{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:50:35Z","timestamp":1787165435230,"version":"build-2736575974"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,1,10]],"date-time":"2018-01-10T00:00:00Z","timestamp":1515542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,1,10]],"date-time":"2018-01-10T00:00:00Z","timestamp":1515542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Glycoprotein 2[GP2] is a specific target of pancreatic autoantibodies[PAbs] in Crohn\u2019s disease(CD) and is involved in gut innate immunity processes. Our aim was to evaluate the prevalence and prognostic potential of PAbs in primary sclerosing cholangitis(PSC). Sixty-five PSC patients were tested for PAbs by indirect immunofluorescence and compared with healthy (n\u2009=\u2009100) and chronic liver disease controls(CLD, n\u2009=\u2009488). Additionally, a panel of anti-microbial antibodies and secretory (s)IgA levels were measured, as markers of bacterial translocation and immune dysregulation. PAbs were more frequent in PSC(46.2%) compared to controls(healthy:0% and CLD:4.5%), [P\u2009&lt;\u20090.001, for each]. Occurrence of anti-GP2 antibody was 30.8% (20\/65) and was exclusively of IgA isotype. Anti-GP2 IgA positive patients had higher sIgA levels (P\u2009=\u20090.021). With flow-cytometry, 68.4% (13\/19) of anti-GP2 IgA antibodies were bound with secretory component, suggesting an active retro-transportation of anti-GP2 from the gut lumen to the mucosa. Anti-GP2 IgA was associated with shorter transplant-free survival [P\n                    <jats:sub>LogRank<\/jats:sub>\n                    \u2009&lt;\u20090.01] during the prospective follow-up (median, IQR: 87 [9\u201399] months) and remained an independent predictor after adjusting for Mayo risk score(HR: 4.69 [1.05\u201321.04], P\u2009=\u20090.043). These results highlight the significance of gut-liver interactions in PSC. Anti-GP2 IgA might be a valuable tool for risk stratification in PSC and considered as a potential therapeutic target.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-18622-1","type":"journal-article","created":{"date-parts":[[2018,1,4]],"date-time":"2018-01-04T12:06:09Z","timestamp":1515067569000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Loss of tolerance to gut immunity protein, glycoprotein 2 (GP2) is associated with progressive disease course in primary sclerosing cholangitis"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4793-9974","authenticated-orcid":false,"given":"Tamas","family":"Tornai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Tornai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Sipeki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Istvan","family":"Tornai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayan","family":"Alsulaimani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Fechner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6861-6827","authenticated-orcid":false,"given":"Dirk","family":"Roggenbuck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8992-1866","authenticated-orcid":false,"given":"Gary L.","family":"Norman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabor","family":"Veres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Par","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alajos","family":"Par","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferenc","family":"Szalay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Laszlo","family":"Lakatos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Antal-Szalmas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3662-4010","authenticated-orcid":false,"given":"Maria","family":"Papp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,1,10]]},"reference":[{"key":"18622_CR1","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1056\/NEJMra1506330","volume":"375","author":"KN Lazaridis","year":"2016","unstructured":"Lazaridis, K. N. & LaRusso, N. F. Primary Sclerosing Cholangitis. N. Engl. J. Med. 375, 1161\u20131170 (2016).","journal-title":"N. Engl. J. Med."},{"key":"18622_CR2","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/S0025-6196(11)64614-4","volume":"75","author":"WR Kim","year":"2000","unstructured":"Kim, W. R. et al. A revised natural history model for primary sclerosing cholangitis. Mayo Clin. Proc. 75, 688\u2013694 (2000).","journal-title":"Mayo Clin. Proc."