{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T15:33:02Z","timestamp":1789831982574,"version":"4.0.1"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI 1148589"],"award-info":[{"award-number":["KAKENHI 1148589"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["1074364"],"award-info":[{"award-number":["1074364"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004948","name":"Astellas Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004948","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Gastroenterol"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Patients with primary sclerosing cholangitis (PSC) possess autoantibodies against biliary epithelial cells. However, the target molecules remain unknown.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The sera of patients with PSC and controls were subjected to enzyme-linked immunosorbent assays to detect autoantibodies using recombinant integrin proteins. Integrin \u03b1v\u03b26 expression in the bile duct tissues was examined using immunofluorescence. The blocking activity of the autoantibodies was examined using solid-phase binding assays.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Anti-integrin \u03b1v\u03b26 antibodies were detected in 49\/55 (89.1%) patients with PSC and 5\/150 (3.3%) controls (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), with a sensitivity and specificity of 89.1% and 96.7%, respectively, for PSC diagnosis. When focusing on the presence or absence of IBD, the proportion of the positive antibodies in PSC with IBD was 97.2% (35\/36) and that in PSC alone was 73.7% (14\/19) (<jats:italic>P<\/jats:italic>\u2009=\u20090.008). Integrin \u03b1v\u03b26 was expressed in bile duct epithelial cells. Immunoglobulin (Ig)G from 15\/33 patients with PSC blocked integrin \u03b1v\u03b26-fibronectin binding through an RGD (Arg\u2013Gly\u2013Asp) tripeptide motif.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Autoantibodies against integrin \u03b1v\u03b26 were detected in most patients with PSC; anti-integrin \u03b1v\u03b26 antibody may serve as a potential diagnostic biomarker for PSC.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00535-023-02006-6","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T10:02:23Z","timestamp":1686650543000},"page":"778-789","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Anti-integrin \u03b1v\u03b26 autoantibodies in patients with primary sclerosing cholangitis"],"prefix":"10.1007","volume":"58","author":[{"given":"Hiroyuki","family":"Yoshida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1551-8721","authenticated-orcid":false,"given":"Masahiro","family":"Shiokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kuwada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Muramoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakiko","family":"Ota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Nishikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirona","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Kakiuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Yamazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Yokode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeharu","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimpei","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomonori","family":"Hirano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saiko","family":"Marui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Sogabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoaki","family":"Matsumori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Mima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norimitsu","family":"Uza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Eso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Takai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihide","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzo","family":"Kodama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Chiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Seno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"2006_CR1","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1056\/NEJMra1506330","volume":"375","author":"KN Lazaridis","year":"2016","unstructured":"Lazaridis KN, LaRusso NF. Primary sclerosing cholangitis. N Engl J Med. 2016;375:1161\u201370.","journal-title":"N Engl J Med"},{"key":"2006_CR2","doi-asserted-by":"publisher","first-page":"2547","DOI":"10.1016\/S0140-6736(18)30300-3","volume":"391","author":"JK Dyson","year":"2018","unstructured":"Dyson JK, Beuers U, Jones DEJ, et al. Primary sclerosing cholangitis. The Lancet. 2018;391:2547\u201359.","journal-title":"The Lancet"},{"key":"2006_CR3","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1007\/s00535-020-01681-z","volume":"55","author":"M Vesterhus","year":"2020","unstructured":"Vesterhus M, Karlsen TH. Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities. J Gastroenterol. 2020;55:588\u2013614.","journal-title":"J Gastroenterol"},{"key":"2006_CR4","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1007\/s00535-020-01663-1","volume":"55","author":"Z Bakhshi","year":"2020","unstructured":"Bakhshi Z, Hilscher MB, Gores GJ, et al. An update on primary sclerosing cholangitis epidemiology, outcomes and quantification of alkaline phosphatase variability in a population-based cohort. J Gastroenterol. 