title: Investigation of a mechanism for accelerated breakdown of immune tolerance to the primary biliary cirrhosis-associated autoantigen, pyruvate dehydrogenase complex.
abstract: Primary biliary cirrhosis (PBC) is an autoimmune liver disease characterized by autoreactive T- and B-cell responses to the highly conserved enzyme pyruvate dehydrogenase complex (PDC). In this study we have examined the breakdown of T-cell tolerance to self-PDC using a mouse model. Female SJL/J mice were sensitized intraperitoneally with foreign-PDC (bovine) and/or self-PDC (murine) in complete Freund's adjuvant, and serum, spleen, and liver tissue was taken 8 weeks later. Animals sensitized with foreign-PDC produced IgG antibodies that were reactive with both foreign and self-PDC, but splenic T cells from these animals only responded to stimulation with foreign PDC. Sensitization with self-PDC elicited neither antibodies nor reactive T cells. Significantly, cosensitization with mixed self-PDC and foreign-PDC resulted in a full breakdown of self-tolerance, with generation of both antibody and T-cell responses to self-PDC of the type seen exclusively in human PBC patients. Mild bile duct lesions deficient in CD8(+) T cells were seen 8 weeks after sensitization with either foreign or self-PDC. However, after sensitization with mixed self-PDC and foreign-PDC, these lesions were significantly larger and heavily infiltrated by CD8(+) T cells. Liver-infiltrating T cells derived from the self-PDC and foreign-PDC cosensitized but not from control animals showed reactivity with self-PDC, suggesting a possible role for autoreactive PDC-specific T-cell responses in the pathogenesis of the observed histologic changes. It is likely that B-cell cross-reactivity between foreign and self-PDC enhances the potential for breakdown of T-cell self-tolerance by allowing efficient presentation of self-antigens in the inoculum. This model may provide a useful system for investigating the etiology and treatment of PBC.
authors.affiliation: Centre for Liver Research, University of Newcastle, Framlington Place, Newcastle-upon-Tyne, United Kingdom. D.E.Jones@ncl.ac.uk
authors.forename: David E J
authors.initials: DE
authors.lastname: Jones
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Palmer
authors.forename: Kate
authors.initials: K
authors.lastname: Bennett
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Robe
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Yeaman
authors.forename: Helen
authors.initials: H
authors.lastname: Robertson
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Bassendine
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Burt
authors.forename: John A
authors.initials: JA
authors.lastname: Kirby
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002455:Cell Division; D005260:Female; D007108:Immune Tolerance; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D051379:Mice; D010641:Phenotype; D011768:Pyruvate Dehydrogenase Complex / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D001324:Autoantigens; D011768:Pyruvate Dehydrogenase Complex