A key role for autoreactive B cells in the breakdown of T‐cell tolerance to pyruvate dehydrogenase complex in the mouse†

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Abstract
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. (HEPATOLOGY 2005.)