title: CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis.
abstract: Approximately 5% of patients with primary biliary cirrhosis (PBC) lack characteristic anti-mitochondrial antibodies (AMA). Yet clinically AMA+ and AMA- patients are similar. Using both AMA+ and AMA- patients, we quantitated the frequency of autoreactive T cells that respond to the major CD4 T-cell epitope, PDC-E2 163-176, using limiting dilution assays and quantitation of IFN-gamma, IL-10 and IL-4. Further, based on data that both PBC patients and healthy subjects have CD4+ T cells that recognize PDC-E2 163-176 but with differing costimulation requirements, assays were performed using two different antigen-presenting cell (APC) systems: either autologous peripheral blood mononuclear cells (PBMC) or HLA DR53 transfected mouse fibroblast cell lines (L-DR53). When costimulation-incompetent L-DR53 were used as APCs, the PDC-E2 CD4 T-cell frequency and capacity for IFN-gamma production were equivalent in both AMA+ and AMA- patients but the frequencies of such cells were significantly lower in normals, with IL-10 production similar in all three groups. Thus, in PBC there is 'universal' autoreactive CD4+ T-cell immune responsiveness to the critical autoantigen, PDC-E2. These observations emphasize that the mitochondrial autoreactivity in PBC is a multi-lineage response and hence, AMA-negative PBC may be an anachronism that refers only to sera autoantibodies.
authors.affiliation: Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. sshimoda@intmed1.med.kyushu-u.ac.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Shimoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyakawa
authors.forename: Minoru
authors.initials: M
authors.lastname: Nakamura
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ishibashi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kita
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Niiro
authors.forename: Youjirou
authors.initials: Y
authors.lastname: Arinobu
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ono
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackay
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024101:Mitochondrial Proteins; D010455:Peptides; C052359:DLAT protein, human; D051047:Dihydrolipoyllysine-Residue Acetyltransferase