The most difficult issue in autoimmunity remains etiology. Although data exist on effector mechanisms in many autoimmune diseases, the underlying cause or causes are still generically ascribed to genetics and environmental influences. Primary biliary cirrhosis (PBC) is considered a model autoimmune disease because of its signature antimitochondrial autoantibody (AMA), the homogeneity of clinical characteristics, and the specificity of biliary epithelial cell (BEC) pathology. Twenty years ago, we reported the cloning and identification of the E2 component of pyruvate dehydrogenase (PDC-E2) as the immunodominant autoantigen of PBC, allowing for vigorous dissection of T and B lymphocyte responses against PDC-E2 and development of several valid experimental models. There has also been considerable study of the biology of BECs, which has included the unique properties of apoptosis in which there is exposure of PDC-E2 to the effector processes of the immune system. In this review, we present these data in the context of our proposal that the proximal cause of PBC is autoimmunity directed against well-identified mitochondrially located autoantigens in individuals with inherited deficits of immune tolerance. We present these data under the umbrella of convenient truths that support this thesis as well as some inconvenient truths that are not readily accommodated by current theory. Conclusion: We emphasize that the potential initiator of PBC includes inter alia particular environmental xenobiotics; pathogenesis is aided and abetted by genetic weaknesses in mechanisms of immune regulation; and subsequent multilineage immunopathology impacts upon uniquely susceptible BECs to culminate clinically in the chronic autoimmune cholangiolitis of PBC.
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