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

Baumdick, Martin; Niehrs, Annika; Schwerk, Maria; Hinrichs, O.; 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 P.; Yuki, Yuko; Ozawa, Miyuki; Sauter, Jürgen; Schmidt, Alexander H.; Pérez, Daniel Rodríguez; Giannou, Anastasios D.; Carrington, Mary; Davis, Randall S.; Schumacher, Udo; Sauter, Guido; Huber, Samuel; Puelles, Victor G.; Melling, Nathaniel; Altfeld, Marcus; Bunders, Madeleine J.; Akar, Antoine H.; Flemming, Claudia L.; Flomm, Felix; Flosbach, Markus; Jäger, Julia; Jeromin, Niklas; Jung, Johannes; Ohms, Mareike; Reinshagen, Konrad; Rische, Johann; Sagebiel, Adrian; Sandfort, Deborah; Steinert, Fenja L; Tomuschat, Christian; Wesche, Jasmin; Abedian, Shifteh; Abraham, Clara; Achkar, Jean–Paul; Ahmad, Tariq; Alberts, Rudi; Alizadeh, Behrooz Z.; Amininejad, Leila; Ananthakrishnan, Ashwin N.; Andersen, Vibeke; Anderson, Carl A.; Andrews, Jane M.; Annese, Vito; Aumais, Guy; Baidoo, Leonard; Baldassano, Robert N.; Bampton, Peter A.; Barclay, Murray L.; Barrett, Jeffrey C.; Bethge, Johannes; Bewshea, Claire; Bis, Joshua C.; Bitton, Alain; Bk, Thelma; Boucher, Gabrielle; Brain, Oliver; Brand, Stephan; Brant, Steven R.; Cheon, Jae Hee; Chew, Angela; Cho, Judy H.; Cleynen, Isabelle; Cohain, Ariella; Cooney, Rachel; Croft, Anthony; Daly, Mark J.; D’Amato, Mauro; Danese, Silvio; Daryani, Naser Ebrahim; Datta, Lisa W.; Degenhardt, Frauke; Denapiene, Goda; Denson, Lee A.; Devaney, Kathy L.; Dewit, Olivier; D’Incà, R.; Drummond, Hazel E.; Dubinsky, Marla; Duerr, Richard H.; Edwards, Cathryn; Ellinghaus, David; Ellul, Pierre; Esaki, Motohiro; Essers, Jonah; Ferguson, Lynnette R.; Festen, Eleonora A. M.; Fleshner, Philip; Florin, Tim; Franchimont, Denis; Franke, André; Fuyuno, Yuta; Gearry, Richard B.; Georges, Michel; Gieger, Christian; Glas, Jürgen; Goyette, Philippe; Green, Todd; Griffiths, Anne M.; Guthery, Stephen L.; Hákonarson, Hákon; Halfvarson, Jonas; Hanigan, Katherine; Haritunians, Talin; Hart, Ailsa; Hawkey, C. J.; Hayward, Nicholas K.; Hedl, Matija; Henderson, Paul; Hold, Georgina L.; Hong, Myhunghee; Hu, Xinli; Huang, Hailiang; Hugot, Jean‐Pierre; Hui, Ken Y.; Imieliński, Marcin; Jazayeri, Omid; Jonaitis, Laimas Virginijus; Jostins, Luke; Juyal, Garima; Juyal, Ramesh C.; Kalla, Rahul; Karlsen, Tom H.; Kennedy, Nicholas A.; Khan, Mohammed Azam; Kim, Won Ho; Kitazono, Takanari; Kiudelis, Gediminas; Kubo, Michiaki; Kugathasan, Subra; Kupčinskas, Limas; Lamb, Christopher A.; Lange, Katrina M. de; Latiano, Anna; Laukens, Debby; Lawrance, Ian C.; Lee, James C.; Lees, Charlie W; Leja, Mārcis; Lewis, Nina; Limbergen, Johan Van; Lionetti, Paolo; Liu, Yushi; Louis, Édouard; Luo, Yang; Mahy, Gillian; Malekzadeh, Masoud; Malekzadeh, Reza; Mansfield, John C.; Marriott, Suzie; Massey, Dunecan; Mathew, Christopher G.; Matsui, Toshiyuki; McGovern, Dermot P.; Jong, Andrea E. van der Meulen–de; Midha, Vandana; Milgrom, Raquel; Mirzaei, Siroos; Mitrovič, Mitja; Montgomery, Grant W.; Mowat, Craig; Müller, Christoph; Newman, William G.; Ng, Aylwin; Ng, Siew C.; Ng, Sok Meng Evelyn; Nikolaus, Susanna; Ning, Kaida; Nöthen, Markus M.; Oikonomou, Ioannis; Okou, David T.; Orchard, Timothy R.; Palmieri, Orazio; Parkes, Miles; Phillips, Anne; Ponsioen, Cyriel Y.; Potočnik, Uroš; Poustchi, Hossein; Prescott, Natalie J.; Proctor, Deborah D.; Radford‐Smith, Graham; Rahier, Jean–François; Regueiro, Miguel; Reinisch, Walter; Rieder, Florian; Rioux, John D.; Roberts, Rebecca; Rogler, Gerhard; Russell, Richard K.; Sanderson, Jeremy; Sans, Miquel; Satsangi, Jack; Schadt, Eric E.; Scharl, Michael; Schembri, John; Schreiber, Stefan; Schumm, L. Philip; Scott, Regan L.; Seielstad, Mark; Shah, Tejas; Sharma, Yashoda; Silverberg, Mark S.; Simmons, Alison; Simms, Lisa A.; Singh, Abhey; Skiecevičienė, Jurgita; Sommeren, Suzanne van; Song, Kyuyoung; Sood, Ajit; Spain, Sarah L.; Steinhart, A. Hillary; Stempak, Joanne M.; Stronati, Laura; Sung, Joseph JY.; Targan, Stephan R.; Taylor, Kirstin M.; Théâtre, Emilie; Törkvist, Leif; Torres, Esther A.; Tremelling, Mark; Uhlig, Holm H.; Umeno, Junji; Vahedi, H; Vasiliauskas, Eric A.; Velde, Anje A. te; Ventham, Nicholas T.; Vermeire, Séverine; Verspaget, Hein W.; Martin, Paul; Thomas, Sonia; Wang, Kai; Wang, Ming‐Hsi; Weersma, Rinse K.; Wei, Zhi; Whiteman, David C.; Wijmenga, Cisca; Wilson, David C.; Winkelmann, Juliane; Wong, Sunny H.; Xavier, Ramnik J.; Yamazaki, Keiko; Yang, Suk-Kyun; Ye, Byong Duk; Zeißig, Sebastian; Zhang, Bin; Zhang, Clarence K.; Hu, Zhang; Zhang, Wei; Zhao, Hongyu; Zhao, Zhen

