title: Breakdown of tolerance to pyruvate dehydrogenase complex in experimental autoimmune cholangitis: a mouse model of primary biliary cirrhosis.
abstract: The autoimmune liver disease primary biliary cirrhosis (PBC) is characterized by autoreactive responses to a highly conserved self-antigen, pyruvate dehydrogenase complex (PDC). We recently reported the development of PBC-like lesions in SJL mice sensitized with PDC and have named this model disease experimental autoimmune cholangitis (EAC). In the present study, the breakdown of tolerance to PDC has been investigated in animals sensitized for EAC. Splenic mononuclear cells from SJL mice sensitized with bovine heart PDC (bPDC) in adjuvant showed T-cell proliferative and mixed Th1/Th2 cytokine secretory responses following in vitro stimulation with bPDC. Despite the likelihood of extensive sequence homology with mouse PDC (there is a greater than 95% sequence identity between rat and human PDC-E2 subunits), bPDC was highly immunogenic inducing significant T- and B-cell responses in the absence of any form of adjuvant. The multi-subunit quaternary structure of intact PDC was critical for this immunostimulatory activity because no response was produced by sensitization with monomeric recombinant PDC-E2 inner lipoyl domain. Mice sensitized with bPDC and CFA developed, within 2 weeks of sensitization, high-titer antibody responses reactive with bPDC that were fully cross-reactive with the murine homologue. Breakdown of T-cell tolerance to self-PDC took significantly longer, not being seen until 20 weeks postsensitization; a similar length of time to that previously shown to be required for EAC lesion development. Conclusions drawn from these data may have important implications for our understanding, and therapeutic manipulation, of PBC in humans.
authors.affiliation: Centre for Liver Research, University of Newcastle, Framlington Place, Newcastle-upon-Tyne, UK. D.E.J.Jones@ncl.ac.uk
authors.forename: D E
authors.initials: DE
authors.lastname: Jones
authors.forename: J M
authors.initials: JM
authors.lastname: Palmer
authors.forename: S J
authors.initials: SJ
authors.lastname: Yeaman
authors.forename: J A
authors.initials: JA
authors.lastname: Kirby
authors.forename: M F
authors.initials: MF
authors.lastname: Bassendine
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000201:enzymology*; D002417:Cattle; D002761:Cholangitis / Q000201:enzymology / Q000276:immunology*; D003429:Cross Reactions; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000201:enzymology / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D051381:Rats; D013154:Spleen / Q000276:immunology; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D011768:Pyruvate Dehydrogenase Complex