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

22 Scopus citations

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

    Fingerprint

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Mix, H., Weiler-Normann, C., Thimme, R., Ahlenstiel, G., Shin, E. C., Herkel, J., David, C. S., Lohse, A. W., & 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