},{"key":"18622_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cld.2015.08.012","volume":"20","author":"B Eksteen","year":"2016","unstructured":"Eksteen, B. The Gut-Liver Axis in Primary Sclerosing Cholangitis. Clinics in Liver Disease 20, 1\u201314 (2016).","journal-title":"Clinics in Liver Disease"},{"key":"18622_CR4","doi-asserted-by":"publisher","first-page":"265","DOI":"10.2147\/CEG.S105872","volume":"10","author":"S Sirpal","year":"2017","unstructured":"Sirpal, S. & Chandok, N. Primary sclerosing cholangitis: diagnostic and management challenges. Clin. Exp. Gastroenterol. 10, 265\u2013273 (2017).","journal-title":"Clin. Exp. Gastroenterol."},{"key":"18622_CR5","first-page":"483","volume":"52","author":"D Roggenbuck","year":"2014","unstructured":"Roggenbuck, D. et al. Crohn\u2019s disease specific pancreatic antibodies: clinical and pathophysiological challenges. Clin. Chem. Lab. Med. 52, 483\u2013494 (2014).","journal-title":"Clin. Chem. Lab. Med."},{"key":"18622_CR6","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1016\/j.crohns.2012.10.011","volume":"7","author":"L Komorowski","year":"2013","unstructured":"Komorowski, L. et al. Autoantibodies against exocrine pancreas in Crohn\u2019s disease are directed against two antigens: the glycoproteins CUZD1 and GP2. J. Crohns. Colitis 7, 780\u2013790 (2013).","journal-title":"J. Crohns. Colitis"},{"key":"18622_CR7","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1136\/gut.2008.162495","volume":"58","author":"D Roggenbuck","year":"2009","unstructured":"Roggenbuck, D. et al. Identification of GP2, the major zymogen granule membrane glycoprotein, as the autoantigen of pancreatic antibodies in Crohn\u2019s disease. Gut 58, 1620\u20131628 (2009).","journal-title":"Gut"},{"key":"18622_CR8","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1136\/gutjnl-2014-307854","volume":"64","author":"P Schierack","year":"2015","unstructured":"Schierack, P. et al. Species-specific and pathotype-specific binding of bacteria to zymogen granule membrane glycoprotein 2 (GP2). Gut 64, 517\u2013519 (2015).","journal-title":"Gut"},{"key":"18622_CR9","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/B978-0-12-407681-5.00006-4","volume":"60","author":"D Roggenbuck","year":"2013","unstructured":"Roggenbuck, D. et al. Glycoprotein 2 antibodies in Crohn\u2019s disease. Adv. Clin. Chem. 60, 187\u2013208 (2013).","journal-title":"Adv. Clin. Chem."},{"key":"18622_CR10","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1093\/ecco-jcc\/jjv087","volume":"9","author":"M Papp","year":"2015","unstructured":"Papp, M. et al. Rediscovery of the Anti-Pancreatic Antibodies and Evaluation of their Prognostic Value in a Prospective Clinical Cohort of Crohn\u2019s Patients: The Importance of Specific Target Antigens [GP2 and CUZD1]. J. Crohns. Colitis 9, 659\u2013668 (2015).","journal-title":"J. Crohns. Colitis"},{"key":"18622_CR11","doi-asserted-by":"publisher","first-page":"e12957","DOI":"10.1371\/journal.pone.0012957","volume":"5","author":"M Papp","year":"2010","unstructured":"Papp, M. et al. Presence of anti-microbial antibodies in liver cirrhosis\u2013a tell-tale sign of compromised immunity? PLoS One 5, e12957 (2010).","journal-title":"PLoS One"},{"key":"18622_CR12","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1016\/j.jhep.2013.04.018","volume":"59","author":"M Papp","year":"2013","unstructured":"Papp, M. et al. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J. Hepatol. 59, 457\u2013466 (2013).","journal-title":"J. Hepatol."},{"key":"18622_CR13","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1136\/gut.2008.157818","volume":"59","author":"B Terjung","year":"2010","unstructured":"Terjung, B. et al. p-ANCAs in autoimmune liver disorders recognise human beta-tubulin isotype 5 and cross-react with microbial protein FtsZ. Gut 59, 808\u2013816 (2010).","journal-title":"Gut"},{"key":"18622_CR14","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1097\/MOG.0000000000000076","volume":"30","author":"M Papp","year":"2014","unstructured":"Papp, M. & Lakatos, P. L. Serological studies in inflammatory bowel disease: how important are they? Curr. Opin. Gastroenterol. 30, 359\u2013364 (2014).","journal-title":"Curr. Opin. Gastroenterol."},{"key":"18622_CR15","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/mi.2011.41","volume":"4","author":"NJ Mantis","year":"2011","unstructured":"Mantis, N. J., Rol, N. & Corthesy, B. Secretory IgA\u2019s complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 4, 603\u2013611 (2011).","journal-title":"Mucosal Immunol."