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Published in: Clinical Reviews in Allergy & Immunology 2-3/2015

01-06-2015

Emperipolesis Mediated by CD8 T Cells Is a Characteristic Histopathologic Feature of Autoimmune Hepatitis

Authors: Qi Miao, Zhaolian Bian, Ruqi Tang, Haiyan Zhang, Qixia Wang, Shanshan Huang, Xiao Xiao, Li Shen, Dekai Qiu, Edward L. Krawitt, M. Eric Gershwin, Xiong Ma

Published in: Clinical Reviews in Allergy & Immunology | Issue 2-3/2015

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Abstract

Emperipolesis has been widely described in patients with autoimmune hepatitis, but the significance and the diagnostic value have not been quantitated. The goal of this study was to define the features and clinical significance of emperipolesis in autoimmune hepatitis (AIH). A retrospective histological evaluation of 101 patients with AIH and 184 controls was performed. Confocal staining for CD4, CD8, CD19, CD56, CD163, and CD11b, CK8/18 and cleaved caspase-3 was performed. Emperipolesis was observed in 65.3 % of the patients with AIH in haematoxylin and eosin (H&E)-stained slides, which was significantly higher than in patients with primary biliary cirrhosis (17.9 %), chronic hepatitis B (14.9 %), and drug-induced liver injury (25.6 %). Among AIH patients, the patients with emperipolesis had significantly higher serum (alanine aminotransferase/aspartate aminotransferase [ALT/AST]) levels. Histologically, emperipolesis was associated with more severe necroinflammatory features and more advanced fibrosis. The lymphocytes in hepatocytes were predominantly as CD8 T cells. Emperipolesis of CD8 T cells induced cleaved caspase-3 expression, and was prominent in areas apoptosis. Emperipolesis is a characteristic feature of AIH which is often seen in conjunction with interface hepatitis, plasmacytic infiltration and hepatocyte rosetting and is associated with more severe necroinflammatory and fibrotic changes. In AIH, emperipolesis is predominantly mediated by CD8 T cells, appears to induce apoptosis and may be another mechanism of autoimmune-mediated hepatocyte injury.
Literature
2.
go back to reference Manns MP, Czaja AJ, Gorham JD et al (2010) Diagnosis and management of autoimmune hepatitis. Hepatology 51(6):2193–2213CrossRefPubMed Manns MP, Czaja AJ, Gorham JD et al (2010) Diagnosis and management of autoimmune hepatitis. Hepatology 51(6):2193–2213CrossRefPubMed
4.
go back to reference Qiu D, Wang Q, Wang H et al (2011) Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients. J Hepatol 54(2):340–347CrossRefPubMed Qiu D, Wang Q, Wang H et al (2011) Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients. J Hepatol 54(2):340–347CrossRefPubMed
5.
go back to reference Longhi MS, Ma Y, Mieli-Vergani G, Vergani D (2010) Aetiopathogenesis of autoimmune hepatitis. J Autoimmun 34(1):7–14CrossRefPubMed Longhi MS, Ma Y, Mieli-Vergani G, Vergani D (2010) Aetiopathogenesis of autoimmune hepatitis. J Autoimmun 34(1):7–14CrossRefPubMed
6.
go back to reference Ohira H, Takahashi A (2012) Current trends in the diagnosis and treatment of autoimmune hepatitis in Japan. Hepatol Res 42(2):131–138CrossRefPubMed Ohira H, Takahashi A (2012) Current trends in the diagnosis and treatment of autoimmune hepatitis in Japan. Hepatol Res 42(2):131–138CrossRefPubMed
7.
go back to reference Dienes HP (1989) Viral and autoimmune hepatitis. Morphologic and pathogenetic aspects of cell damage in hepatitis with potential chronicity. Veroff Pathol 132:1–107PubMed Dienes HP (1989) Viral and autoimmune hepatitis. Morphologic and pathogenetic aspects of cell damage in hepatitis with potential chronicity. Veroff Pathol 132:1–107PubMed
8.
