Autoreactive CD4+ LKM-specific and anticlonotypic T-cell responses in LKM-1 antibody-positive autoimmune hepatitis.
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.
Löhr
H F
HF
Department of Internal Medicine, Johannes Gutenberg-University Mainz, Germany.
Schlaak
J F
JF
Lohse
A W
AW
Böcher
W O
WO
Arenz
M
M
Gerken
G
G
Meyer Zum Büschenfelde
K H
KH
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000097:blood* / Q000737:chemistry; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006681:HLA-D Antigens / Q000032:analysis; D006505:Hepatitis / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008297:Male; D008861:Microsomes / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D016207:Cytokines; D006681:HLA-D Antigens; D010446:Peptide Fragments; C060729:anti-liver kidney microsome antibody