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 - Hamburg Intestinal Tissue Study Group
AU - Akar, Alaa
AU - Flemming, Cornelius
AU - Flomm, Felix J.
AU - Flosbach, Markus
AU - Jäger, Julia
AU - Jeromin, Niklas
AU - Jung, Johannes
AU - Ohms, Mareike
AU - Reinshagen, Konrad
AU - Rische, Johann
AU - Sagebiel, Adrian
AU - Sandfort, Deborah
AU - Steinert, Fenja
AU - Tomuschat, Christian
AU - Wesche, Jasmin
AU - International Inflammatory Bowel Disease Genetics Consortium
AU - Martin, Maureen P.
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 - Shifteh Abedian, Abedian
AU - Abraham, Clara
AU - Achkar, Jean Paul
AU - Ahmad, Tariq
AU - Alberts, Rudi
AU - Alizadeh, Behrooz
AU - Amininejad, Leila
AU - Ananthakrishnan, Ashwin N.
AU - Andersen, Vibeke
AU - Anderson, Carl A.
AU - Andrews, Jane M.
AU - Annese, Vito
AU - Aumais, Guy
AU - Baidoo, Leonard
AU - Baldassano, Robert N.
AU - Bampton, Peter A.
AU - Barclay, Murray
AU - Barrett, Jeffrey C.
AU - Bethge, Johannes
AU - Bewshea, Claire
AU - Bis, Joshua C.
AU - Bitton, Alain
AU - BK, Thelma
AU - Boucher, Gabrielle
AU - Brain, Oliver
AU - Brand, Stephan
AU - Brant, Steven R.
AU - Cheon, Jae Hee
AU - Chew, Angela
AU - Cho, Judy H.
AU - Cleynen, Isabelle
AU - Cohain, Ariella
AU - Cooney, Rachel
AU - Croft, Anthony
AU - Daly, Mark J.
AU - D'Amato, Mauro
AU - Danese, Silvio
AU - Daryani, Naser Ebrahim
AU - Datta, Lisa Wu
AU - Denapiene, Goda
AU - Denson, Lee A.
AU - Devaney, Kathy L.
AU - Dewit, Olivier
AU - D'Inca, Renata
AU - Drummond, Hazel E.
AU - Dubinsky, Marla
AU - Duerr, Richard H.
AU - Edwards, Cathryn
AU - Ellinghaus, David
AU - Ellul, Pierre
AU - Esaki, Motohiro
AU - Essers, Jonah
AU - Ferguson, Lynnette R.
AU - Festen, Eleonora A.
AU - Fleshner, Philip
AU - Florin, Tim
AU - Franchimont, Denis
AU - Fuyuno, Yuta
AU - Gearry, Richard
AU - Georges, Michel
AU - Gieger, Christian
AU - Glas, Jürgen
AU - Goyette, Philippe
AU - Green, Todd
AU - Griffiths, Anne M.
AU - Guthery, Stephen L.
AU - Hakonarson, Hakon
AU - Halfvarson, Jonas
AU - Hanigan, Katherine
AU - Haritunians, Talin
AU - Hart, Ailsa
AU - Hawkey, Chris
AU - Hayward, Nicholas K.
AU - Hedl, Matija
AU - Henderson, Paul
AU - Hold, Georgina L.
AU - Hong, Myhunghee
AU - Hu, Xinli
AU - Huang, Hailiang
AU - Hugot, Jean Pierre
AU - Hui, Ken Y.
AU - Imielinski, Marcin
AU - Jazayeri, Omid
AU - Jonaitis, Laimas
AU - Jostins, Luke
AU - Juyal, Garima
AU - Chandra Juyal, Ramesh
AU - Kalla, Rahul
AU - Karlsen, Tom H.
AU - Kennedy, Nicholas A.
AU - Khan, Mohammed Azam
AU - Kim, Won Ho
AU - Kitazono, Takanari
AU - Kiudelis, Gediminas
AU - Kubo, Michiaki
AU - Kugathasan, Subra
AU - Kupcinskas, Limas
AU - Lamb, Christopher A.
AU - de Lange, Katrina M.
