title: Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis.
abstract: Autoantibodies against microsomal antigen of liver and kidney (LKM-1) are diagnostic markers for a subgroup of autoimmune chronic active hepatitis (AI-CAH). Cytochrome P450dbl, now classified as cytochrome P450 IID6, is the major antigen of LKM-1 antibodies. Immunohistological studies suggest that hepatic injury in AI-CAH is mediated by liver-infiltrating T cells. In the present study the specificity and function of liver-infiltrating T cells was analysed at the clonal level. Phenotypical characterization of 189 T cell clones isolated from four liver biopsies of LKM-1 antibody-positive patients showed an enrichment of CD4+ CD8- T cell clones proliferated specifically in the presence of recombinant human LKM-1 antigen (rLKM). This reaction was restricted to autologous antigen-presenting cells and to HLA class II molecules. In order to see whether rLKM was also recognized by peripheral blood T lymphocytes (PBL) we tested the proliferative response of PBL from several individuals. PBL from three of the four patients with LKM-1 antibody-positive AI-CAH proliferated to rLKM, whereas no response was seen with PBL from patients with LKM-1 antibody-negative chronic liver diseases and from healthy blood donors. These data demonstrate that the LKM-1 antigen is recognized by liver-infiltrating T cells in LKM-1 antibody-positive AI-CAH. For further functional characterization, liver-derived T cell clones were tested for their cytotoxic activity. In the presence of phytohaemagglutinin 24 out of 26 CD4- CD8+ but also 20 out of 63 CD4+ CD8- T cell clones lysed autologous as well as allogenic EBV-transformed B cell lines or K562 cells. Five CD4- CD8+ T cell clones lysed autologous but not allogenic B cell lines spontaneously in a HLA class I-restricted manner. Although the antigen specificity of these clones is still unknown the data show the presence of autoreactive T cells at the site of inflammation that could contribute in the pathogenesis of AI-CAH.
authors.affiliation: First Department of Medicine, University of Mainz, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Löhr
authors.forename: M
authors.initials: M
authors.lastname: Manns
authors.forename: A
authors.initials: A
authors.lastname: Kyriatsoulis
authors.forename: A W
authors.initials: AW
authors.lastname: Lohse
authors.forename: C
authors.initials: C
authors.lastname: Trautwein
authors.forename: K H
authors.initials: KH
authors.lastname: Meyer zum Büschenfelde
authors.forename: B
authors.initials: B
authors.lastname: Fleischer
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D005260:Female; D006521:Hepatitis, Chronic / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D008099:Liver / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013936:Thymidine / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D001323:Autoantibodies; D011994:Recombinant Proteins; C060729:anti-liver kidney microsome antibody; D013936:Thymidine