},{"key":"18622_CR16","doi-asserted-by":"publisher","first-page":"2864","DOI":"10.1097\/MIB.0000000000000564","volume":"21","author":"MA Michaels","year":"2015","unstructured":"Michaels, M. A. et al. Pancreatic Autoantibodies Against CUZD1 and GP2 Are Associated with Distinct Clinical Phenotypes of Crohn\u2019s Disease. Inflamm. Bowel Dis. 21, 2864\u20132872 (2015).","journal-title":"Inflamm. Bowel Dis."},{"key":"18622_CR17","doi-asserted-by":"publisher","first-page":"S647","DOI":"10.1016\/S0168-8278(16)01208-3","volume":"64","author":"ST Jendrek","year":"2016","unstructured":"Jendrek, S. T. et al. SAT-387 - Autoreactive Iga Antibodies against the Pancreatic Major Glycoprotein 2 are Associated with Primary Sclerosing Cholangitis and Related Biliary Tract Cancer. J. Hepatol. 64, S647 (2016).","journal-title":"J. Hepatol."},{"key":"18622_CR18","unstructured":"Papp, M. et al. Target-specific anti-pancreatic antibodies are frequent in patients with primary sclerosing cholangitis and associated with poor disease outcome. In Falk Symposia 201 - Gut-Liver Interactions: From IBD to NASH 33\u201334 (2016)."},{"key":"18622_CR19","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1136\/gutjnl-2016-311739","volume":"66","author":"ST Jendrek","year":"2017","unstructured":"Jendrek, S. T. et al. Anti-GP2 IgA autoantibodies are associated with poor survival and cholangiocarcinoma in primary sclerosing cholangitis. Gut 66, 137\u2013144 (2017).","journal-title":"Gut"},{"key":"18622_CR20","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1136\/gut.38.4.610","volume":"38","author":"U Broome","year":"1996","unstructured":"Broome, U. et al. Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 38, 610\u2013615 (1996).","journal-title":"Gut"},{"key":"18622_CR21","doi-asserted-by":"publisher","first-page":"1710","DOI":"10.1016\/0016-5085(91)90673-9","volume":"100","author":"JM Farrant","year":"1991","unstructured":"Farrant, J. M. et al. Natural history and prognostic variables in primary sclerosing cholangitis. Gastroenterology 100, 1710\u20131717 (1991).","journal-title":"Gastroenterology"},{"key":"18622_CR22","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1002\/hep.26565","volume":"58","author":"K Boonstra","year":"2013","unstructured":"Boonstra, K. et al. Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 58, 2045\u20132055 (2013).","journal-title":"Hepatology"},{"key":"18622_CR23","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1093\/ecco-jcc\/jju013","volume":"9","author":"H Yanai","year":"2015","unstructured":"Yanai, H. et al. Prognosis of primary sclerosing cholangitis in israel is independent of coexisting inflammatory bowel Disease. J. Crohns. Colitis 9, 177\u2013184 (2015).","journal-title":"J. Crohns. Colitis"},{"key":"18622_CR24","doi-asserted-by":"publisher","first-page":"2648","DOI":"10.1097\/MIB.0000000000000936","volume":"22","author":"F Degenhardt","year":"2016","unstructured":"Degenhardt, F. et al. Serologic Anti-GP2 Antibodies Are Associated with Genetic Polymorphisms, Fibrostenosis, and Need for Surgical Resection in Crohn\u2019s Disease. Inflamm. Bowel Dis. 22, 2648\u20132657 (2016).","journal-title":"Inflamm. Bowel Dis."},{"key":"18622_CR25","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1038\/nature08529","volume":"462","author":"K Hase","year":"2009","unstructured":"Hase, K. et al. Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response. Nature 462, 226\u2013230 (2009).","journal-title":"Nature"},{"key":"18622_CR26","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1074\/jbc.M109.059220","volume":"285","author":"M Duc","year":"2010","unstructured":"Duc, M., Johansen, F.-E. & Corthesy, B. Antigen binding to secretory immunoglobulin A results in decreased sensitivity to intestinal proteases and increased binding to cellular Fc receptors. J. Biol. Chem. 285, 953\u2013960 (2010).","journal-title":"J. Biol. Chem."},{"key":"18622_CR27","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1016\/j.bpg.2011.10.009","volume":"25","author":"MJ Pollheimer","year":"2011","unstructured":"Pollheimer, M. J., Halilbasic, E., Fickert, P. & Trauner, M. Pathogenesis of primary sclerosing cholangitis. Best Pract. Res. Clin. Gastroenterol. 25, 727\u2013739 (2011).","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"18622_CR28","doi-asserted-by":"publisher","first-page":"6702","DOI":"10.4049\/jimmunol.181.10.6702","volume":"181","author":"KL Mossman","year":"2008","unstructured":"Mossman, K. L. et al. Cutting edge: FimH adhesin of type 1 fimbriae is a novel TLR4 ligand. J. Immunol. 