Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis

Hepatology. 1996 Dec;24(6):1416-21. doi: 10.1002/hep.510240619.

Abstract

Peripheral blood mononuclear cells (PBMC) of patients with autoimmune hepatitis (AIH) and controls were studied for their proliferative response to six overlapping synthetic peptides covering the 33-amino acid immunodominant region of cytochrome P450IID6, the main target antigen of LKM-1 antibody-positive type II AIH. PBMC from 8 of 8 type II AIH patients (100%), 6 of 12 LKM-1 antibody-negative type I AIH patients (50%), but only 4 of 31 patients with chronic hepatitis C (12.9%) reacted with a 23-amino acid LKM peptide and mainly with a shorter 18-amino acid LKM peptide. Follow-up showed that LKM-specific T-cell responses decreased after immunosuppression had started. Fine specificity, HLA restriction, and cytokine release of LKM-specific T cells were analyzed with 16 CD4+ peptide-specific T-cell lines and 21 CD4+ T-cell clones isolated and expanded from blood and liver tissue of six AIH patients. Activated LKM-specific T cells released interferon gamma (IFN-gamma) but no or little interleukin-4. In three AIH patients, PBMC showed specific recognition of autologous LKM-specific T cells, suggesting the presence of a regulatory T-cell network. These T cells also showed the CD4+ phenotype and secreted large amounts of IFN-gamma. Furthermore, it was assessed that the regulatory T-cell response is clonotypic. To conclude, we describe a major T-cell epitope in AIH that was recognized by Th1 helper cells isolated from blood and liver tissue. This autoreactive T-cell response correlated widely with disease activity and LKM-1 antibody status and seemed to be regulated by anticlonotypic T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Antibodies, Monoclonal
  • Autoantibodies / blood*
  • Autoantibodies / chemistry
  • Autoimmune Diseases / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Female
  • HLA-D Antigens / analysis
  • Hepatitis / immunology*
  • Humans
  • Immunophenotyping
  • Lymphocyte Activation
  • Male
  • Microsomes / immunology
  • Middle Aged
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • T-Lymphocytes / immunology*

Substances

  • Antibodies, Monoclonal
  • Autoantibodies
  • Cytokines
  • HLA-D Antigens
  • Peptide Fragments
  • anti-liver kidney microsome antibody