go back to reference Alvarez F, Berg PA, Bianchi FB et al (1999) International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31(5):929–938CrossRefPubMed Alvarez F, Berg PA, Bianchi FB et al (1999) International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31(5):929–938CrossRefPubMed
9.
go back to reference Hennes EM, Zeniya M, Czaja AJ et al (2008) Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 48(1):169–176CrossRefPubMed Hennes EM, Zeniya M, Czaja AJ et al (2008) Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 48(1):169–176CrossRefPubMed
10.
go back to reference Ishak K, Baptista A, Bianchi L et al (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22(6):696–699CrossRefPubMed Ishak K, Baptista A, Bianchi L et al (1995) Histological grading and staging of chronic hepatitis. J Hepatol 22(6):696–699CrossRefPubMed
11.
go back to reference Kleiner DE, Chalasani NP, Lee WM et al (2014) Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology 59(2):661–670CrossRefPubMedCentralPubMed Kleiner DE, Chalasani NP, Lee WM et al (2014) Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations. Hepatology 59(2):661–670CrossRefPubMedCentralPubMed
12.
go back to reference Suzuki A, Brunt EM, Kleiner DE et al (2011) The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology 54(3):931–939CrossRefPubMedCentralPubMed Suzuki A, Brunt EM, Kleiner DE et al (2011) The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury. Hepatology 54(3):931–939CrossRefPubMedCentralPubMed
13.
go back to reference Humble JG, Jayne WH, Pulvertaft RJ (1956) Biological interaction between lymphocytes and other cells. Br J Haematol 2(3):283–294CrossRefPubMed Humble JG, Jayne WH, Pulvertaft RJ (1956) Biological interaction between lymphocytes and other cells. Br J Haematol 2(3):283–294CrossRefPubMed
14.
go back to reference Overholtzer M, Brugge JS (2008) The cell biology of cell-in-cell structures. Nat Rev Mol Cell Biol 9(10):796–809CrossRefPubMed Overholtzer M, Brugge JS (2008) The cell biology of cell-in-cell structures. Nat Rev Mol Cell Biol 9(10):796–809CrossRefPubMed
15.
go back to reference Larsen TE (1970) Emperipolesis of granular leukocytes within megakaryocytes in human hemopoietic bone marrow. Am J Clin Pathol 53(4):485–489PubMed Larsen TE (1970) Emperipolesis of granular leukocytes within megakaryocytes in human hemopoietic bone marrow. Am J Clin Pathol 53(4):485–489PubMed
16.
go back to reference Saxena S, Beena KR, Bansal A, Bhatnagar A (2002) Emperipolesis in a common breast malignancy. A case report. Acta Cytol 46(5):883–886CrossRefPubMed Saxena S, Beena KR, Bansal A, Bhatnagar A (2002) Emperipolesis in a common breast malignancy. A case report. Acta Cytol 46(5):883–886CrossRefPubMed
17.
go back to reference Sinkovics JG, Shullenberger CC, Howe CD (1966) Cell destruction by lymphocytes. Lancet 287:1215–1216CrossRef Sinkovics JG, Shullenberger CC, Howe CD (1966) Cell destruction by lymphocytes. Lancet 287:1215–1216CrossRef
18.
go back to reference Sandilands GP, Reid FM, Gray KG, Anderson JR (1978) Lymphocyte emperipolesis revisited: I. Development of in vitro assay and preliminary characterisation of the lymphocyte subpopulation involved. Immunology 35(2):381–389PubMedCentralPubMed Sandilands GP, Reid FM, Gray KG, Anderson JR (1978) Lymphocyte emperipolesis revisited: I. Development of in vitro assay and preliminary characterisation of the lymphocyte subpopulation involved. Immunology 35(2):381–389PubMedCentralPubMed
19.
