{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T12:28:56Z","timestamp":1762432136863,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["MU 2864\/1-3 and MU 2864\/3-1"],"award-info":[{"award-number":["MU 2864\/1-3 and MU 2864\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) constitute rare chronic inflammatory biliary diseases which likely comprise genetic, environmental and autoimmune factors. Specific inhibitory (auto-) antibodies against the muscarinic acetylcholine receptor type 3 (mAChR3 auto-ab) may contribute to the pathogenesis of chronic biliary inflammation by modulating mAChR3\u2212 mediated signaling. Aims: The aim of this study was to analyze the prevalence and relevance of inhibitory mAChR3 auto-ab (mAChR3inh+ auto-ab) in a large cohort of PBC patients from two independent tertiary centers in Berlin and Leipzig in comparison to a large PSC cohort. Baseline parameters and response rates to standard treatment with ursodeoxycholic acid (UDCA) were characterized with respect to the individual mAChR3 auto-ab status. Methods: In total, the study population comprised 437 PBC patients, 187 PSC patients and 80 healthy controls. Clinical and laboratory baseline characteristics were retrieved from medical records. The response to ursodeoxycholic acid (UDCA) therapy after 12 months of treatment was available in 176 PBC and 45 PSC patients. Results: The prevalence of mAChR3inh+ auto-ab was significantly higher among PBC patients (11.2%, 49\/437; p = 0.008 vs. healthy controls) and PSC patients (33.6%, 63\/187; p &lt; 0.0001 vs. healthy controls) compared to healthy controls (2.5%, 2\/80), respectively. PBC patients with mAChR3inh+ auto-ab exhibited significantly higher levels of alkaline phosphatase (ALP) and bilirubin, which constitute established parameters for PBC risk stratification. Moreover, mAChR3inh+ PBC patients tended to show decreased response rates to UDCA therapy compared to PBC patients without mAChR3inh+ auto-ab (mAChR3\u2212 PBC). In contrast, PSC patients with mAChR3inh+ auto-ab showed no significant differences in laboratory findings compared to mAChR3 auto-ab negative (mAChR3\u2212) PSC patients. Conclusion: MAChR3inh+ auto-ab might be involved in the pathogenesis and treatment response of chronic biliary inflammation in patients with PBC but not in patients with PSC.<\/jats:p>","DOI":"10.3390\/jcm11030681","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T05:26:17Z","timestamp":1643433977000},"page":"681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of Inhibitory Antibodies against the Muscarinic Acetylcholine Receptor Type 3 in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-2158","authenticated-orcid":false,"given":"Anne-Christin Beatrice","family":"Wilde","sequence":"first","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena Maria","family":"Greverath","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lara Marleen","family":"Steinhagen","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina Wald","family":"de Chamorro","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elise","family":"Leicht","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janett","family":"Fischer","sequence":"additional","affiliation":[{"name":"Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toni","family":"Herta","sequence":"additional","affiliation":[{"name":"Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0003-6241","authenticated-orcid":false,"given":"Thomas","family":"Berg","sequence":"additional","affiliation":[{"name":"Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, 04103 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beate","family":"Preuss","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6111-3901","authenticated-orcid":false,"given":"Reinhild","family":"Klein","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-0226","authenticated-orcid":false,"given":"Frank","family":"Tacke","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3426-5421","authenticated-orcid":false,"given":"Tobias","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/hep.30145","article-title":"Primary biliary cholangitis: 2018 practice guidance from the american association for the study of liver diseases","volume":"69","author":"Lindor","year":"2019","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1016\/S0140-6736(18)30300-3","article-title":"Primary sclerosing cholangitis","volume":"391","author":"Dyson","year":"2018","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1053\/j.gastro.2004.08.006","article-title":"The cholangiopathies: Disorders of biliary epithelia","volume":"127","author":"Lazaridis","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41575-019-0125-y","article-title":"Cholangiocyte pathobiology","volume":"16","author":"Banales","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1016\/j.bbadis.2017.07.023","article-title":"Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium","volume":"1864 Pt B","author":"Strazzabosco","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1002\/hep.23810","article-title":"The biliary HCO3\u2212 umbrella: A unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies","volume":"52","author":"Beuers","year":"2010","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1159\/000324687","article-title":"Biliary bicarbonate secretion constitutes a protective mechanism against bile acid-induced injury in man","volume":"29","author":"Hohenester","year":"2011","journal-title":"Dig. