A key role for autoreactive B cells in the breakdown of T-cell tolerance to pyruvate dehydrogenase complex in the...

The key immunological event in the pathogenesis of the autoimmune liver disease primary biliary cirrhosis is breakdown of T-cell self-tolerance to pyruvate dehydrogenase complex (PDC). The mechanism resulting in this breakdown of tolerance remains unclear. Mice exposed to self-PDC mount no immune response; however, animals coexposed to self-PDC and PDC of foreign origin (which in isolation induces a cross-reactive antibody but not an autoreactive T-cell response) show breakdown of T-cell as well as B-cell tolerance. This observation raises the possibility that a cross-reactive antibody response to self-PDC can promote breakdown of T-cell tolerance. The aim of this study was to address the hypothesis that breakdown of T-cell tolerance to PDC can be driven by the presence of B cells and/or antibodies cross-reactive with this self-antigen. Naive female SJL/J mice were exposed to self-PDC alone and in the presence of purified splenic B cells from animals primed with foreign PDC (or controls) or purified immunoglobulin (Ig) G from the same animals. Breakdown of T-cell tolerance was assessed by splenic T-cell proliferative response to antigen at 5 weeks. CD4(+) T-cell proliferative responses indicative of breakdown of T-cell tolerance to self-PDC were seen in the majority (7 of 9, 78%) of animals receiving self-PDC together with purified PDC-reactive B cells. Tolerance breakdown was not seen in animals receiving self-PDC with purified anti-PDC IgG or with B cells from animals sensitized with an irrelevant antigen. In conclusion, breakdown of T-cell tolerance to the highly conserved self-antigen PDC may be mediated by high-level presentation of self-derived epitopes by activated cross-reactive B cells.