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Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)
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 jem_20240699.pdf | Published version | 6.38 MB | Adobe PDF | View/Open |
| Title: | Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C) |
| Authors: | Bellos, E Santillo, D Vantourout, P Jackson, HR Duret, A Hearn, H Seeleuthner, Y Talouarn, E Hodeib, S Patel, H Powell, O Yeoh, S Mustafa, S Habgood-Coote, D Nichols, S Estramiana Elorrieta, L D’Souza, G Wright, VJ Estrada-Rivadeneyra, D Tremoulet, AH Dummer, KB Netea, SA Condino-Neto, A Lau, YL Núñez Cuadros, E Toubiana, J Holanda Pena, M Rieux-Laucat, F Luyt, C-E Haerynck, F Mège, JL Chakravorty, S Haddad, E Morin, M-P Metin Akcan, Ö Keles, S Emiroglu, M Alkan, G Tüter Öz, SK Elmas Bozdemir, S Morelle, G Volokha, A Kendir-Demirkol, Y Sözeri, B Coskuner, T Yahsi, A Gulhan, B Kanik-Yuksek, S Bayhan, GI Ozkaya-Parlakay, A Yesilbas, O Hatipoglu, N Ozcelik, T Belot, A Chopin, E Barlogis, V Sevketoglu, E Menentoglu, E Gayretli Aydin, ZG Bloomfield, M AlKhater, SA Cyrus, C Stepanovskiy, Y Bondarenko, A Öz, FN Polat, M Fremuth, J Lebl, J Geraldo, A Jouanguy, E Aiuti, A Alsina, L Andreakos, E De Andrés Martín, A Biggs, CM Borghesi, A Bousfiha, AA Blazquez-Gamero, D Brodin, P Casari, G Condino-Neto, A Fellay, J Flores, C Gorochov, G Erdeniz, EH Hammarström, L Garcia, YJ Karbuz, A Klocperk, A Lapuente-Suanzes, P Lau, Y-L Leung, C Mansouri, D Mogensen, TH Ng, LFP Novelli, A Novelli, G Okamoto, K Okada, S Pan-Hammarström, Q Pesole, G Renia, L Rodriguez-Gallego, C Sediva, A Shahrooei, M Soler-Palacin, P Spaan, AN Tanir, G Tayoun, AA Temel, ŞG Vinh, DC Cunnington, A Herberg, J Kaforou, M Wright, VJ Bellos, E Broderick, C Channon-Wells, S Cooray, S De, T D'Souza, G Elorrieta, LE Estrada-Rivadeneyra, D Galassini, R Habgood-Coote, D Hamilton, S Jackson, H Kavangh, J Keren, I Marjaneh, MM Menikou, S Nichols, S Nijman, R Pennisi, I Powell, O Reid, R Shah, P Vito, O Whittaker, E Wilson, C Womersley, R Abdulla, A Darnell, S Mustafa, S Georgiou, P Manzano, J-R Moser, N Carter, M Tibby, S Cohen, J Davis, F Kenny, J Wellman, P White, M Fish, M Jennings, A Shankar-Hari, M Fidler, K Agranoff, D Richmond, V Seal, M Faust, S Owen, D Ensom, R McKay, S Shaji, M Schranz, R Rughni, P Anpanthar, A Liebeschuetz, S Riddell, A Divakaran, D Han, L Khalid, N Malcolm, IL Schofield, J Simagan, T Peters, M Bamford, A O'Neill, L Pathan, N Daubney, E White, D Heightman, M Eisen, S Segal, T Wellings, L Drysdale, SB Branch, N Hamzah, L Jarman, H Nyirenda, M Capozzi, L Gardiner, E Moots, R Nasher, M Hanson, A Linforth, M O'Riordan, S Ellis, D Deep, A Caro, I Shackley, F Bellini, A Gormley, S Neshat, S Scholefield, B Robbins, C Winmill, H Paulus, SC Pollard, AJ Anthony, M Hopton, S Miller, D Oliver, Z Beer, S Ward, B Shrestha, S Gurung, M Amatya, P Pokhrel, B Bijukchhe, SM Gautam, MC Kelly, S O'Reilly, P Shrestha, S Martinón-Torres, F Salas, A Álvez González, F Gómez, SA Bello, X García, MB Caamaño Viña, F Carnota, S Curras-Tuala, MJ Dacosta Urbieta, A Suárez, CD Vidal, IF Vicente, LG Gómez-Carballa, A Rial, JG Iglesias, PL Mallah, N Martinón-Torres, N Martinón, JM Mosquera Pérez Sánchez, B Pardo-Seco, J Pischedda, S Vázquez, SR Calle, IR Rodríguez-Tenreiro, C Redondo-Collazo, L Fernández, SS Iglesias, MV Carrol, ED Cocklin, E Beckley, R Bracken, A Evans, C Khanijau, A Lenihan, R Lewis-Burke, N Newall, K Romaine, S