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/hep.24691","article-title":"A biliary HCO3\u2212 umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes","volume":"55","author":"Hohenester","year":"2012","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.jhep.2020.10.010","article-title":"Hepatobiliary acid-base homeostasis: Insights from analogous secretory epithelia","volume":"74","author":"Trampert","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1111\/j.1478-3231.2011.02457.x","article-title":"The role of the innate immune recognition system in the pathogenesis of primary biliary cirrhosis: A conceptual view","volume":"31","author":"Berg","year":"2011","journal-title":"Liver Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/nrrheum.2017.134","article-title":"Functional autoantibodies targeting G protein-coupled receptors in rheumatic diseases","volume":"13","author":"Riemekasten","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1046\/j.1365-2249.1996.42748.x","article-title":"Circulating antibodies against rat parotid gland M3 muscarinic receptors in primary Sj\u00f6gren\u2019s syndrome","volume":"104","author":"Bacman","year":"1996","journal-title":"Clin. Exp. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1002\/art.20371","article-title":"Detection of anti-type 3 muscarinic acetylcholine receptor autoantibodies in the sera of Sj\u00f6gren\u2019s syndrome patients by use of a transfected cell line assay","volume":"50","author":"Gao","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"841","DOI":"10.3109\/s10165-012-0788-5","article-title":"Anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sj\u00f6gren\u2019s syndrome","volume":"23","author":"Sumida","year":"2013","journal-title":"Mod. Rheumatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1365-2249.2010.04188.x","article-title":"New epitopes and function of anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sj\u00f6gren\u2019s syndrome","volume":"162","author":"Tsuboi","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Musayeva, A., Jiang, S., Ruan, Y., Zadeh, J.K., Chronopoulos, P., Pfeiffer, N., M\u00fcller, W.E., Ackermann, M., Xia, N., and Li, H. (2021). Aged mice devoid of the M3 muscarinic acetylcholine receptor develop mild dry eye disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22116133"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/hep.22906","article-title":"Primary biliary cirrhosis","volume":"50","author":"Lindor","year":"2009","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s40744-017-0074-2","article-title":"Chronic autoimmune epithelitis in sj\u00f6gren\u2019s syndrome and primary biliary cholangitis: A comprehensive review","volume":"4","author":"Selmi","year":"2017","journal-title":"Rheumatol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s12016-015-8471-1","article-title":"The coexistence of Sj\u00f6gren\u2019s syndrome and primary biliary cirrhosis: A comprehensive review","volume":"48","author":"Sun","year":"2015","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0002-9440(10)64208-3","article-title":"The vagal nerve stimulates activation of the hepatic progenitor cell compartment via muscarinic acetylcholine receptor type 3","volume":"161","author":"Cassiman","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/hepr.13455","article-title":"Evaluation of muscarinic acetylcholine receptor type 3 gene polymorphisms in patients with primary biliary cholangitis and primary sclerosing cholangitis","volume":"50","author":"Greverath","year":"2020","journal-title":"Hepatol. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1172\/JCI119655","article-title":"Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions","volume":"100","author":"Alvaro","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"E471","DOI":"10.1111\/hepr.12346","article-title":"Anti-M3 muscarinic acetylcholine receptor antibodies in patients with primary biliary cirrhosis","volume":"44","author":"Tsuboi","year":"2014","journal-title":"Hepatol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Berg, C.P., Blume, K., Lauber, K., Gregor, M., Berg, P.A., Wesselborg, S., and Stein, G.M. (2010). Autoantibodies to muscarinic acetylcholine receptors found in patients with primary biliary cirrhosis. BMC Gastroenterol., 10.","DOI":"10.1186\/1471-230X-10-120"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E68","DOI":"10.1111\/hepr.12928","article-title":"Genetic loss of the muscarinic M3 receptor markedly alters bile formation and cholestatic liver injury in mice","volume":"48","author":"Durchschein","year":"2018","journal-title":"Hepatol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/cei.12324","article-title":"A novel luminescence-based method for the detection of functionally active antibodies to muscarinic acetylcholine receptors of the M3 type (mAchR3) in patients\u2019 sera","volume":"177","author":"Preuss","year":"2014","journal-title":"Clin. Exp. