CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis.
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.
Shimoda
Shinji
S
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
Miyakawa
Hiroshi
H
Nakamura
Minoru
M
Ishibashi
Hiromi
H
Kikuchi
Kentaro
K
Kita
Hiroto
H
Niiro
Hiroaki
H
Arinobu
Youjirou
Y
Ono
Nobuyuki
N
Mackay
Ian R
IR
Gershwin
M Eric
ME
Akashi
Koichi
K
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
D001323:Autoantibodies; D001324:Autoantigens; D024101:Mitochondrial Proteins; D010455:Peptides; C052359:DLAT protein, human; D051047:Dihydrolipoyllysine-Residue Acetyltransferase