doi:10.1053/j.gastro.2023.06.034

Cited by 5 publications

(5 citation statements)

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“…As recently demonstrated in the context of ulcerative colitis, TNF production of intestinal NKp44+ILCs increased after incubation with NKp44-binding HLA-DP molecules compared with incubation with NKp44-non-binding HLA-DP molecules. 63 To determine the role of NKp44/HLA-DP interactions for colonic inflammation in PSC-IBD, further investigations are needed, including comparative analysis to ulcerative colitis and Crohn’s disease. Taken together, these studies combining genetic association studies of PSC risk, patient samples and in vitro human cholangiocyte organoid models identify HLA-DPA1*02:01~DPB1*01:01 as a highly significant risk haplotype for PSC that can be recognised by NKp44+NK cells and induce NK cell activation.…”

Section: Discussionmentioning

confidence: 99%

HLA-DPA102:01~B101:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

Zecher,

Ellinghaus,

Schloer

et al. 2023

Gut

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ObjectivePrimary 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.DesignLiver 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.ResultsNKp44+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 forHLA-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.ConclusionOur studies identify a novel PSC risk haplotypeHLA-DP A1*02:01~DPB1*01:01and provide clinical and functional data implicating NKp44+NK cells that recognise HLA-DPA1*02:01-DPB1*01:01 expressed on cholangiocytes in PSC pathogenesis.

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Section: Discussionmentioning

confidence: 99%

HLA-DPA102:01~B101:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

Zecher,

Ellinghaus,

Schloer

et al. 2023

Gut

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“… 42 , 130 , 131 , 132 , 133 Besides, organoids models are also employed to elucidate the interactions between different cellular components within the tumor microenvironment, 134 , 135 , 136 which leads to an indirect impact on facilitating tumor progression. 137 , 138 , 139 Organoids models also enable the detection of alterations in gene expression and epigenetic modifications during precancerous stages. 140 , 141 …”