go back to reference Chen YH, Wang S, He MF et al (2013) Prevalence of heterotypic tumor/immune cell-in-cell structure in vitro and in vivo leading to formation of aneuploidy. PLoS One 8(3):e59418CrossRefPubMedCentralPubMed Chen YH, Wang S, He MF et al (2013) Prevalence of heterotypic tumor/immune cell-in-cell structure in vitro and in vivo leading to formation of aneuploidy. PLoS One 8(3):e59418CrossRefPubMedCentralPubMed
20.
go back to reference Takeuchi M, Inoue T, Otani T, Yamasaki F, Nakamura S, Kibata M (2010) Cell-in-cell structures formed between human cancer cell lines and the cytotoxic regulatory T-cell line HOZOT. J Mol Cell Biol 2(3):139–151CrossRefPubMed Takeuchi M, Inoue T, Otani T, Yamasaki F, Nakamura S, Kibata M (2010) Cell-in-cell structures formed between human cancer cell lines and the cytotoxic regulatory T-cell line HOZOT. J Mol Cell Biol 2(3):139–151CrossRefPubMed
21.
go back to reference Tamura A, Kikuchi S, Hata M et al (2005) Achlorhydria by ezrin knockdown: defects in the formation/expansion of apical canaliculi in gastric parietal cells. J Cell Biol 169(1):21–28CrossRefPubMedCentralPubMed Tamura A, Kikuchi S, Hata M et al (2005) Achlorhydria by ezrin knockdown: defects in the formation/expansion of apical canaliculi in gastric parietal cells. J Cell Biol 169(1):21–28CrossRefPubMedCentralPubMed
22.
go back to reference Tanaka M, Aze Y, Fujita T (1997) Adhesion molecule LFA-1/ICAM-1 influences on LPS-induced megakaryocytic emperipolesis in the rat bone marrow. Vet Pathol 34(5):463–466CrossRefPubMed Tanaka M, Aze Y, Fujita T (1997) Adhesion molecule LFA-1/ICAM-1 influences on LPS-induced megakaryocytic emperipolesis in the rat bone marrow. Vet Pathol 34(5):463–466CrossRefPubMed
23.
go back to reference Okuyama S, Mishina H, Yamamoto K, Matsuzawa T (1979) Emperipolesis as a cancer antagonism: report of 2 cases. Sci Rep Res Inst Tohoku Univ Med 26(1–2):11–17PubMed Okuyama S, Mishina H, Yamamoto K, Matsuzawa T (1979) Emperipolesis as a cancer antagonism: report of 2 cases. Sci Rep Res Inst Tohoku Univ Med 26(1–2):11–17PubMed
24.
go back to reference Wang X, Li W (1987) Mechanisms of natural killer cell-mediated tumor cell cytolysis at a single cell level. J Med Coll PLA 2:107–117 Wang X, Li W (1987) Mechanisms of natural killer cell-mediated tumor cell cytolysis at a single cell level. J Med Coll PLA 2:107–117
25.
go back to reference Wang S, Guo Z, Xia P et al (2009) Internalization of NK cells into tumor cells requires ezrin and leads to programmed cell-in-cell death. Cell Res 19(12):1350–1362CrossRefPubMed Wang S, Guo Z, Xia P et al (2009) Internalization of NK cells into tumor cells requires ezrin and leads to programmed cell-in-cell death. Cell Res 19(12):1350–1362CrossRefPubMed
26.
go back to reference Colmenero I, Molho-Pessach V, Torrelo A, Zlotogorski A, Requena L (2012) Emperipolesis: an additional common histopathologic finding in H syndrome and Rosai–Dorfman disease. Am J Dermatopathol 34(3):315–320CrossRefPubMed Colmenero I, Molho-Pessach V, Torrelo A, Zlotogorski A, Requena L (2012) Emperipolesis: an additional common histopathologic finding in H syndrome and Rosai–Dorfman disease. Am J Dermatopathol 34(3):315–320CrossRefPubMed
27.
go back to reference Djaldetti M, Strauss Z (1982) Emperipolesis by megakaryocytes in patients with non-Hodgkin's lymphoma and megaloblastic anemia. J Submicrosc Cytol 14(2):407–413PubMed Djaldetti M, Strauss Z (1982) Emperipolesis by megakaryocytes in patients with non-Hodgkin's lymphoma and megaloblastic anemia. J Submicrosc Cytol 14(2):407–413PubMed
28.
go back to reference Kumari N, Kathuria R, Srivastav A, Krishnani N, Poddar U, Yachha SK (2013) Significance of histopathological features in differentiating autoimmune liver disease from nonautoimmune chronic liver disease in children. Eur J Gastroenterol Hepatol 25(3):333–337CrossRefPubMed Kumari N, Kathuria R, Srivastav A, Krishnani N, Poddar U, Yachha SK (2013) Significance of histopathological features in differentiating autoimmune liver disease from nonautoimmune chronic liver disease in children. Eur J Gastroenterol Hepatol 25(3):333–337CrossRefPubMed
