Breakdown of tolerance to pyruvate dehydrogenase complex in experimental autoimmune cholangitis: A mouse model of primary biliary cirrhosis

The autoimmune liver disease primary biliary cirrhosis (PBC) is characteriz ed by autoreactive responses to a highly conserved self-antigen, pyruvate d ehydrogenase complex (PDC), We recently reported the development of PBC-lik e lesions in SJL mice sensitized with PDC and have named this model disease experimental autoimmune cholangitis (EAC), In the present study, the break down of tolerance to PDC has been investigated in animals sensitized for EA C, 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 l ikelihood of extensive sequence homology with mouse PDC (there is a greater than 95% sequence identity between rat and human PDC-E2 subunits), bPDC wa s highly immunogenic inducing significant T- and B-cell responses in the ab sence of any form of adjuvant. The multi-subunit quaternary structure of in tact PDC was critical for this immunostimulatory activity because no respon se was produced by sensitization with monomeric recombinant PDC-E2 inner li poyl 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 toleran ce to self-PDC took significantly longer, not being seen until 20 weeks pos tsensitization; a similar length of time to that previously shown to be req uired for EAC lesion development. Conclusions drawn from these data may hav e important implications for our understanding, and therapeutic manipulatio n, of PBC in humans.