Whitbread, J Tsolia, M Eleftheriou, I Spyridis, N Tambouratzi, M Maritsi, D Marmarinos, A Xagorari, M Panagiota, L Aggelos, P Karoli, A Charalambos, G Markos, M Michalis, V Ioan, S Emonts, M Lim, E Isaacs, J Bell, K Crulley, S Fabian, D Thomson, E Wallia, D Miller, C Bell, A Van der Velden, FJS Shenton, G Price, A Treloar, O Thomas, D Rojo, P Epalza, C Villaverde, S Márquez, S Gijón, M Machín, F Cabello, L Hernández, I Gutiérrez, L Manzanares, Á Kuijpers, TW Van de Kuip, M Van Furth, M Van den Berg, M Biesbroek, G Verkuil, F Van der Zee, C Pajkrt, D Van Hensbroek, MB Schonenberg, D Gruppen, M Nagelkerke, S Jansen, MH Goetschalckx, I Romani, L De Luca, M Chiurchiù, S Tripiciano, C Mercadante, S Vermont, CL Moll, HA Borensztajn, DM Hagedoorn, NN Tan, C Zachariasse, J Dik, W Shen, C-F Zavadska, D Laivacuma, S Rudzate, A Stoldere, D Barzdi, A Barzdi, E Madelane, M Gravele, D Svilz, D Basmaci, R Lachaume, N Bories, P Tkhayat, R Chériaux, L Davoust, J Ong, K-T Cotillon, M De Groc, T Le, S Vergnault, N Sée, H Cohen, L De Tugny, A Danekova, N Mommert-Tripon, M Brengel-Pesce, K Pokorn, M Kolnik, M Avčin, T Avramoska, T Bahovec, N Bogovič, P Kitanovski, L Nahtigal, M Papst, L Plankar Srovin, T Strle, F Vincek, K Van der Flier, M Tissing, WJE Wösten-van Asperen, RM Vastert, SJ Vijlbrief, DC Bont, LJ Beudeker, CR Agyeman, P Schlapbach, L Aebi, C Usman, M Schlüchter, S Wyss, V Schöbi, N Zimmermann, E Meier, M Weber, K Fink, C Voice, M Calvo-Bado, L Steele, M Holden, J Taylor, A Calvez, R Davies, C Evans, B Stevens, J Matthews, P Billing, K Zenz, W Binder, A Kohlmaier, B Kohlfürst, DS Schweintzger, NA Zurl, C Hösele, S Leitner, M Pölz, L Rusu, A Rajic, G Stoiser, B Strempfl, M Sagmeister, MG Bauchinger, S Benesch, M Ceolotto, A Eber, E Gallistl, S Haidl, H Hauer, A Hude, C Kapper, A Keldorfer, M Löffler, S Niedrist, T Pilch, H Pfleger, A Pfurtscheller, K Rödl, S Skrabl-Baumgartner, A Strenger, V Wallner, E Tauchert, MK Yeung, S Dewez, M Bath, D Fitchett, E Cresswell, F Usuf, E Bojang, K Roca, A Sarr, I Saidykhan, M Ndure, E Von Both, U Kolberg, L Schmied, P Mavridi, I Alba-Alejandre, I Haas, N Maier, E Juranek, S Feuchtinger, T Danhauser, K Griese, M Kappler, M Lurz, E Schroepf, S Hoffmann, F Reiter, K Schoen, C Schlapbach, LJ Giannoni, E Stocker, M Posfay-Barbe, KM Heininger, U Bernhard-Stirnemann, S Niederer-Loher, A Kahlert, C Talucci, G Relly, C Berger, C Riedel, T Madrigal, P Fexova, S Levin, M Coin, L Gormley, S Hamilton, S Herberg, J Hourmat, B Hoggart, C Kaforou, M Sancho-Shimizu, V Wright, V Abdulla, A Agapow, P Bartlett, M Bellos, E Eleftherohorinou, H Galassini, R Inwald, D Mashbat, M Menikou, S Mustafa, S Nadel, S Rahman, R Shailes, H Thakker, C Bokhandi, S Power, S Barham, H Pathan, N Ridout, J White, D Thurston, S Faust, S Patel, S McCorkell, J Davies, P Crate, L Navarra, H Carter, S Ramaiah, R Patel, R Tuffrey, C Gribbin, A McCready, S Peters, M Hardy, K Standing, F O'Neill, L Abelake, E Deep, A Nsirim, E Pollard, A Willis, L Young, Z Royad, C White, S Fortune, P-M Hudnott, P Martinón-Torres, F Salas, A González, FA Barral-Arca, R Cebey-López, M Curras-Tuala, MJ García, N Vicente, LG Gómez-Carballa, A Rial, JG Beiroa, AG Grande, AJ Leboráns Iglesias, P Martínez Santos, AE Martinón-Torres, F Martinón-Torres, N Martinón Sánchez, JM Morillo Gutiérrez, B Mosquera Pérez, B Obando Pacheco, P Pardo-Seco, J Pischedda, S Rivero-Calle, I Rodríguez-Tenreiro, C Redondo-Collazo, L