Objective 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.Design 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.Results 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 HLA-DPA1* 02:01 similar to B1*01:01 (OR 1.99, p=6.7x10-50). 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-gamma-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.Conclusion Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01 similar to DPB1*01:01 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.
HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells / 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; Fehse, Boris; Oldhafer, Karl J; Schumacher, Udo; Sauter, Guido; Carrington, Mary; Franke, Andre; Bunders, Madeleine J; Schramm, Christoph; Altfeld, Marcus; Marzioni, Marco. - In: EGUT. - ISSN 1468-3288. - 73:2(2024). [10.1136/gutjnl-2023-329524]
HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells
Marzioni, Marco
2024-01-01
Abstract
Objective 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.Design 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.Results 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 HLA-DPA1* 02:01 similar to B1*01:01 (OR 1.99, p=6.7x10-50). 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-gamma-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.Conclusion Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01 similar to DPB1*01:01 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
