T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis

Li, Wen; Peakman, Mark; Lobo-Yeo, A; Vergani, Diego; Mowat, Alex P.; Mieli-Vergani,; McFarlane, Barbara M.

doi:10.1016/0140-6736(90)93306-a

Cited by 94 publications

(44 citation statements)

References 11 publications

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“…12,13 Perhaps this is not surprising in light of the prominent role played by T cells in the pathogenesis of AIH. 14,15 Better candidates are genes that control the magnitude, phenotype, and/or termination of T-cell responses.…”

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confidence: 99%

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

et al. 2000

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confidence: 99%

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

et al. 2000

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“…[7][8][9][10][11] Another suggested that T cells play a crucial role in hepatocyte injury in AIH. [3][4][5][6] In the previous study, we reported the features of liver-specific human MoAb produced from Epstein-Barr virus-infected peripheral blood mononuclear cells obtained from an AIH patient, and hypothesized that this MoAb might be involved in immunomediated liver injury in this disease. 15 In the present study, we found that this human MoAb reacted with murine hepatocytes membrane as with that of human hepatocytes (see Fig.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 Based on the observation of alterations in several T cell functions, AIH is generally thought to be a disorder mediated by T cells. [3][4][5][6] However, various types of hepatocyte-specific autoantibodies frequently found in AIH patients are also suspected of being involved in immune-mediated liver injury in this disease. This was supported by the following results: (1) Serum autoantibodies obtained from AIH patients were able to kill human hepatocytes, [7][8][9][10][11][12] (2) the titer of hepatocyte-specific autoantibody was tightly correlated with liver damage in AIH patients.…”

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confidence: 99%

A murine model of acute liver injury induced by human monoclonal autoantibody

et al. 2005

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We have previously reported an immunoglobulin (Ig) M autoantibody to hepatocyte-related 190-kd molecules in patients with type 1 autoimmune hepatitis (AIH). This molecule was first isolated by hepatocyte-specific human monoclonal antibody (MoAb). To elucidate the role of this IgM autoantibody in hepatocyte injury, we examined the reactivity of this MoAb to murine hepatocytes and then questioned whether acute hepatic injury could be induced in mice via injection of this MoAb. The reactivity of MoAb was examined via both FACS analysis using murine hepatocytes and immunostaining of liver tissues. We then identified the murine hepatocyte membrane molecule recognized by this MoAb A utoimmune hepatitis (AIH) is a chronic disorder of hepatocytes that is accompanied by immunological abnormality as determined by serological examination. 1,2 Based on the observation of alterations in several T cell functions, AIH is generally thought to be a disorder mediated by T cells. [3][4][5][6] However, various types of hepatocyte-specific autoantibodies frequently found in AIH patients are also suspected of being involved in immune-mediated liver injury in this disease. This was supported by the following results: (1) Serum autoantibodies obtained from AIH patients were able to kill human hepatocytes, 7-12 (2) the titer of hepatocyte-specific autoantibody was tightly correlated with liver damage in AIH patients. 13,14 However, despite these important observations, because of the lack of an adequate in vivo system, the precise role of such autoantibodies in immunomediated liver injury has remained obscure.We have previously reported the hepatocyte-specific human monoclonal autoantibody (MoAb) produced by human clone established by peripheral blood mononuclear cells of patients with AIH. 15 This MoAb recognized a 190-kd molecule on the hepatocyte membrane and was able to kill human hepatocyte cell lines in a complementdependent manner. In addition, a similar 190-kd molecule-recognizing immunoglobulin M (IgM) autoantibody was also found in AIH patients, and its titer was Abbreviations: Ig, immunoglobulin; AIH, autoimmune hepatitis; MoAb, monoclonal autoantibody; MP, myeloma protein; TBS, C3, complement component 3; AST, asparate aminotransferase; ALT, alanine aminotransferase. From the

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“…2 In the 1990s, CD8 T cell clones were isolated from peripheral blood and liver biopsies of LKM-1ϩ patients, but their CYP2D6 specificity was not tested. 3,4 CYP2D6-specific, HLA class II-restricted CD4 T cell immune responses have recently been characterized with the identification of six major epitopic regions. 5 The observation that the intensity of immune responses to these regions is associated with the severity of liver damage implicates antigen-specific CD4 T cell responses in disease pathogenesis.…”

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confidence: 99%

Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2

et al. 2007

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Autoimmune hepatitis type 2 (AIH-2) is a severe organ-specific disorder characterized by liver kidney microsomal antibody type 1 targeting cytochrome P4502D6 (CYP2D6). Growing evidence implicates the involvement of CD8 T cell immune responses in its pathogenesis. We investigated CYP2D6-specific CD8 T cell human leukocyte antigen (HLA)-A2 restricted responses in AIH-2 (20 patients, 11 HLA-A2؉). Binding affinity of CYP2D6 peptides to HLA-A2 was predicted by the algorithm SYFPEITHI and assessed in vivo by T2 cell assays. CD8 T cell interferon (IFN)-␥ production was assessed via intracellular cytokine staining, cytotoxicity via chromium release assay, and frequency of circulating and intrahepatic CYP2D6-specific CD8 T cells via tetramer staining. CYP2D6-specific CD8 T cell reactivity was tested at diagnosis and during treatment and correlated with indices of disease activity. Seven CYP2D6 peptides with high HLA-A2 binding affinity colocalizing with known B cell or CD4 T cell epitopes were selected. Five sequences inducing high levels of IFN-␥ were used for HLA-A2 tetramer construction. Frequency, IFN-␥ production, and cytotoxicity of CYP2D6-specific CD8 T cells were higher at diagnosis than during treatment. Intensity of CYP2D6-specific CD8 T cell responses correlated with disease activity. Immune responses to CYP2D6 245-254 were the strongest both at diagnosis and during treatment. Conclusion: HLA-A2-restricted, CYP2D6-specific CD8 T cell immune responses vary according to disease stage and correlate with hepatocyte damage. CD8 T cell targets on CYP2D6 -in particular CYP2D6 245-254 -may be the focus of novel immune intervention in AIH-2. (HEPATOLOGY 2007;46:472-484.)

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T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis

Cited by 94 publications

References 11 publications

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

A murine model of acute liver injury induced by human monoclonal autoantibody

Cytochrome P450IID6-specific CD8 T cell immune responses mirror disease activity in autoimmune hepatitis type 2

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