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      Laminin 511-E8, an autoantigen in IgG4-related cholangitis, contributes to cholangiocyte protection

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          Abstract

          Background & Aims

          IgG4-related cholangitis (IRC) is the hepatobiliary manifestation of IgG4-related disease. Anti-laminin 511-E8 autoantibodies have been identified in its pancreatic manifestation. Laminin 511-E8 promotes endothelial barrier function, lymphocyte recruitment, and cholangiocyte differentiation. Here, we investigate anti-laminin 511-E8 autoantibody presence in IRC, and mechanisms via which laminin 511 may contribute to cholangiocyte protection.

          Methods

          Anti-laminin 511-E8 serum autoantibody positivity was assessed by ELISA. RNA sequencing and RT-qPCR were performed on human H69 cholangiocytes treated with recombinant laminin 511-E8. H69 cholangiocytes were subjected to shRNA knockdown targeting genes encoding laminin 511 ( LAMA5, LAMB1, LAMC1) or treated with recombinant laminin 511-E8. Cholangiocellular bile acid influx was quantified radiochemically using 22,23- 3H-glycochenodeoxycholic acid (GCDC). GCDC-induced apoptosis was determined by Caspase-3/7 assays. Cholangiocellular barrier function was assessed by FITC-Dextran permeability assays. Immunofluorescent staining of laminin 511 and claudin 1 was performed on extrahepatic bile duct tissue of control and anti-laminin 511-E8 positive individuals with IRC.

          Results

          Seven out of 52 individuals with IRC had autoantibodies against laminin 511-E8. Recombinant laminin 511-E8 led to differential expression of genes involved in secretion, barrier function, and inflammation. Knockdown of laminin 511 constituents increased toxic bile acid permeation and GCDC-induced apoptosis. Laminin 511-E8 treatment decreased toxic bile acid permeation and dose-dependently alleviated GCDC-induced apoptosis. LAMA5 and LAMC1 knockdown increased transepithelial permeability. Laminin 511-E8 treatment reduced transepithelial permeability and prevented T lymphocyte-induced barrier dysfunction. Laminin 511 and claudin 1 staining patterns appeared altered in anti-laminin 511-E8 positive individuals with IRC.

          Conclusions

          Laminin 511-E8 is an autoantigen in subsets of individuals with IRC. Laminin 511 enhances cholangiocellular barrier function and protects cholangiocytes against T lymphocyte-induced barrier dysfunction, toxic bile acid permeation and bile acid-induced apoptosis.

          Impact and implications

          A subset of patients with IgG4-related cholangitis (IRC) has autoantibodies against laminin 511-E8. In human cholangiocytes, laminin 511 protects against (T lymphocyte-induced) epithelial barrier dysfunction and hydrophobic bile acids. Laminin 511 and claudin 1 staining may be altered in extrahepatic bile ducts of patients with IRC who are anti-laminin 511-E8 positive. This makes it tempting to speculate that a decreased epithelial barrier function with attraction of immune cells and impaired bicarbonate secretion as a result of dysfunction of laminin 511 by autoantibody binding could potentially be a common systemic pathogenic mechanism in a subset of patients with IgG4-RD.

          Graphical abstract

          Highlights

          • •

            Laminin 511-E8 is an autoantigen in a subset of individuals with IRC.

          • •

            Laminin 511 protects cholangiocytes against toxic bile acids.

          • •

            Laminin 511 improves cholangiocellular barrier function.

          • •

            Laminin 511 protects the cholangiocyte barrier from T lymphocyte-induced damage.

          • •

            Laminin 511 and claudin 1 expression may be altered in individuals with IRC.

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          Most cited references44

          • Record: found
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          Genetic compensation: A phenomenon in search of mechanisms

          Mohamed El-Brolosy, Didier Y. R. Stainier (2017)
          Several recent studies in a number of model systems including zebrafish, Arabidopsis, and mouse have revealed phenotypic differences between knockouts (i.e., mutants) and knockdowns (e.g., antisense-treated animals). These differences have been attributed to a number of reasons including off-target effects of the antisense reagents. An alternative explanation was recently proposed based on a zebrafish study reporting that genetic compensation was observed in egfl7 mutant but not knockdown animals. Dosage compensation was first reported in Drosophila in 1932, and genetic compensation in response to a gene knockout was first reported in yeast in 1969. Since then, genetic compensation has been documented many times in a number of model organisms; however, our understanding of the underlying molecular mechanisms remains limited. In this review, we revisit studies reporting genetic compensation in higher eukaryotes and outline possible molecular mechanisms, which may include both transcriptional and posttranscriptional processes.
          Article 0 comments Cited 351 times – based on 0 reviews     Review now
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            Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.

