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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. (HEPATOLOGY 2008;47:737-745.)

The classification of adults with diabetes mellitus can be invalidated by patients who initially present as NIDDM but who later become frankly insulin dependent. In some of these, the pathogenesis could be similar to that in IDDM, namely autoimmune destruction of the pancreatic p-cells. We studied 102 patients >35 yr of age at diabetes onset who had initially been nonketotic and non-insulin-dependent for >6 mo. They were classified according to glucagonstimulated C-peptide levels into an insulin-deficient group (n = 33) and a non-insulin-deficient group (n = 69). We measured antibodies to GAD, islet cell cytoplasm, thyroid antigens, and gastric parietal cells in both groups. Anti-GAD was significantly higher in the insulin deficient group, 76% (25 of 33), than in the non-insulin deficient group, 12% (8 of 69), and this difference was substantially greater than that shown for ICAs. Thus, in a proportion of adults who present with NIDDM, a slowly evolving autoimmune insulitis can be revealed by testing for anti-GAD. This could have important connotations not only for early intervention, but also for the correct classification of diabetes. Diabetes 42:359-62,1993