{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:48:30Z","timestamp":1790113710637,"version":"4.0.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2011,9,12]],"date-time":"2011-09-12T00:00:00Z","timestamp":1315785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,9,12]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>A void in understanding primary biliary cirrhosis (PBC) is the absence of appropriate animal models. Our laboratory has studied a murine model of autoimmune cholangitis induced following immunization with 2-octynoic acid (2OA), an antigen identified following extensive quantitative structural activity relationship (QSAR) analysis, using human autoantibodies and three-dimensional analysis of the mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). Mice immunized with 2OA coupled to bovine serum albumin (BSA) develop anti-mitochondrial antibodies (AMAs) of the identical specificity as humans with PBC, and in addition develop inflammatory portal cell infiltrates in liver. However, the natural history of disease is less severe than in humans and does not include fibrosis. Data from human and autoimmune murine models suggest that environmental and\/or infectious agents can exacerbate autoimmune reactions, and a model of PBC has been described in which polyinosinic-polycytidylic acid (poly I:C), a viral RNA mimetic and Toll-like receptor 3 (TLR-3) agonist induces low-titre AMAs and in mild portal infiltrates. We took advantage of our established model to determine whether immunization with 2OA-BSA coupled with poly I:C alters the disease process. Indeed, the addition of poly I:C produces a profound exacerbation of autoimmune cholangitis, including a significant increase in CD8+ infiltrating T cells, as well as a marked increase of proinflammatory cytokines. In addition, mice have evidence of fibrosis. These findings lend support to the concept that besides breakdown of self-tolerance, there is a requirement of a second \u2018hit\u2019 during the breakdown process that leads to disease which more faithfully mimics human PBC.<\/jats:p>","DOI":"10.1111\/j.1365-2249.2011.04453.x","type":"journal-article","created":{"date-parts":[[2011,7,5]],"date-time":"2011-07-05T09:27:17Z","timestamp":1309858037000},"page":"110-120","source":"Crossref","is-referenced-by-count":35,"title":["The multi-hit hypothesis of primary biliary cirrhosis: polyinosinic-polycytidylic acid (poly I:C) and murine autoimmune cholangitis"],"prefix":"10.1093","volume":"166","author":[{"given":"Y M","family":"Ambrosini","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G-X","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Shu","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Tsuneyama","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, JapanJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P S C","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A A","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Pathology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R L","family":"Coppel","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Monash University, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M E","family":"Gershwin","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, Davis, 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