Identification of CD4 T-Cell Epitopes in Soluble Liver Antigen/Liver Pancreas Autoantigen in Autoimmune Hepatitis

Heiko Mix, Christina Weiler-Normann, Robert Thimme, Golo Ahlenstiel, Eui Cheol Shin, Johannes Herkel, Chella S. David, Ansgar W. Lohse, Barbara Rehermann

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with autoantibodies and liver-infiltrating lymphocytes. Although autoantibodies are tested routinely to diagnose and classify AIH, liver-infiltrating lymphocytes are regarded as the primary factor for disease pathogenesis. The purpose of this study was to identify and characterize autoantigenic peptides within human AIH-specific soluble liver antigen/liver pancreas antigen (SLA/LP) that are targeted by CD4+ T cells and restricted by the disease susceptibility gene HLA-DRB1*0301. Methods: HLA-DRB1*0301 transgenic mice were immunized with SLA/LP. Antibody and T-cell responses were analyzed with SLA/LP-overlapping peptides in enzyme immunoassay, proliferation, and enzyme-linked immunospot (ELISpot) assays. Minimal optimal T-cell epitopes were identified, characterized with cloned T-cell hybridomas, and confirmed in tetramer and ELISpot assays with AIH patients' peripheral blood mononuclear cells. Results: All mice developed SLA/LP-specific IgG1/IgG2a antibodies against the same SLA/LP peptides as human beings. T cells targeted several peptides within SLA/LP, 2 of which were DR3-restricted and one overlapped the sequence recognized by human autoantibodies. Minimal optimal epitopes were mapped, DRB1*0301/epitope-tetramers were generated, and the frequency and function of HLA-DRB1*0301-restricted autoantigen-specific T cells in AIH patients were analyzed with tetramer and interferon-γ ELISpot assays. Conclusions: This study identified T-cell epitopes within SLA/LP, restricted by the disease susceptibility gene DRB1*0301 and in close proximity to the human autoantibody epitope. These results and the generated reagents now provide the opportunity to directly monitor autoreactive T cells in AIH patients in clinical studies.

Original languageEnglish (US)
Pages (from-to)2107-2118
Number of pages12
JournalGastroenterology
Volume135
Issue number6
DOIs
StatePublished - Dec 2008

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Autoimmune Hepatitis
T-Lymphocyte Epitopes
Autoantigens
Pancreas
Liver
T-Lymphocytes
Enzyme-Linked Immunospot Assay
Autoantibodies
Antigens
Epitopes
Peptides
Disease Susceptibility
Lymphocytes
liver antigen LA-1
CD4 Antigens
Antibodies
Hybridomas
Immunoenzyme Techniques
Interferons
Transgenic Mice

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Mix, H., Weiler-Normann, C., Thimme, R., Ahlenstiel, G., Shin, E. C., Herkel, J., ... Rehermann, B. (2008). Identification of CD4 T-Cell Epitopes in Soluble Liver Antigen/Liver Pancreas Autoantigen in Autoimmune Hepatitis. Gastroenterology, 135(6), 2107-2118. https://doi.org/10.1053/j.gastro.2008.07.029

Identification of CD4 T-Cell Epitopes in Soluble Liver Antigen/Liver Pancreas Autoantigen in Autoimmune Hepatitis. / Mix, Heiko; Weiler-Normann, Christina; Thimme, Robert; Ahlenstiel, Golo; Shin, Eui Cheol; Herkel, Johannes; David, Chella S.; Lohse, Ansgar W.; Rehermann, Barbara.

In: Gastroenterology, Vol. 135, No. 6, 12.2008, p. 2107-2118.

Research output: Contribution to journalArticle

Mix, H, Weiler-Normann, C, Thimme, R, Ahlenstiel, G, Shin, EC, Herkel, J, David, CS, Lohse, AW & Rehermann, B 2008, 'Identification of CD4 T-Cell Epitopes in Soluble Liver Antigen/Liver Pancreas Autoantigen in Autoimmune Hepatitis', Gastroenterology, vol. 135, no. 6, pp. 2107-2118. https://doi.org/10.1053/j.gastro.2008.07.029
Mix, Heiko ; Weiler-Normann, Christina ; Thimme, Robert ; Ahlenstiel, Golo ; Shin, Eui Cheol ; Herkel, Johannes ; David, Chella S. ; Lohse, Ansgar W. ; Rehermann, Barbara. / Identification of CD4 T-Cell Epitopes in Soluble Liver Antigen/Liver Pancreas Autoantigen in Autoimmune Hepatitis. In: Gastroenterology. 2008 ; Vol. 135, No. 6. pp. 2107-2118.
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abstract = "Background & Aims: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with autoantibodies and liver-infiltrating lymphocytes. Although autoantibodies are tested routinely to diagnose and classify AIH, liver-infiltrating lymphocytes are regarded as the primary factor for disease pathogenesis. The purpose of this study was to identify and characterize autoantigenic peptides within human AIH-specific soluble liver antigen/liver pancreas antigen (SLA/LP) that are targeted by CD4+ T cells and restricted by the disease susceptibility gene HLA-DRB1*0301. Methods: HLA-DRB1*0301 transgenic mice were immunized with SLA/LP. Antibody and T-cell responses were analyzed with SLA/LP-overlapping peptides in enzyme immunoassay, proliferation, and enzyme-linked immunospot (ELISpot) assays. Minimal optimal T-cell epitopes were identified, characterized with cloned T-cell hybridomas, and confirmed in tetramer and ELISpot assays with AIH patients' peripheral blood mononuclear cells. Results: All mice developed SLA/LP-specific IgG1/IgG2a antibodies against the same SLA/LP peptides as human beings. T cells targeted several peptides within SLA/LP, 2 of which were DR3-restricted and one overlapped the sequence recognized by human autoantibodies. Minimal optimal epitopes were mapped, DRB1*0301/epitope-tetramers were generated, and the frequency and function of HLA-DRB1*0301-restricted autoantigen-specific T cells in AIH patients were analyzed with tetramer and interferon-γ ELISpot assays. Conclusions: This study identified T-cell epitopes within SLA/LP, restricted by the disease susceptibility gene DRB1*0301 and in close proximity to the human autoantibody epitope. These results and the generated reagents now provide the opportunity to directly monitor autoreactive T cells in AIH patients in clinical studies.",
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AU - Weiler-Normann, Christina

AU - Thimme, Robert

AU - Ahlenstiel, Golo

AU - Shin, Eui Cheol

AU - Herkel, Johannes

AU - David, Chella S.

AU - Lohse, Ansgar W.

AU - Rehermann, Barbara

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