Autoreactive liver-infiltrating T cells in primary biliary cirrhosis recognize inner mitochondrial epitopes and the pyruvate dehydrogenase complex.
Primary biliary cirrhosis (PBC) is characterized by lymphoid infiltrates in the portal tracts of the liver and the occurrence of antimitochondrial autoantibodies in serum directed against components of the pyruvate dehydrogenase complex and the other alpha-keto acid dehydrogenase complexes. These enzymes are located on the inner mitochondrial membrane. The destruction of the biliary tract in PBC is thought to be mediated by autoreactive liver-infiltrating T cells exerting cytotoxic activity or releasing certain lymphokines. In this study the reactivity of liver infiltrating T cells was shown to a bovine pyruvate dehydrogenase complex (PDH), a purified E2 subunit (PDH-E2) and a crude preparation of human liver mitoplasts (HLM), i.e. mitochondria depleted of their outer membranes. Peripheral blood lymphocytes (PBL) from 11 of 15 patients (73.3%) with PBC showed a HLA class II-restricted proliferative response to the PDH complex whereas PBL from patients with chronic viral hepatitis, autoimmune hepatitis or extrahepatic cholestatic icterus (n = 20) and healthy controls (n = 5) did not. In addition 13 of 15 PBL from patients with PBC (86.6%) and three of nine PBL from patients with autoimmune hepatitis (33.3%) reacted with the crude HLM preparation whereas no reactivity was found with PBL from eight patients with chronic viral hepatitis, three patients with extrahepatic cholestasis or five healthy controls. Clonal analysis of 115 liver-infiltrating T cells derived from two diagnostic liver biopsies of patients with PBC revealed a predominance of activated CD4+CD8- T helper cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Löhr
H
H
I. Department of Internal Medicine, University of Mainz, Germany.
Fleischer
B
B
Gerken
G
G
Yeaman
S J
SJ
Meyer zum Büschenfelde
K H
KH
Manns
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000032:analysis / Q000276:immunology; D001323:Autoantibodies / Q000032:analysis* / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000032:analysis / Q000276:immunology*; D005260:Female; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000648:ultrastructure; D008105:Liver Cirrhosis, Biliary / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000201:enzymology / Q000276:immunology* / Q000648:ultrastructure; D010641:Phenotype; D011768:Pyruvate Dehydrogenase Complex / Q000032:analysis / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D000939:Epitopes; D011768:Pyruvate Dehydrogenase Complex