AU - Latiano, Anna
AU - Laukens, Debby
AU - Lawrance, Ian C.
AU - Lee, James C.
AU - Lees, Charlie W.
AU - Leja, Marcis
AU - Lewis, Nina
AU - Van Limbergen, Johan
AU - Lionetti, Paolo
AU - Liu, Jimmy Z.
AU - Louis, Edouard
AU - Luo, Yang
AU - Mahy, Gillian
AU - Malekzadeh, Masoud Mohammad
AU - Malekzadeh, Reza
AU - Mansfield, John
AU - Marriott, Suzie
AU - Massey, Dunecan
AU - Mathew, Christopher G.
AU - Matsui, Toshiyuki
AU - McGovern, Dermot P.B.
AU - van der Meulen, Andrea
AU - Midha, Vandana
AU - Milgrom, Raquel
AU - Mirzaei, Samaneh
AU - Mitrovic, Mitja
AU - Montgomery, Grant W.
AU - Mowat, Craig
AU - Müller, Christoph
AU - Newman, William G.
AU - Ng, Aylwin
AU - Ng, Siew C.
AU - Evelyn Ng, Sok Meng
AU - Nikolaus, Susanna
AU - Ning, Kaida
AU - Nöthen, Markus
AU - Oikonomou, Ioannis
AU - Okou, David
AU - Orchard, Timothy R.
AU - Palmieri, Orazio
AU - Parkes, Miles
AU - Phillips, Anne
AU - Ponsioen, Cyriel Y.
AU - Potocnik, Urõs
AU - Poustchi, Hossein
AU - Prescott, Natalie J.
AU - Proctor, Deborah D.
AU - Radford-Smith, Graham
AU - Rahier, Jean Francois
AU - Regueiro, Miguel
AU - Reinisch, Walter
AU - Rieder, Florian
AU - Rioux, John D.
AU - Roberts, Rebecca
AU - Rogler, Gerhard
AU - Russell, Richard K.
AU - Sanderson, Jeremy D.
AU - Sans, Miquel
AU - Satsangi, Jack
AU - Schadt, Eric E.
AU - Scharl, Michael
AU - Schembri, John
AU - Schreiber, Stefan
AU - Schumm, L. Philip
AU - Scott, Regan
AU - Seielstad, Mark
AU - Shah, Tejas
AU - Sharma, Yashoda
AU - Silverberg, Mark S.
AU - Simmons, Alison
AU - Simms, Lisa A.
AU - Singh, Abhey
AU - Skieceviciene, Jurgita
AU - van Sommeren, Suzanne
AU - Song, Kyuyoung
AU - Sood, Ajit
AU - Spain, Sarah L.
AU - Steinhart, A. Hillary
AU - Stempak, Joanne M.
AU - Stronati, Laura
AU - Sung, Joseph J.Y.
AU - Targan, Stephan R.
AU - Taylor, Kirstin M.
AU - Theatre, Emilie
AU - Torkvist, Leif
AU - Torres, Esther A.
AU - Tremelling, Mark
AU - Uhlig, Holm H.
AU - Umeno, Junji
AU - Vahedi, Homayon
AU - Vasiliauskas, Eric
AU - Velde, Anje ter
AU - Ventham, Nicholas T.
AU - Vermeire, Severine
AU - Verspaget, Hein W.
AU - De Vos, Martine
AU - Walters, Thomas
AU - Wang, Kai
AU - Wang, Ming Hsi
AU - Weersma, Rinse K.
AU - Wei, Zhi
AU - Whiteman, David
AU - Zhang, Wei
AU - Altfeld, Marcus
AU - Bunders, Madeleine J.
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.
KW - HLA-DP
KW - Intestinal Organoids
KW - NK Cells
KW - NKp44
KW - Ulcerative Colitis
UR - http://www.scopus.com/inward/record.url?scp=85170657087&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2023.06.034
DO - 10.1053/j.gastro.2023.06.034
M3 - Article
C2 - 37454979
AN - SCOPUS:85170657087
SN - 0016-5085
VL - 165
SP - 946-962.e13
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -