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Zecher, Britta F; Ellinghaus, David; Schloer, Sebastian; Niehrs, Annika; Padoan, Benedetta; Baumdick, Martin E; Yuki, Yuko; Martin, Maureen P; Glow, Dawid; Schröder-Schwarz, Jennifer; Niersch, Jennifer; Brias, Sébastien; Müller, Luisa M; Habermann, Robin; Kretschmer, Paul; Früh, Tristan; Dänekas, Janis; Wehmeyer, Malte H; Poch, Tobias; Sebode, Marcial; Ellinghaus, Eva; Degenhardt, Frauke; Körner, Christian; Hoelzemer, Angelique; [...]

HLA-DPA1*02:01~B1*01:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

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  • Media type: E-Article
  • Title: HLA-DPA1*02:01~B1*01:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells
  • Contributor: Zecher, Britta F; Ellinghaus, David; Schloer, Sebastian; Niehrs, Annika; Padoan, Benedetta; Baumdick, Martin E; Yuki, Yuko; Martin, Maureen P; Glow, Dawid; Schröder-Schwarz, Jennifer; Niersch, Jennifer; Brias, Sébastien; Müller, Luisa M; Habermann, Robin; Kretschmer, Paul; Früh, Tristan; Dänekas, Janis; Wehmeyer, Malte H; Poch, Tobias; Sebode, Marcial; Ellinghaus, Eva; Degenhardt, Frauke; Körner, Christian; Hoelzemer, Angelique; [...]
  • Published: BMJ, 2024
  • Published in: Gut, 73 (2024) 2, Seite 325-337
  • Language: English
  • DOI: 10.1136/gutjnl-2023-329524
  • ISSN: 0017-5749; 1468-3288
  • Origination:
  • Footnote:
  • Description: <jats:sec><jats:title>Objective</jats:title><jats:p>Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activating NK-cell receptor NKp44, we investigated the role of HLA-DP/NKp44-interactions in PSC.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Liver tissue, intrahepatic and peripheral blood lymphocytes of individuals with PSC and control individuals were characterised using flow cytometry, immunohistochemical and immunofluorescence analyses. HLA-DPA1 and HLA-DPB1 imputation and association analyses were performed in 3408 individuals with PSC and 34 213 controls. NK cell activation on NKp44/HLA-DP interactions was assessed in vitro using plate-bound HLA-DP molecules and HLA-DPB wildtype versus knock-out human cholangiocyte organoids.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>NKp44+NK cells were enriched in livers, and intrahepatic bile ducts of individuals with PSC showed higher expression of HLA-DP. HLA-DP haplotype analysis revealed a highly elevated PSC risk for<jats:italic>HLA-DPA1*02:01~B1*01:01</jats:italic>(OR 1.99, p=6.7×10<jats:sup>−50</jats:sup>). Primary NKp44+NK cells exhibited significantly higher degranulation in response to plate-bound HLA-DPA1*02:01-DPB1*01:01 compared with control HLA-DP molecules, which were inhibited by anti-NKp44-blocking. Human cholangiocyte organoids expressing HLA-DPA1*02:01-DPB1*01:01 after IFN-γ-exposure demonstrated significantly increased binding to NKp44-Fc constructs compared with unstimulated controls. Importantly, HLA-DPA1*02:01-DPB1*01:01-expressing organoids increased degranulation of NKp44+NK cells compared with HLA-DPB1-KO organoids.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our studies identify a novel PSC risk haplotype<jats:italic>HLA-DP A1*02:01~DPB1*01:01</jats:italic>and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.</jats:p></jats:sec>