Identification of CD4 T-cell epitopes in soluble liver antigen/liver pancreas autoantigen in autoimmune hepatitis.

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.
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.
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-gamma ELISpot assays.
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.
AuthorsHeiko Mix, Christina Weiler-Normann, Robert Thimme, Golo Ahlenstiel, Eui-Cheol Shin, Johannes Herkel, Chella S David, Ansgar W Lohse, Barbara Rehermann
JournalGastroenterology (Gastroenterology) Vol. 135 Issue 6 Pg. 2107-18 (Dec 2008) ISSN: 1528-0012 [Electronic] United States
PMID18773898 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Autoantibodies
  • Autoantigens
  • Epitopes, T-Lymphocyte
  • liver antigen LA-1
  • Adult
  • Aged
  • Animals
  • Autoantibodies (immunology, metabolism)
  • Autoantigens (immunology, metabolism)
  • CD4-Positive T-Lymphocytes (immunology)
  • Disease Models, Animal
  • Epitopes, T-Lymphocyte (immunology, metabolism)
  • Female
  • Hepatitis, Autoimmune (immunology, pathology)
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Young Adult

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