Section: Organoids Models In Clinic: Gi Disease Simulation and Treatmentmentioning

confidence: 99%

“…Organoids models representing varying degrees of disease severity can be employed to investigate disease progression 149 and facilitate the validation of distinct gene deletions or mutations in disease development. 130 , 138 While the exact causes of many GI inflammatory diseases remain unclear, factors such as genetics, immune system dysfunction, environmental triggers, and dietary habits are believed to play significant roles.…”

Section: Organoids Models In Clinic: Gi Disease Simulation and Treatmentmentioning

confidence: 99%

Organoids in gastrointestinal diseases: from bench to clinic

Wang,

Guo,

Zhang

et al. 2024

MedComm

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The etiology of gastrointestinal (GI) diseases is intricate and multifactorial, encompassing complex interactions between genetic predisposition and gut microbiota. The cell fate change, immune function regulation, and microenvironment composition in diseased tissues are governed by microorganisms and mutated genes either independently or through synergistic interactions. A comprehensive understanding of GI disease etiology is imperative for developing precise prevention and treatment strategies. However, the existing models used for studying the microenvironment in GI diseases—whether cancer cell lines or mouse models—exhibit significant limitations, which leads to the prosperity of organoids models. This review first describes the development history of organoids models, followed by a detailed demonstration of organoids application from bench to clinic. As for bench utilization, we present a layer‐by‐layer elucidation of organoid simulation on host–microbial interactions, as well as the application in molecular mechanism analysis. As for clinical adhibition, we provide a generalized interpretation of organoid application in GI disease simulation from inflammatory disorders to malignancy diseases, as well as in GI disease treatment including drug screening, immunotherapy, and microbial‐targeting and screening treatment. This review draws a comprehensive and systematical depiction of organoids models, providing a novel insight into the utilization of organoids models from bench to clinic.

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“…5 UC is essentially a type of intestinal barrier disease that initially manifests as damage of the intestinal epithelial structure. 6 Thus, the progression of UC is always associated with damage to the intestinal mucosal barrier. At this time, a variety of intestinal microorganisms, pathogens, and microbial metabolites enter the liver through the mesenteric vein and portal circulation.…”

Section: Introductionmentioning

confidence: 99%

“…The gut–liver axis is a channel for bidirectional interaction between intestinal and liver functions by means of portal circulation . UC is essentially a type of intestinal barrier disease that initially manifests as damage of the intestinal epithelial structure . Thus, the progression of UC is always associated with damage to the intestinal mucosal barrier.…”

Section: Introductionmentioning

confidence: 99%

Study on the Protective Effect and Mechanism of Umbilicaria esculenta Polysaccharide in DSS-Induced Mice Colitis and Secondary Liver Injury

Wang,

Liu,

Gao

et al. 2024

J. Agric. Food Chem.

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This study aimed to explore the ameliorative effects and potential mechanisms of Huangshan Umbilicaria esculenta polysaccharide (UEP) in dextran sulfate sodium-induced acute ulcerative colitis (UC) and UC secondary liver injury (SLI). Results showed that UEP could ameliorate both colon and liver pathologic injuries, upregulate mouse intestinal tight junction proteins (TJs) and MUC2 expression, and reduce LPS exposure, thereby attenuating the effects of the gut−liver axis. Importantly, UEP significantly downregulated the secretion levels of TNF-α, IL-1β, and IL-6 through inhibition of the NF-κB pathway and activated the Nrf2 signaling pathway to increase the expression levels of SOD and GSH-Px. In vitro, UEP inhibited the LPS-induced phosphorylation of NF-κB P65 and promoted nuclear translocation of Nrf2 in RAW264.7 cells. These results revealed that UEP ameliorated UC and SLI through NF-κB and Nrf2-mediated inflammation and oxidative stress. The study first investigated the anticolitis effect of UEP, suggesting its potential for the treatment of colitis and colitis-associated liver disease.

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

Cited by 5 publications

References 53 publications

HLA-DPA102:01~B101:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

HLA-DPA102:01~B101:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

Organoids in gastrointestinal diseases: from bench to clinic

Study on the Protective Effect and Mechanism of Umbilicaria esculenta Polysaccharide in DSS-Induced Mice Colitis and Secondary Liver Injury

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

Cited by 5 publications

References 53 publications

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

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

Organoids in gastrointestinal diseases: from bench to clinic

Study on the Protective Effect and Mechanism of Umbilicaria esculenta Polysaccharide in DSS-Induced Mice Colitis and Secondary Liver Injury

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Product

Resources

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HLA-DPA102:01~B101:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells

HLA-DPA102:01~B101:01is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells