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HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

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HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis. / Baumdick, Martin E; Niehrs, Annika; Degenhardt, Frauke; Schwerk, Maria; Hinrichs, Ole; Jordan-Paiz, Ana; Padoan, Benedetta; Wegner, Lucy H M; Schloer, Sebastian; Zecher, Britta F; Malsy, Jakob; Joshi, Vinita R; Illig, Christin; Schröder-Schwarz, Jennifer; Möller, Kimberly J; Martin, Maureen; Yuki, Yuko; Ozawa, Mikki; Sauter, Jürgen; Schmidt, Alexander H; Perez, Daniel; Giannou, Anastasios D; Carrington, Mary; Davis, Randall S; Schumacher, Udo; Sauter, Guido; Huber, Samuel; Puelles, Victor G; Melling, Nathaniel; Franke, Andre; Altfeld, Marcus; Bunders, Madeleine J; Hamburg Intestinal Tissue Study Group; International Inflammatory Bowel Disease Genetics Consortium.

in: GASTROENTEROLOGY, Jahrgang 165, Nr. 4, 10.2023, S. 946-962.e13.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Baumdick, ME, Niehrs, A, Degenhardt, F, Schwerk, M, Hinrichs, O, Jordan-Paiz, A, Padoan, B, Wegner, LHM, Schloer, S, Zecher, BF, Malsy, J, Joshi, VR, Illig, C, Schröder-Schwarz, J, Möller, KJ, Martin, M, Yuki, Y, Ozawa, M, Sauter, J, Schmidt, AH, Perez, D, Giannou, AD, Carrington, M, Davis, RS, Schumacher, U, Sauter, G, Huber, S, Puelles, VG, Melling, N, Franke, A, Altfeld, M, Bunders, MJ, Hamburg Intestinal Tissue Study Group & International Inflammatory Bowel Disease Genetics Consortium 2023, 'HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis', GASTROENTEROLOGY, Jg. 165, Nr. 4, S. 946-962.e13. https://doi.org/10.1053/j.gastro.2023.06.034

APA

Baumdick, M. E., Niehrs, A., Degenhardt, F., Schwerk, M., Hinrichs, O., Jordan-Paiz, A., Padoan, B., Wegner, L. H. M., Schloer, S., Zecher, B. F., Malsy, J., Joshi, V. R., Illig, C., Schröder-Schwarz, J., Möller, K. J., Martin, M., Yuki, Y., Ozawa, M., Sauter, J., ... International Inflammatory Bowel Disease Genetics Consortium (2023). HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis. GASTROENTEROLOGY, 165(4), 946-962.e13. https://doi.org/10.1053/j.gastro.2023.06.034

Vancouver

Baumdick ME, Niehrs A, Degenhardt F, Schwerk M, Hinrichs O, Jordan-Paiz A et al. HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis. GASTROENTEROLOGY. 2023 Okt;165(4):946-962.e13. https://doi.org/10.1053/j.gastro.2023.06.034

Bibtex

@article{f92c723921314b61a20ed71de2c573d6,
title = "HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis",
abstract = "BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.METHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.RESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.CONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.",
author = "Baumdick, {Martin E} and Annika Niehrs and Frauke Degenhardt and Maria Schwerk and Ole Hinrichs and Ana Jordan-Paiz and Benedetta Padoan and Wegner, {Lucy H M} and Sebastian Schloer and Zecher, {Britta F} and Jakob Malsy and Joshi, {Vinita R} and Christin Illig and Jennifer Schr{\"o}der-Schwarz and M{\"o}ller, {Kimberly J} and Maureen Martin and Yuko Yuki and Mikki Ozawa and J{\"u}rgen Sauter and Schmidt, {Alexander H} and Daniel Perez and Giannou, {Anastasios D} and Mary Carrington and Davis, {Randall S} and Udo Schumacher and Guido Sauter and Samuel Huber and Puelles, {Victor G} and Nathaniel Melling and Andre Franke and Marcus Altfeld and Bunders, {Madeleine J} and {Hamburg Intestinal Tissue Study Group} and {International Inflammatory Bowel Disease Genetics Consortium}",
note = "Copyright {\textcopyright} 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2023",
month = oct,
doi = "10.1053/j.gastro.2023.06.034",
language = "English",
volume = "165",
pages = "946--962.e13",
journal = "GASTROENTEROLOGY",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",

}

RIS

TY - JOUR

T1 - HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

AU - Baumdick, Martin E

AU - Niehrs, Annika

AU - Degenhardt, Frauke

AU - Schwerk, Maria

AU - Hinrichs, Ole

AU - Jordan-Paiz, Ana

AU - Padoan, Benedetta

AU - Wegner, Lucy H M

AU - Schloer, Sebastian

AU - Zecher, Britta F

AU - Malsy, Jakob

AU - Joshi, Vinita R

AU - Illig, Christin

AU - Schröder-Schwarz, Jennifer

AU - Möller, Kimberly J

AU - Martin, Maureen

AU - Yuki, Yuko

AU - Ozawa, Mikki

AU - Sauter, Jürgen

AU - Schmidt, Alexander H

AU - Perez, Daniel

AU - Giannou, Anastasios D

AU - Carrington, Mary

AU - Davis, Randall S

AU - Schumacher, Udo

AU - Sauter, Guido

AU - Huber, Samuel

AU - Puelles, Victor G

AU - Melling, Nathaniel

AU - Franke, Andre

AU - Altfeld, Marcus

AU - Bunders, Madeleine J

AU - Hamburg Intestinal Tissue Study Group

AU - International Inflammatory Bowel Disease Genetics Consortium

N1 - Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2023/10

Y1 - 2023/10

N2 - BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.METHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.RESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.CONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.

AB - BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.METHODS: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.RESULTS: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.CONCLUSIONS: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC.

U2 - 10.1053/j.gastro.2023.06.034

DO - 10.1053/j.gastro.2023.06.034

M3 - SCORING: Journal article

C2 - 37454979

VL - 165

SP - 946-962.e13

JO - GASTROENTEROLOGY

JF - GASTROENTEROLOGY

SN - 0016-5085

IS - 4

ER -