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.3389\/fimmu.2020.01151","article-title":"Antibodies to the muscarinic acetylcholine receptor M3 in primary biliary cholangitis inhibit receptor function on cholangiocytes","volume":"11","author":"Mayer","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"European Association for the Study of Liver (2017). EASL clinical practice guidelines: The diagnosis and management of patients with primary biliary cholangitis. J. Hepatol., 67, 145\u2013172.","DOI":"10.1016\/j.jhep.2017.03.022"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wilde, A.C.B., Lieb, C., Leicht, E., Greverath, L.M., Steinhagen, L.M., Chamorro, N.W.D., Petersen, J., Hofmann, W.P., Hinrichsen, H., and Heyne, R. (2021). Real-world clinical management of patients with primary biliary cholangitis\u2014A retrospective multicenter study from Germany. J. Clin. Med., 10.","DOI":"10.3390\/jcm10051061"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.dld.2014.06.010","article-title":"The impact of elevated serum IgG4 levels in patients with primary sclerosing cholangitis","volume":"46","author":"Otten","year":"2014","journal-title":"Dig. Liver Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.jhep.2015.06.030","article-title":"EASL clinical practice guidelines: Autoimmune hepatitis","volume":"63","author":"Lohse","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/BF00432479","article-title":"Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis)","volume":"379","author":"Ludwig","year":"1978","journal-title":"Virchows Arch. A Pathol Anat Histol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.jhep.2019.06.012","article-title":"Validation, clinical utility and limitations of the Amsterdam-Oxford model for primary sclerosing cholangitis","volume":"71","author":"Goet","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/hep.22428","article-title":"Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis","volume":"48","author":"Corpechot","year":"2008","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1016\/S0140-6736(15)00154-3","article-title":"Primary biliary cirrhosis","volume":"386","author":"Carey","year":"2015","journal-title":"Lancet"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1002\/eji.201344270","article-title":"Implications of genome-wide association studies in novel therapeutics in primary biliary cirrhosis","volume":"44","author":"Carbone","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"326","DOI":"10.2174\/156652409787314525","article-title":"Innate immunity and primary biliary cirrhosis","volume":"9","author":"Selmi","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1365-2249.2006.03090.x","article-title":"Transgenic mice aberrantly expressing pyruvate dehydrogenase complex E2 component on biliary epithelial cells do not show primary biliary cirrhosis","volume":"145","author":"Inamura","year":"2006","journal-title":"Clin. Exp. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1034\/j.1600-0676.2000.020005351.x","article-title":"Experimental autoimmune cholangitis: A mouse model of immune-mediated cholangiopathy","volume":"20","author":"Jones","year":"2000","journal-title":"Liver"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1053\/j.gastro.2007.01.039","article-title":"Biliary epithelial cell antibodies link adaptive and innate immune responses in primary sclerosing cholangitis","volume":"132","author":"Karrar","year":"2007","journal-title":"Gastroenterology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1177\/1535370213489926","article-title":"Recent advances in the morphological and functional heterogeneity of the biliary epithelium","volume":"238","author":"Han","year":"2013","journal-title":"Exp. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1055\/s-2002-34501","article-title":"Functional heterogeneity of cholangiocytes","volume":"22","author":"Marzioni","year":"2002","journal-title":"Semin. Liver Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s12935-018-0667-z","article-title":"M3 muscarinic acetylcholine receptors regulate epithelial-mesenchymal transition, perineural invasion, and migration\/metastasis in cholangiocarcinoma through the AKT pathway","volume":"18","author":"Feng","year":"2018","journal-title":"Cancer Cell Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/S1499-3872(12)60201-X","article-title":"Muscarinic acetylcholine receptor M3 in proliferation and perineural invasion of cholangiocarcinoma cells","volume":"11","author":"Feng","year":"2012","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hering, N.A., Liu, V., Kim, R., Weixler, B., Droeser, R.A., Arndt, M., Pozios, I., Beyer, K., Kreis, M.E., and Seeliger, H. (2021). Blockage of cholinergic signaling via muscarinic acetylcholine receptor 3 inhibits tumor growth in human colorectal adenocarcinoma. Cancers, 13.","DOI":"10.3390\/cancers13133220"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/681\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:09:53Z","timestamp":1760134193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/11\/3\/681"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,28]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["jcm11030681"],"URL":"https:\/\/doi.org\/10.3390\/jcm11030681","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2022,1,28]]}}}