29.
go back to reference Mallick S, Ghosh R, Iyer VK, Jain D, Mathur SR (2013) Cytomorphological and morphometric analysis of 22 cases of Rosai–Dorfman disease: a large series from a tertiary care centre. Acta Cytol 57(6):625–632CrossRefPubMed Mallick S, Ghosh R, Iyer VK, Jain D, Mathur SR (2013) Cytomorphological and morphometric analysis of 22 cases of Rosai–Dorfman disease: a large series from a tertiary care centre. Acta Cytol 57(6):625–632CrossRefPubMed
30.
go back to reference Chabot S, Fakhfakh A, Beland K et al (2013) Mouse liver-specific CD8(+) T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes. J Autoimmun 42:19–28CrossRefPubMed Chabot S, Fakhfakh A, Beland K et al (2013) Mouse liver-specific CD8(+) T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes. J Autoimmun 42:19–28CrossRefPubMed
31.
go back to reference Longhi MS, Hussain MJ, Bogdanos DP et al (2007) Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology 46(2):472–484CrossRefPubMed Longhi MS, Hussain MJ, Bogdanos DP et al (2007) Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2. Hepatology 46(2):472–484CrossRefPubMed
32.
go back to reference Wen L, Peakman M, Lobo-Yeo A et al (1990) T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet 336(8730):1527–1530CrossRefPubMed Wen L, Peakman M, Lobo-Yeo A et al (1990) T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis. Lancet 336(8730):1527–1530CrossRefPubMed
33.
go back to reference Krawitt EL, Kilby AE, Albertini RJ et al (1988) An immunogenetic study of suppressor cell activity in autoimmune chronic active hepatitis. Clin Immunol Immunopathol 46(2):249–257CrossRefPubMed Krawitt EL, Kilby AE, Albertini RJ et al (1988) An immunogenetic study of suppressor cell activity in autoimmune chronic active hepatitis. Clin Immunol Immunopathol 46(2):249–257CrossRefPubMed
34.
go back to reference Ehser J, Holdener M, Christen S et al (2013) Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune hepatitis. J Autoimmun 42:39–49CrossRefPubMed Ehser J, Holdener M, Christen S et al (2013) Molecular mimicry rather than identity breaks T-cell tolerance in the CYP2D6 mouse model for human autoimmune hepatitis. J Autoimmun 42:39–49CrossRefPubMed
35.
go back to reference Hintermann E, Holdener M, Bayer M et al (2011) Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J Autoimmun 37(3):242–253CrossRefPubMed Hintermann E, Holdener M, Bayer M et al (2011) Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model. J Autoimmun 37(3):242–253CrossRefPubMed
36.
go back to reference Benseler V, Warren A, Vo M et al (2011) Hepatocyte entry leads to degradation of autoreactive CD8 T cells. Proc Natl Acad Sci U S A 108(40):16735–16740CrossRefPubMedCentralPubMed Benseler V, Warren A, Vo M et al (2011) Hepatocyte entry leads to degradation of autoreactive CD8 T cells. Proc Natl Acad Sci U S A 108(40):16735–16740CrossRefPubMedCentralPubMed
Metadata
Title
Emperipolesis Mediated by CD8 T Cells Is a Characteristic Histopathologic Feature of Autoimmune Hepatitis
Authors
Qi Miao
Zhaolian Bian
Ruqi Tang
Haiyan Zhang
Qixia Wang
Shanshan Huang
Xiao Xiao
Li Shen
Dekai Qiu
Edward L. Krawitt
M. Eric Gershwin
Xiong Ma
Publication date
01-06-2015
Publisher
Springer US
Published in
Clinical Reviews in Allergy & Immunology / Issue 2-3/2015
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI
https://doi.org/10.1007/s12016-014-8432-0

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