Evaluation of Inhibitory Antibodies Against the Muscarinic Acetylcholine Receptor Type 3 in Patients with Primary Biliary Cholangitis and Primary Sclerosing Cholangitis

Overview

Journal J Clin Med

Specialty General Medicine

Date 2022 Feb 15

PMID 35160133

Authors

Anne-Christin Beatrice Wilde

Lena Maria Greverath

Lara Marleen Steinhagen

Nina Wald de Chamorro

Elise Leicht

Janett Fischer

Toni Herta

Thomas Berg

Beate Preuss

Reinhild Klein

Frank Tacke

Tobias Muller

Affiliations

Soon will be listed here.

Abstract

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- 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; = 0.008 vs. healthy controls) and PSC patients (33.6%, 63/187; < 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- PBC). In contrast, PSC patients with mAChR3inh+ auto-ab showed no significant differences in laboratory findings compared to mAChR3 auto-ab negative (mAChR3-) 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.

References

Han Y, Glaser S, Meng F, Francis H, Marzioni M, McDaniel K . Recent advances in the morphological and functional heterogeneity of the biliary epithelium. Exp Biol Med (Maywood). 2013; 238(5):549-65. PMC: 3965268. DOI: 10.1177/1535370213489926. View

Mayer C, Preuss B, Grottenthaler J, Berg C, Klein R . Antibodies to the Muscarinic Acetylcholine Receptor M3 in Primary Biliary Cholangitis Inhibit Receptor Function on Cholangiocytes. Front Immunol. 2020; 11:1151. PMC: 7339122. DOI: 10.3389/fimmu.2020.01151. View

Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E . Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim Biophys Acta Mol Basis Dis. 2017; 1864(4 Pt B):1374-1379. PMC: 5785585. DOI: 10.1016/j.bbadis.2017.07.023. View

Wilde A, Lieb C, Leicht E, Greverath L, Steinhagen L, de Chamorro N . Real-World Clinical Management of Patients with Primary Biliary Cholangitis-A Retrospective Multicenter Study from Germany. J Clin Med. 2021; 10(5). PMC: 7961881. DOI: 10.3390/jcm10051061. View

Hohenester S, Maillette de Buy Wenniger L, Jefferson D, Elferink R, Beuers U . Biliary bicarbonate secretion constitutes a protective mechanism against bile acid-induced injury in man. Dig Dis. 2011; 29(1):62-5. DOI: 10.1159/000324687. View

Greverath L, Leicht E, de Chamorro N, Wilde A, Steinhagen L, Lieb C . Evaluation of muscarinic acetylcholine receptor type 3 gene polymorphisms in patients with primary biliary cholangitis and primary sclerosing cholangitis. Hepatol Res. 2019; 50(3):321-329. DOI: 10.1111/hepr.13455. View

Ludwig J, Dickson E, McDonald G . Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol. 1978; 379(2):103-12. DOI: 10.1007/BF00432479. View

Tsuboi H, Ohira H, Asashima H, Tsuzuki S, Iizuka M, Matsuo N . Anti-M3 muscarinic acetylcholine receptor antibodies in patients with primary biliary cirrhosis. Hepatol Res. 2014; 44(14):E471-9. DOI: 10.1111/hepr.12346. View

Cabral-Marques O, Riemekasten G . Functional autoantibodies targeting G protein-coupled receptors in rheumatic diseases. Nat Rev Rheumatol. 2017; 13(11):648-656. DOI: 10.1038/nrrheum.2017.134. View

10.

Lindor K, Gershwin M, Poupon R, Kaplan M, Bergasa N, Heathcote E . Primary biliary cirrhosis. Hepatology. 2009; 50(1):291-308. DOI: 10.1002/hep.22906. View

11.

Carey E, Ali A, Lindor K . Primary biliary cirrhosis. Lancet. 2015; 386(10003):1565-75. DOI: 10.1016/S0140-6736(15)00154-3. View

12.

Lindor K, Bowlus C, Boyer J, Levy C, Mayo M . Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 69(1):394-419. DOI: 10.1002/hep.30145. View

13.

Jones D, Palmer J, Kirby J, De Cruz D, McCaughan G, Sedgwick J . Experimental autoimmune cholangitis: a mouse model of immune-mediated cholangiopathy. Liver. 2000; 20(5):351-6. DOI: 10.1034/j.1600-0676.2000.020005351.x. View

14.

Sun Y, Zhang W, Li B, Zou Z, Selmi C, Gershwin M . The coexistence of Sjögren's syndrome and primary biliary cirrhosis: a comprehensive review. Clin Rev Allergy Immunol. 2015; 48(2-3):301-15. DOI: 10.1007/s12016-015-8471-1. View

15.

Sumida T, Tsuboi H, Iizuka M, Asashima H, Matsumoto I . Anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren's syndrome. Mod Rheumatol. 2012; 23(5):841-5. DOI: 10.1007/s10165-012-0788-5. View

16.

. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017; 67(1):145-172. DOI: 10.1016/j.jhep.2017.03.022. View

17.

Tsuboi H, Matsumoto I, Wakamatsu E, Nakamura Y, Iizuka M, Hayashi T . New epitopes and function of anti-M3 muscarinic acetylcholine receptor antibodies in patients with Sjögren's syndrome. Clin Exp Immunol. 2010; 162(1):53-61. PMC: 2990929. DOI: 10.1111/j.1365-2249.2010.04188.x. View

18.

Corpechot C, Abenavoli L, Rabahi N, Chretien Y, Andreani T, Johanet C . Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008; 48(3):871-7. DOI: 10.1002/hep.22428. View

19.

Dyson J, Beuers U, Jones D, Lohse A, Hudson M . Primary sclerosing cholangitis. Lancet. 2018; 391(10139):2547-2559. DOI: 10.1016/S0140-6736(18)30300-3. View

20.

Selmi C, Lleo A, Pasini S, Zuin M, Gershwin M . Innate immunity and primary biliary cirrhosis. Curr Mol Med. 2009; 9(1):45-51. DOI: 10.2174/156652409787314525. View