Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis

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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 P4S0dbl, 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 cells. Five 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 phytohacmagglutinin 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.