HLA-DPA1*02:01~B1*01:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells
Author:
Zecher Britta FORCID, Ellinghaus DavidORCID, 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, Fehse BorisORCID, Oldhafer Karl J, Schumacher Udo, Sauter Guido, Carrington Mary, Franke Andre, Bunders Madeleine J, Schramm Christoph, Altfeld MarcusORCID,
Abstract
ObjectivePrimary 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.DesignLiver 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.ResultsNKp44+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 forHLA-DPA1*02:01~B1*01:01(OR 1.99, p=6.7×10−50). 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.ConclusionOur studies identify a novel PSC risk haplotypeHLA-DP A1*02:01~DPB1*01:01and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.
Funder
Landesforschungsförderung Hamburg Daisy Hüet Roel Foundation Frederick National Laboratory for Cancer Research Bundesministerium für Bildung und Forschung Deutsche Forschungsgemeinschaft H2020 European Research Council
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