181, 6702\u20136706 (2008).","journal-title":"J. Immunol."},{"key":"18622_CR29","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1038\/nm1663","volume":"13","author":"E Seki","year":"2007","unstructured":"Seki, E. et al. TLR4 enhances TGF-[beta] signaling and hepatic fibrosis. Nat Med 13, 1324\u20131332 (2007).","journal-title":"Nat Med"},{"key":"18622_CR30","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1038\/nrrheum.2009.237","volume":"6","author":"JC Hall","year":"2010","unstructured":"Hall, J. C. & Rosen, A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nat. Rev. Rheumatol. 6, 40\u201349 (2010).","journal-title":"Nat. Rev. Rheumatol."},{"key":"18622_CR31","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1517\/13543776.2016.1131266","volume":"26","author":"LK Mydock-McGrane","year":"2016","unstructured":"Mydock-McGrane, L. K., Cusumano, Z. T. & Janetka, J. W. Mannose-derived FimH antagonists: a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn\u2019s disease. Expert Opin. Ther. Pat. 26, 175\u2013197 (2016).","journal-title":"Expert Opin. Ther. Pat."},{"key":"18622_CR32","doi-asserted-by":"publisher","first-page":"e1003141","DOI":"10.1371\/journal.ppat.1003141","volume":"9","author":"N Dreux","year":"2013","unstructured":"Dreux, N. et al. Point Mutations in FimH Adhesin of Crohn\u2019s Disease-Associated Adherent-Invasive Escherichia coli Enhance Intestinal Inflammatory Response. PLoS Pathog. 9, e1003141 (2013).","journal-title":"PLoS Pathog."},{"key":"18622_CR33","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.4155\/fmc-2016-0134","volume":"8","author":"SG Gouin","year":"2016","unstructured":"Gouin, S. G. Repurposing Escherichia coli antiadhesives in Crohn\u2019s disease. Future Med. Chem. 8, 1903\u20131906 (2016).","journal-title":"Future Med. Chem."},{"key":"18622_CR34","doi-asserted-by":"publisher","first-page":"5412","DOI":"10.3748\/wjg.v23.i29.5412","volume":"23","author":"T Tornai","year":"2017","unstructured":"Tornai, T. et al. Gut barrier failure biomarkers are associated with poor disease outcome in patients with primary sclerosing cholangitis. World J. Gastroenterol. 23, 5412\u20135421 (2017).","journal-title":"World J. Gastroenterol."},{"key":"18622_CR35","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1097\/00001574-200109000-00010","volume":"17","author":"EB Martins","year":"2001","unstructured":"Martins, E. B. & Chapman, R. W. Sclerosing cholangitis. Curr. Opin. Gastroenterol. 17, 458\u2013462 (2001).","journal-title":"Curr. Opin. Gastroenterol."},{"key":"18622_CR36","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1056\/NEJMra043898","volume":"353","author":"MM Kaplan","year":"2005","unstructured":"Kaplan, M. M. & Gershwin, M. E. Primary biliary cirrhosis. N. Engl. J. Med. 353, 1261\u20131273 (2005).","journal-title":"N. Engl. J. Med."},{"key":"18622_CR37","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1128\/CVI.00002-09","volume":"16","author":"M Papp","year":"2009","unstructured":"Papp, M. et al. Evaluation of the combined application of ethanol-fixed and formaldehyde-fixed neutrophil substrates for identifying atypical perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. Clin. Vaccine Immunol. 16, 464\u2013470 (2009).","journal-title":"Clin. Vaccine Immunol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18622-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18622-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18622-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T20:50:00Z","timestamp":1671828600000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-18622-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,10]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["18622"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-18622-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,10]]},"assertion":[{"value":"29 August 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 January 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Gary L. Norman is an employee of Inova Diagnostics, an <i>in-vitro<\/i> diagnostic manufacturer. Kai Fechner is an employee of EUROIMMUN Medizinische Labordiagnostika AG, an <i>in-vitro<\/i> diagnostic manufacturer. Prof. Dr. Dirk Roggenbuck is an employee and owns shares of GA Generic Assays GmbH, an <i>in-vitro<\/i> diagnostic manufacturer.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"399"}}