1. There is strong and compelling evidence to support molecular mechanisms of cross-reactivity between the PDC-E2 lipoic acid co-factor and environmental xenobiotics inducing auto-immunogenity of modified self-PDC-E2. Animal modeling data would argue that a cross-reactive B cell response induced to xenobioticmodified self-PDC can, through a process of epitope spreading driven by antigen-specific cross-reactive B cells, translate into the breakdown of T cell tolerance responsible for the effector T cell mechanisms thought to be directly responsible for BEC loss. The clinical implication of this observation again is that immunomodulatory approaches to therapy should play a role particularly in the earliest stages of PBC. 2. Alternatively or in addition, molecular mimicry mechanisms with cross-reactivity between self-PDC and bacterial or potentially viral structures may support or induce breakdown of tolerance.