2020;55:523\u201332.","journal-title":"J Gastroenterol"},{"key":"2006_CR5","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1007\/s00535-018-1484-9","volume":"53","author":"H Isayama","year":"2018","unstructured":"Isayama H, Tazuma S, Kokudo N, et al. Clinical guidelines for primary sclerosing cholangitis 2017. J Gastroenterol. 2018;53:1006\u201334.","journal-title":"J Gastroenterol"},{"key":"2006_CR6","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.1053\/j.gastro.2007.01.039","volume":"132","author":"A Karrar","year":"2007","unstructured":"Karrar A, Broome U, Sodergren T, et al. Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis. Gastroenterology. 2007;132:1504\u201314.","journal-title":"Gastroenterology"},{"key":"2006_CR7","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1136\/gut.51.1.120","volume":"51","author":"B Xu","year":"2002","unstructured":"Xu B, Broome U, Ericzon B-G, et al. High frequency of autoantibodies in patients with primary sclerosing cholangitis that bind biliary epithelial cells and induce expression of CD44 and production of interleukin 6. Gut. 2002;51:120\u20137.","journal-title":"Gut"},{"issue":"2383\u201394","key":"2006_CR8","volume":"160","author":"T Kuwada","year":"2021","unstructured":"Kuwada T, Shiokawa M, Kodama Y, et al. Identification of an anti-integrin alphavbeta6 autoantibody in patients with ulcerative colitis. Gastroenterology. 2021;160(2383\u201394): e21.","journal-title":"Gastroenterology"},{"key":"2006_CR9","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1038\/s41591-022-01680-y","volume":"28","author":"M Uzzan","year":"2022","unstructured":"Uzzan M, Martin JC, Mesin L, et al. Ulcerative colitis is characterized by a plasmablast-skewed humoral response associated with disease activity. Nat Med. 2022;28:766\u201379.","journal-title":"Nat Med"},{"key":"2006_CR10","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.3390\/jcm11071881","volume":"11","author":"N Rydell","year":"2022","unstructured":"Rydell N, Ekoff H, Hellstrom PM, et al. Measurement of serum IgG anti-integrin alphavbeta6 autoantibodies is a promising tool in the diagnosis of ulcerative colitis. J Clin Med. 2022;11:1881.","journal-title":"J Clin Med."},{"key":"2006_CR11","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/0092-8674(92)90115-S","volume":"69","author":"R Hynes","year":"1992","unstructured":"Hynes R. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69:11\u201325.","journal-title":"Cell"},{"key":"2006_CR12","doi-asserted-by":"publisher","first-page":"2241","DOI":"10.1242\/jcs.108.6.2241","volume":"108","author":"JM Breuss","year":"1995","unstructured":"Breuss JM, Gallo J, DeLisser HM, et al. Expression of the \u03b26 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci. 1995;108:2241\u201351.","journal-title":"J Cell Sci"},{"key":"2006_CR13","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.1177\/41.10.8245410","volume":"41","author":"JM Breuss","year":"1993","unstructured":"Breuss JM, Gillett N, Lu L, et al. Restricted distribution of integrin beta 6 mRNA in primate epithelial tissues. J Histochem Cytochem. 1993;41:1521\u20137.","journal-title":"J Histochem Cytochem"},{"key":"2006_CR14","doi-asserted-by":"publisher","first-page":"e132305","DOI":"10.1172\/JCI132305","volume":"131","author":"A Guillot","year":"2021","unstructured":"Guillot A, Guerri L, Feng D, et al. Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin alphavbeta6 upregulation following liver injury. J Clin Invest. 2021;131:e132305.","journal-title":"J Clin Invest."},{"key":"2006_CR15","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1136\/gutjnl-2019-319015","volume":"69","author":"P Weil","year":"2020","unstructured":"Weil P, Rvd Bruck, Ziegenhals T, et al. \u03b26 integrinosis: a new lethal autosomal recessive ITGB6 disorder leading to impaired conformational transitions of the \u03b1V\u03b26 integrin receptor. Gut. 2020;69:1359\u201361.","journal-title":"Gut."},{"key":"2006_CR16","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1007\/s00261-022-03551-z","volume":"48","author":"DR Ludwig","year":"2023","unstructured":"Ludwig DR, Anderson MA, Itani M, et al. Secondary sclerosing cholangitis: mimics of primary sclerosing cholangitis. Abdom Radiol (NY). 2023;48:151\u201365.","journal-title":"Abdom Radiol (NY)"},{"key":"2006_CR17","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1038\/ajg.2009.727","volume":"105","author":"A Kornbluth","year":"2010","unstructured":"Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of G. Ulcerative colitis practice guidelines in adults: American college of gastroenterology practice parameters committee. Am J Gastroenterol. 2010;105:501\u201323 (quiz 24).","journal-title":"Am J Gastroenterol."},{"key":"2006_CR18","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1093\/ecco-jcc\/jjy113","volume":"13","author":"C Maaser","year":"2019","unstructured":"Maaser C, Sturm A, Vavricka SR, et al. ECCO-ESGAR guideline for diagnostic assessment in IBD part 1: initial diagnosis, monitoring of known IBD, detection of complications. J Crohns Colitis. 