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

Standard

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; 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.

In: GUT, Vol. 73, No. 2, 05.01.2024, p. 325-337.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

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, International PSC Study Group (IPSCSG), 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 2024, 'HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells', GUT, vol. 73, no. 2, pp. 325-337. https://doi.org/10.1136/gutjnl-2023-329524

APA

Zecher, B. F., Ellinghaus, D., Schloer, S., Niehrs, A., Padoan, B., Baumdick, M. E., Yuki, Y., Martin, M. P., Glow, D., Schröder-Schwarz, J., Niersch, J., Brias, S., Müller, L. M., Habermann, R., Kretschmer, P., Früh, T., Dänekas, J., Wehmeyer, M. H., Poch, T., ... Altfeld, M. (2024). HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells. GUT, 73(2), 325-337. https://doi.org/10.1136/gutjnl-2023-329524

Vancouver

Zecher BF, Ellinghaus D, Schloer S, Niehrs A, Padoan B, Baumdick ME et al. HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells. GUT. 2024 Jan 5;73(2):325-337. https://doi.org/10.1136/gutjnl-2023-329524

Bibtex

@article{1b1cabe9f0c3419b8ac77ef3d086af2d,
title = "HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells",
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.",
author = "Zecher, {Britta F} and David Ellinghaus and Sebastian Schloer and Annika Niehrs and Benedetta Padoan and Baumdick, {Martin E} and Yuko Yuki and Martin, {Maureen P} and Dawid Glow and Jennifer Schr{\"o}der-Schwarz and Jennifer Niersch and S{\'e}bastien Brias and M{\"u}ller, {Luisa M} and Robin Habermann and Paul Kretschmer and Tristan Fr{\"u}h and Janis D{\"a}nekas and Wehmeyer, {Malte H} and Tobias Poch and Marcial Sebode and {International PSC Study Group (IPSCSG)} and Eva Ellinghaus and Frauke Degenhardt and Christian K{\"o}rner and Angelique Hoelzemer and Boris Fehse and Oldhafer, {Karl J} and Udo Schumacher and Guido Sauter and Mary Carrington and Andre Franke and Bunders, {Madeleine J} and Christoph Schramm and Marcus Altfeld",
note = "{\textcopyright} Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",
year = "2024",
month = jan,
day = "5",
doi = "10.1136/gutjnl-2023-329524",
language = "English",
volume = "73",
pages = "325--337",
journal = "GUT",
issn = "0017-5749",
publisher = "BMJ PUBLISHING GROUP",
number = "2",

}

RIS

TY - JOUR

T1 - HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

AU - Zecher, Britta F

AU - Ellinghaus, David

AU - Schloer, Sebastian

AU - Niehrs, Annika

AU - Padoan, Benedetta

AU - Baumdick, Martin E

AU - Yuki, Yuko

AU - Martin, Maureen P

AU - Glow, Dawid

AU - Schröder-Schwarz, Jennifer

AU - Niersch, Jennifer

AU - Brias, Sébastien

AU - Müller, Luisa M

AU - Habermann, Robin

AU - Kretschmer, Paul

AU - Früh, Tristan

AU - Dänekas, Janis

AU - Wehmeyer, Malte H

AU - Poch, Tobias

AU - Sebode, Marcial

AU - International PSC Study Group (IPSCSG)

AU - Ellinghaus, Eva

AU - Degenhardt, Frauke

AU - Körner, Christian

AU - Hoelzemer, Angelique

AU - Fehse, Boris

AU - Oldhafer, Karl J

AU - Schumacher, Udo

AU - Sauter, Guido

AU - Carrington, Mary

AU - Franke, Andre

AU - Bunders, Madeleine J

AU - Schramm, Christoph

AU - Altfeld, Marcus

N1 - © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2024/1/5

Y1 - 2024/1/5

N2 - 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.

AB - 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.

U2 - 10.1136/gutjnl-2023-329524

DO - 10.1136/gutjnl-2023-329524

M3 - SCORING: Journal article

C2 - 37788895

VL - 73

SP - 325

EP - 337

JO - GUT

JF - GUT

SN - 0017-5749

IS - 2

ER -