{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:42:56Z","timestamp":1791222176047,"version":"4.1.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We previously reported that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial Abs, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis. In this article, we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in polycystic kidney and hepatic disease 1 (Pkhd1). We show that a long terminal repeat element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated Pkhd1 transcript. A novel NOD congenic mouse expressing aberrant Pkhd1, but lacking the c3 and c4 chromosomal regions (NOD.Abd3), reproduces the immunopathological features of NOD ABD. RNA sequencing of NOD.Abd3 common bile duct early in disease demonstrates upregulation of genes involved in cholangiocyte injury\/morphology and downregulation of immunoregulatory genes. Consistent with this, bone marrow chimera studies show that aberrant Pkhd1 must be expressed in the target tissue (cholangiocytes) and the immune system (bone marrow). Mutations of Pkhd1 produce biliary abnormalities in mice but have not been previously associated with autoimmunity. In this study, we eliminate clinical biliary disease by backcrossing this Pkhd1 mutation onto the C57BL\/6 genetic background; thus, the NOD genetic background (which promotes autoimmunity) is essential for disease. We propose that loss of functional Pkhd1 on the NOD background produces early bile duct abnormalities, initiating a break in tolerance that leads to autoimmune cholangitis in NOD.Abd3 congenic mice. This model is important for understanding loss of tolerance to cholangiocytes and is relevant to the pathogenesis of several human cholangiopathies.<\/jats:p>","DOI":"10.4049\/jimmunol.1701087","type":"journal-article","created":{"date-parts":[[2017,11,20]],"date-time":"2017-11-20T16:50:25Z","timestamp":1511196625000},"page":"147-162","source":"Crossref","is-referenced-by-count":11,"title":["A Novel <i>Pkhd1<\/i> Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis"],"prefix":"10.1093","volume":"200","author":[{"given":"Wenting","family":"Huang","sequence":"first","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine , Cincinnati, OH 45267"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel B","family":"Rainbow","sequence":"additional","affiliation":[{"name":"JDRF\/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford , Oxford OX3 7BN,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehong","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine , Cincinnati, OH 45267"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Adams","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine , Cincinnati, OH 45267"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2095-0623","authenticated-orcid":false,"given":"Pranavkumar","family":"Shivakumar","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3979-2220","authenticated-orcid":false,"given":"Leah","family":"Kottyan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekah","family":"Karns","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Aronow","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9667-7742","authenticated-orcid":false,"given":"Jorge","family":"Bezerra","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children\u2019s Hospital Medical Center , Cincinnati, OH 45229"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Eric","family":"Gershwin","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis , Davis, CA 95616"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence B","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Merck Research Laboratories , Rahway, NJ 07065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7771-0324","authenticated-orcid":false,"given":"Linda S","family":"Wicker","sequence":"additional","affiliation":[{"name":"JDRF\/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust Center for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford , Oxford OX3 7BN,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M","family":"Ridgway","sequence":"additional","affiliation":[{"name":"Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine , Cincinnati, OH 45267"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,1,1]]},"reference":[{"key":"2025030610003452700_r1","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1056\/NEJMra043898","article-title":"Primary biliary cirrhosis","volume":"353","author":"Kaplan","year":"2005","journal-title":"N. 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