Fernández, SS Del Sol Porto Silva, M Vega, A Trillo, LV Reyes, SB León, MCL Mingorance, AN Barrios, XG Vergara, EO Torre, AC Vivanco, A Fernández, R Sánchez, FG Forte, MS Rojo, P Contreras, JR Palacios, A Ibarrondo, CE Cooke, EF Navarro, M Álvarez, CA Lozano, MJ Carreras, E Sanagustín, SB Neth, O Del Carmen Martínez Padilla, M Tato, LMP Guillén, S Silveira, LF Moreno, D De Groot, R Van Furth, AMT Van der Flier, M Boeddha, NP Driessen, GJA Hazelzet, J Kuijpers, TW Pajkrt, D Sanders, EAM Van de Beek, D Van der Ende, A Philipsen, RHLA Adeel, AOA Breukels, MA Brinkman, DMC De Korte, CCMM De Vries, E De Waal, WJ Dekkers, R Dings-Lammertink, A Doedens, RA Donker, AE Dousma, M Faber, TE Gerrits, GPJM Gerver, JAM Heidema, J Homan-van der Veen, J Jacobs, MAM Jansen, NJG Kawczynski, P Klucovska, K Kneyber, MCJ Koopman-Keemink, Y Langenhorst, VJ Leusink, J Loza, BF Merth, IT Miedema, CJ Neeleman, C Noordzij, JG Obihara, CC Van Overbeek - van Gils, ALT Poortman, GH Potgieter, ST Potjewijd, J Rosias, PPR Sprong, T Ten Tussher, GW Thio, BJ Tramper-Stranders, GA Van Deuren, M Van der Meer, H Van Kuppevelt, AJM Van Wermeskerken, A-M Verwijs, WA Wolfs, TFW Schlapbach, LJ Agyeman, P Aebi, C Berger, C Giannoni, E Stocker, M Posfay-Barbe, KM Heininger, U Bernhard-Stirnemann, S Niederer-Loher, A Kahlert, C Hasters, P Relly, C Baer, W Carrol, ED Paulus, S Frederick, H Jennings, R Johnston, J Kenwright, R Fink, CG Pinnock, E Emonts, M Agbeko, R Anderson, S Secka, F Bojang, K Sarr, I Kebbeh, N Sey, G Saidykhan, M Cole, F Thomas, G Antonio, M Zenz, W Kohlfürst, DS Binder, A Schweintzger, NA Sagmeister, M Baumgart, H Baumgartner, M Behrends, U Biebl, A Birnbacher, R Blanke, J-G Boelke, C Breuling, K Brunner, J Buller, M Dahlem, P Dietrich, B Eber, E Elias, J Emhofer, J Etschmaier, R Farr, S Girtler, Y Grigorow, I Heimann, K Ihm, U Jaros, Z Kalhoff, H Kaulfersch, W Kemen, C Klocker, N Köster, B Kohlmaier, B Komini, E Kramer, L Neubert, A Ortner, D Pescollderungg, L Pfurtscheller, K Reiter, K Ristic, G Rödl, S Sellner, A Sonnleitner, A Sperl, M Stelzl, W Till, H Trobisch, A Vierzig, A Vogel, U Weingarten, C Welke, S Wimmer, A Wintergerst, U Wüller, D Zaunschirm, A Ziuraite, I Žukovskaja, V Hibberd, ML Davila, S Delany, I Carter, MJ Wellman, P Peters, M Pérez de Diego, R Edwards, LA Chiu, C Noursadeghi, M Bolze, A Shimizu, C Kaforou, M Hamilton, MS Herberg, JA Schmitt, EG Rodriguez-Palmero, A Pujol, A Kim, J Cobat, A Abel, L Zhang, S-Y Casanova, J-L Kuijpers, TW Burns, JC Levin, M Hayday, AC Sancho-Shimizu, V |
| Item Type: | Journal Article |
| Abstract: | Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, “burdenMC,” which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5–5.3, P < 10−6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2. |
| Issue Date: | Dec-2024 |
| Date of Acceptance: | 27-Sep-2024 |
| URI: | http://hdl.handle.net/10044/1/115001 |
| DOI: | 10.1084/jem.20240699 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Journal / Book Title: | Journal of Experimental Medicine |
| Volume: | 221 |
| Issue: | 12 |
| Copyright Statement: | © 2024 Bellos et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
| Publication Status: | Published |
| Article Number: | e920240699 |
| Online Publication Date: | 2024-11-22 |
| Appears in Collections: | Department of Immunology and Inflammation Department of Infectious Diseases Faculty of Medicine |
This item is licensed under a Creative Commons License