            Amaar Ghazale, Suresh T. Chari, Lizhi Zhang … (2008)
            Immunoglobulin (Ig)G4-associated cholangitis (IAC) is the biliary manifestation of a steroid-responsive multisystem fibroinflammatory disorder in which affected organs have a characteristic lymphoplasmacytic infiltrate rich in IgG4-positive cells. We describe clinical features, treatment response, and predictors of relapse in IAC and compare relapse rates in IAC with intrapancreatic vs proximal bile duct strictures. We reviewed clinical, serologic, and imaging characteristics and treatment response in 53 IAC patients. IAC patients generally were older (mean age, 62 y) men (85%), presenting with obstructive jaundice (77%) associated with autoimmune pancreatitis (92%), increased serum IgG4 levels (74%), and abundant IgG4-positive cells in bile duct biopsy specimens (88%). At presentation, biliary strictures were confined to the intrapancreatic bile duct in 51%; the proximal extrahepatic/intrahepatic ducts were involved in 49%. Initial presentation was treated with steroids (n = 30; median follow-up period, 29.5 months), surgical resection (n = 18; median follow-up period, 58 months), or was conservative (n = 5; median follow-up period, 35 months). Relapses occurred in 53% after steroid withdrawal; 44% relapsed after surgery and were treated with steroids. The presence of proximal extrahepatic/intrahepatic strictures was predictive of relapse. Steroid therapy normalized liver enzyme levels in 61%; biliary stents could be removed in 17 of 18 patients. Fifteen patients treated with steroids for relapse after steroid withdrawal responded; 7 patients on additional immunomodulatory drugs remain in steroid-free remission (median follow-up period, 6 months). IAC should be suspected in unexplained biliary strictures associated with increased serum IgG4 and unexplained pancreatic disease. Relapses are common after steroid withdrawal, especially with proximal strictures. The role of immunomodulatory drugs for relapses needs further study.
            Article 0 comments Cited 171 times – based on 0 reviews     Review now
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              The laminin family.

              Monique Aumailley (2016)
              Laminins are large molecular weight glycoproteins constituted by the assembly of three disulfide-linked polypeptides, the α, β and γ chains. The human genome encodes 11 genetically distinct laminin chains. Structurally, laminin chains differ by the number, size and organization of a few constitutive domains, endowing the various members of the laminin family with common and unique important functions. In particular, laminins are indispensable building blocks for cellular networks physically bridging the intracellular and extracellular compartments and relaying signals critical for cellular behavior, and for extracellular polymers determining the architecture and the physiology of basement membranes.
              Article 0 comments Cited 145 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Ulrich Beuers
                Journal
                Journal ID (nlm-ta): JHEP Rep
                Journal ID (iso-abbrev): JHEP Rep
                Title: JHEP Reports
                Publisher: Elsevier
                ISSN (Electronic): 2589-5559
                Publication date PMC-release: 23 January 2024
                Publication date Collection: April 2024
                Publication date (Electronic): 23 January 2024
                Volume: 6
                Issue: 4
                Electronic Location Identifier: 101015
                Affiliations
                [1 ]Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, The Netherlands
                [2 ]Department of Epidemiology & Data Science, Bioinformatics Laboratory, Amsterdam Public Health Research Institute, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, The Netherlands
                Author notes
                [∗ ]Corresponding author. Address: Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Location AMC (C2-327), Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31-20-5662422; Fax: +31-20-5669701. u.h.beuers@ 123456amsterdamumc.nl
                [†]

                These authors contributed equally to this work and share first authorship.

                Article
                Publisher Item ID: S2589-5559(24)00016-8 Publisher ID: 101015
                DOI: 10.1016/j.jhepr.2024.101015
                PMC ID: 10959701
                PubMed ID: 38524667
                SO-VID: 741f4c79-f5d2-4521-9d3d-2f4b47b579f5
                Copyright © © 2024 The Author(s)
                License:

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 19 June 2023
                Date revision received : 4 January 2024
                Date accepted : 11 January 2024
                Categories
                Subject: Research Article

                Keywords: activated t lymphocytes,biliary bicarbonate umbrella,cholangiopathy,epithelial barrier function,gcdc,glycochenodeoxycholate,hydrophobic bile acids,igg4-related disease,igg4-rd,immune-mediated disease,laminin
                Data availability:
                Keywords: activated t lymphocytes, biliary bicarbonate umbrella, cholangiopathy, epithelial barrier function, gcdc, glycochenodeoxycholate, hydrophobic bile acids, igg4-related disease, igg4-rd, immune-mediated disease, laminin

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