TY - JOUR
T1 - Toward solving the etiological mystery of primary biliary cholangitis
AU - Tanaka, Atsushi
AU - Leung, Patrick S.C.
AU - Young, Howard A.
AU - Gershwin, M. Eric
N1 - Publisher Copyright:
© 2017 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
PY - 2017
Y1 - 2017
N2 - Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti-mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome-wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced by chemical xenobiotic immunization, and by “designer” mice with altered interferon metabolism. Herein, we describe five such models, including 1) NOD.c3c4 mice, 2) dominant negative form of transforming growth factor receptor type II mice, 3) interleukin-2R α−/− mice, 4) adenylate-uridylate-rich element Del−/− mice, and 5) 2-octynoic acid-conjugated bovine serum albumin immunized mice. Individually there is no perfect murine model, but collectively the models point to loss of tolerance to PDC-E2, the major mitochondrial autoantigen, as the earliest event that occurs before clinical disease is manifest. Although there is no direct association of AMA titer and PBC disease progression, it is noteworthy that the triad of PBC monocytes, biliary apotopes, and AMA leads to an intense proinflammatory cytokine burst. Further, the recurrence of PBC after liver transplantation indicates that, due to major histocompatibility complex restriction, disease activity must include not only adaptive immunity but also innate immune mechanisms. We postulate that successful treatment of PBC may require a personalized approach with therapies designed for different stages of disease. (Hepatology Communications 2017;1:275–287).
AB - Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti-mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome-wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced by chemical xenobiotic immunization, and by “designer” mice with altered interferon metabolism. Herein, we describe five such models, including 1) NOD.c3c4 mice, 2) dominant negative form of transforming growth factor receptor type II mice, 3) interleukin-2R α−/− mice, 4) adenylate-uridylate-rich element Del−/− mice, and 5) 2-octynoic acid-conjugated bovine serum albumin immunized mice. Individually there is no perfect murine model, but collectively the models point to loss of tolerance to PDC-E2, the major mitochondrial autoantigen, as the earliest event that occurs before clinical disease is manifest. Although there is no direct association of AMA titer and PBC disease progression, it is noteworthy that the triad of PBC monocytes, biliary apotopes, and AMA leads to an intense proinflammatory cytokine burst. Further, the recurrence of PBC after liver transplantation indicates that, due to major histocompatibility complex restriction, disease activity must include not only adaptive immunity but also innate immune mechanisms. We postulate that successful treatment of PBC may require a personalized approach with therapies designed for different stages of disease. (Hepatology Communications 2017;1:275–287).
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U2 - 10.1002/hep4.1044
DO - 10.1002/hep4.1044
M3 - Review article
AN - SCOPUS:85036597360
VL - 1
SP - 275
EP - 287
JO - Hepatology Communications
JF - Hepatology Communications
SN - 2471-254X
IS - 4
ER -