Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zecher, BF; Ellinghaus, D; Schloer, S; Niehrs, A; Padoan, B; Baumdick, ME; Yuki, Y; Martin, MP; Glow, D; Schröder-Schwarz, J; Niersch, J; Brias, S; Müller, LM; Habermann, R; Kretschmer, P; Früh, T; Dänekas, J; Wehmeyer, MH; Poch, T; Sebode, M; Ellinghaus, E; Degenhardt, F; Körner, C; Hoelzemer, A; Fehse, B; Oldhafer, KJ; Schumacher, U; Sauter, G; Carrington, M; Franke, A; Bunders, MJ; Schramm, C; Altfeld, M, , International, PSC, Study, Group, (IPSCSG).
HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells.
Gut. 2024; 73(2): 325-337.
Doi: 10.1136/gutjnl-2023-329524
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- Study Group Mitglieder der Med Uni Graz:
- Fickert Peter
- Halilbasic Emina
- Trauner Michael
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- 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~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.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Haplotypes - administration & dosage
- Cholangitis, Sclerosing - genetics
- HLA-DP alpha-Chains - genetics
- Killer Cells, Natural - administration & dosage
- Find related publications in this database (Keywords)
- IMMUNOLOGY IN HEPATOLOGY
- AUTOIMMUNE BILIARY DISEASE
- IMMUNOGENETICS
- IMMUNE-MEDIATED LIVER DAMAGE
- PRIMARY SCLEROSING CHOLANGITIS