HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells.
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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, International PSC Study Group (IPSCSG), 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
Аннотация
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~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.
CONCLUSION: Our studies identify a novel PSC risk haplotype HLA-DP A1*02:01~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.