{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T06:09:56Z","timestamp":1777442996356,"version":"3.51.4"},"reference-count":100,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T00:00:00Z","timestamp":1495065600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti\u2010mitochondrial 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\u2010wide 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 \u201cdesigner\u201d 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\u20102R \u03b1<jats:sup>\u2212\/\u2212<\/jats:sup>mice, 4) adenylate\u2010uridylate\u2010rich element Del<jats:sup>\u2212\/\u2212<\/jats:sup>mice, and 5) 2\u2010octynoic acid\u2010conjugated bovine serum albumin immunized mice. Individually there is no perfect murine model, but collectively the models point to loss of tolerance to PDC\u2010E2, 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. 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Eric","family":"Gershwin","sequence":"additional","affiliation":[{"name":"Division of Rheumatology Allergy and Clinical Immunology,University of California School of Medicine,Davis,CA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2017,5,18]]},"reference":[{"key":"hep41044-bib-0001-20240114","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1056\/NEJMra043898","article-title":"Primary biliary cirrhosis","volume":"353","year":"2005","journal-title":"New Engl J Med"},{"key":"hep41044-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/hep.22906","article-title":"Primary biliary cirrhosis","volume":"50","year":"2009","journal-title":"Hepatology"},{"key":"hep41044-bib-0003-20240114","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1055\/s-2007-1007183","article-title":"Antimitochondrial antibodies in primary biliary cirrhosis","volume":"17","year":"1997","journal-title":"Semin Liver Dis"},{"key":"hep41044-bib-0004-20240114","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1586\/14737159.2016.1164038","article-title":"A contemporary perspective on the molecular characteristics of mitochondrial autoantigens and diagnosis in primary biliary cholangitis","volume":"16","year":"2016","journal-title":"Expert Rev Mol Diagn"},{"key":"hep41044-bib-0005-20240114","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1002\/hep.28140","article-title":"Changing nomenclature for PBC: from \u2018cirrhosis\u2019 to \u2018cholangitis","volume":"62","year":"2015","journal-title":"Hepatology"},{"key":"hep41044-bib-0006-20240114","first-page":"387","article-title":"Primary biliary cirrhosis. 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