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

TY - JOUR

T1 - Identification of CD4 T-cell epitopes in soluble liver antigen/liver pancreas autoantigen in autoimmune hepatitis.

AU - Mix, Heiko

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

PY - 2008

Y1 - 2008

N2 - 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-gamma 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.

AB - 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-gamma 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 135

SP - 2107

EP - 2118

JO - GASTROENTEROLOGY

JF - GASTROENTEROLOGY

SN - 0016-5085

IS - 6

M1 - 6

ER -