value of liver biopsy in chronic hepatitis[J].Orv Hetil,2011,152(22):856-858.
20 Choubey D,Walter S,Geng Y,et al.Cytoplasmic localization of the interferon-inducible protein that is encoded by the AIM2(absent in melanoma)gene from the 200-gene family[J].Febs Lett,2000,474(1):38-42.
21 Wu DL,Xu GH,Lu SM,et al.Correlation of AIM2 expression in peripheral blood mononuclear cells from humans with acute and chronic hepatitis B[J].Hum Immunol,2013,74(5):514-521.
22 Bieghs V,Trautwein C.The innate immune response during liver inflammation and metabolic disease[J].Trends Immunol,2013,34(9):446-452.