2019;13:144\u201364.","journal-title":"J Crohns Colitis"},{"key":"2006_CR19","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1136\/gut.2004.046615","volume":"54","author":"EV Loftus Jr","year":"2005","unstructured":"Loftus EV Jr, Harewood GC, Loftus CG, et al. PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis. Gut. 2005;54:91\u20136.","journal-title":"Gut"},{"key":"2006_CR20","doi-asserted-by":"publisher","first-page":"2270","DOI":"10.1002\/ibd.22938","volume":"18","author":"K Boonstra","year":"2012","unstructured":"Boonstra K, van Erpecum KJ, van Nieuwkerk KM, et al. Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2270\u20136.","journal-title":"Inflamm Bowel Dis"},{"key":"2006_CR21","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.cgh.2017.07.023","volume":"16","author":"N Krugliak Cleveland","year":"2018","unstructured":"Krugliak Cleveland N, Rubin DT, Hart J, et al. Patients with ulcerative colitis and primary sclerosing cholangitis frequently have subclinical inflammation in the proximal colon. Clin Gastroenterol Hepatol. 2018;16:68\u201374.","journal-title":"Clin Gastroenterol Hepatol"},{"key":"2006_CR22","doi-asserted-by":"publisher","first-page":"17","DOI":"10.5009\/gnl16510","volume":"12","author":"C Palmela","year":"2018","unstructured":"Palmela C, Peerani F, Castaneda D, et al. Inflammatory Bowel disease and primary sclerosing cholangitis: a review of the phenotype and associated specific features. Gut Liver. 2018;12:17\u201329.","journal-title":"Gut Liver"},{"key":"2006_CR23","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/ajg.2016.55","volume":"111","author":"AF Gulamhusein","year":"2016","unstructured":"Gulamhusein AF, Eaton JE, Tabibian JH, et al. Duration of inflammatory bowel disease is associated with increased risk of cholangiocarcinoma in patients with primary sclerosing cholangitis and IBD. Am J Gastroenterol. 2016;111:705\u201311.","journal-title":"Am J Gastroenterol"},{"key":"2006_CR24","doi-asserted-by":"publisher","first-page":"17875","DOI":"10.1074\/jbc.M312103200","volume":"279","author":"PH Weinreb","year":"2004","unstructured":"Weinreb PH, Simon KJ, Rayhorn P, et al. Function-blocking integrin alphavbeta6 monoclonal antibodies: distinct ligand-mimetic and nonligand-mimetic classes. J Biol Chem. 2004;279:17875\u201387.","journal-title":"J Biol Chem"},{"key":"2006_CR25","doi-asserted-by":"publisher","first-page":"20","DOI":"10.4161\/cam.18702","volume":"6","author":"K Zhang","year":"2012","unstructured":"Zhang K, Chen J. The regulation of integrin function by divalent cations. Cell Adh Migr. 2012;6:20\u20139.","journal-title":"Cell Adh Migr"},{"key":"2006_CR26","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/S0092-8674(02)00935-2","volume":"110","author":"J Takagi","year":"2002","unstructured":"Takagi J, Petre BM, Walz T, et al. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell. 2002;110:599\u2013611.","journal-title":"Cell"},{"key":"2006_CR27","doi-asserted-by":"publisher","first-page":"eaaq0997","DOI":"10.1126\/scitranslmed.aaq0997","volume":"10","author":"M Shiokawa","year":"2018","unstructured":"Shiokawa M, Kodama Y, Sekiguchi K, et al. Laminin 511 is a target antigen in autoimmune pancreatitis. Sci Transl Med. 2018;10:eaaq0997.","journal-title":"Sci Transl Med."},{"key":"2006_CR28","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/ng.3745","volume":"49","author":"SG Ji","year":"2017","unstructured":"Ji SG, Juran BD, Mucha S, et al. Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease. Nat Genet. 2017;49:269\u201373.","journal-title":"Nat Genet"},{"key":"2006_CR29","doi-asserted-by":"publisher","first-page":"12597","DOI":"10.1016\/S0021-9258(18)45247-7","volume":"262","author":"LV Parise","year":"1987","unstructured":"Parise LV, Helgerson SL, Steiner B, et al. Synthetic peptides derived from fibrinogen and fibronectin change the conformation of purified platelet glycoprotein IIb-IIIa. J Biol Chem. 1987;262:12597\u2013602.","journal-title":"J Biol Chem"}],"container-title":["Journal of Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00535-023-02006-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00535-023-02006-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00535-023-02006-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T15:06:29Z","timestamp":1690211189000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00535-023-02006-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,13]]},"references-count":29,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["2006"],"URL":"https:\/\/doi.org\/10.1007\/s00535-023-02006-6","relation":{},"ISSN":["0944-1174","1435-5922"],"issn-type":[{"value":"0944-1174","type":"print"},{"value":"1435-5922","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,13]]},"assertion":[{"value":"11 February 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 May 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 June 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Dr. Masahiro Shiokawa received a research grant from Astellas Pharma.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}