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1. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

Author

Jackson, Heather Ruth, Zandstra, Judith, Menikou, Stephanie, Hamilton, Shea, McArdle, Andrew J, De, Tisham, Agyeman, Philipp K A, Von Both, Ulrich, Carrol, Enitan D, Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, De Groot, Ronald, Moll, Henriette A, Pokorn, Marko, Pollard, Andrew, Schlapbach, Luregn J, Tsolia, Maria, Usuf, Effua, Wright, Victoria, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan JM, Cunnington, Aubrey J, Martinon-Torres, Federico, Herberg, Jethro, De Jonge, Marien I, Levin, Michael, Kuijpers, Taco, Kaforou, Myrsini, Abdulla, Amina, Aebi, Christoph, Agbeko, Rachel, Ali, Ladan, Alkema, Wynand, Allen, Karen, Anderson, Suzanne, Ansari, Imran, Arif, Tasnim, Avramoska, Tanja, Baas, Bryan, Bahovec, Natalija, Balode, Anda, Bãrdzdina, Arta, Barendregt, A M, Barral-Arca, Ruth, Bath, David, Bauchinger, Sebastian, Baumard, Lucas, Baumgart, Hinrich, Baxter, Frances, Bell, Kathryn, Bell, Ashley, Bello, Xabier, Bellos, Evangelos, Benesch, Martin, Bennet, Joshua, Berger, Christoph, Bernhard-Stirnemann, Sara, Bibi, Sagida, Bidlingmaier, Christoph, Binder, Alexander, Binder, Vera, Blackmore, Jennifer, Bojang, Kalifa, Borensztajn, Dorine M, Brengel-Pesce, Karen, Broderick, Claire, Buschbeck, Judith, Calvo-Bado, Leonides, Carnota, Sandra, Carter, Michael J, Castro, María Barreiro, Cebey-López, Miriam, Ceesay, Samba, Ceolotto, Astrid, Chan, Adora, Cocklin, Elizabeth, Collings, Kalvin, Crulley, Stephen, Curras-Tuala, María José, D'alessandro, Umberto, D'Souza, Giselle, Danhauser, Katharina, Darboe, Saffiatou, Darnell, Sarah, De Haan, L, De Vries, Gabriella, Deksne, Dãrta, Devine, Kirsty, Dewez, Juan Emmanuel, Dik, W, Dudley, Julia, Eber, Ernst, Fabian, Daniel, Farto, Cristina Balo, Fernández, Sonia Serén, Fidler, Katy, Fitchett, Elizabeth, Galassini, Rachel, Gallisti, Siegfried, García, Mirian Ben, Gardovska, Dace, Geissler, J, Gerrits, G P J M, Giannoni, Eric, Gloerich, Jolein, Gómez-Carballa, Alberto, González, Fernando Álves, Gores, Gunther, Grãvele, Dagne, Griese, Matthias, Grope, Ilze, Gurung, Meeru, Haas, Nikolaus, Habgood-Coote, Dominic, Hagedoorn, Nienke N, Haidl, Harald, Harrison, Rebekah, Hauer, Almuthe, Heidema, J, Heininger, Ulrich, Henriet, Stefanie, Hibberd, Martin, Hoggart, Cllive, Hösele, Susanne, Hourmat, Sara, Hude, Christa, Huijnen, Martijn, Iglesias, Pilar Leboráns, Iglesias, Marisol Vilas, Jennings, Rebecca, Johnson, Joanne, Jongerius, Ilse, Jorgensen, Rikke, Kahlert, Christian, Kandasamy, Rama, Kappler, Matthias, Keldorfer, Markus, Kelly, Dominic F, Khanijau, Aakash, Kim, Nayoung, Kim, Eunjung, King, Sharon, Kolberg, Laura, Kolnik, Mojca, Kloosterhuis, Lieke, Kohlfürst, Daniela S, Kohlmaier, Benno, Krenn, Larissa, Leigh, Simon, Leitner, Manuel, Leurent, Baptiste, Lim, Emma, Lin, Naomi, Liu, Ching-Chuan, Löffler, Sabine, Lurz, Eberhard, Mackerness, Christine, Maconochie, Ian, Mallet, Francois, Marmarinos, Antonis, Martin, Alex, Martin, Mike, Martinón Sánchez, José María, Martinón-Torres, Nazareth, McAlinden, Paul, McDonald, Sam, McDonell, Anne, Meiere, Anija, Meierford, Anne, Miedema, C J, Miners, Alec, Mistry, Ravi, Mommert, Marine, Morris, Sophie, Muench, Georg, Murdoch, David R, Mustafa, Sobia, Natalucci, Giancarlo, Neeleman, C, Newall, Karen, Nichols, Samuel, Niederer-Loher, Anita, Niedrist, Tobias, Nijman, Ruud, Nokalna, Ieve, Nordberg, Gudrun, O'Connor, Daniel, Obihara, C C, Oliver, Zoe, Oosthoek, Wilma, Ora, Miguel Sadiki, Osterman, Veronika, Pachot, Alexandre, Pajkrt, D, Pardo-Seco, Jacobo, Pavãre, Jana, Paz, Ivonne Pena, Paulus, Stéphane, Pérez, Belén Mosquera, Persand, Salina, Pfleger, Andreas, Pfurtscheller, Klaus, Philipsen, Ria, Pickering, Alisa, Pierce, Benjamin, Pilch, Heidemarie, Pischedda, Sara, Pölz, Lena, Posfay-Barbe, Klara M, Powell, Oliver, Prunk, Petra, Pučuka, Zanda, Rajic, Glorija, Rashid, Aqeela, Redondo-Collazo, Lorenzo, Reiter, Karl, Relly, Christa, Rhodes, Mathew, Rial, Jose Gómez, Richmond, Vivien, Riedel, Thomas, Rivero Calle, Irene, Roca, Anna, Rödl, Siegfried, Rodríguez, Lidia Piñeiro, Rodríguez-Tenreiro, Carmen, Romaine, Sam, Rowlands, Emily, Rudzate, Aleksandra, Sagmeister, Manfred, Saidykhan, Momodou, Sallas, Antonio, Sarr, Isatou, Schoen, Carola, Schonenberg, D, Schweintzger, Nina, Secka, Fatou, Selecka, Katrīna, Shah, Priyen, Shen, Ching-Fen, Shrestha, Shrijana, Skrabl-Baumgartner, Andrea, Soon, Joshua, Sperl, Matthias, Sprenkeler, Evelien, Spyridis, Nikos, Srovin, Tina Plankar, Stampfer, Laura, Stevens, Molly, Stocker, Martin, Strenger, Volker, Suárez, Carlos Durán, Svile, Dace, Syggelou, Kelly, Tal, Chantal, Tambouratzi, Maria, Tavliavini, Emma, Thakker, Clare, Thomson, Evelyn, Throson, Stephen, Till, Holger, Tramper-Stranders, G A, Trasorras, Cristina Serén, Trobisch, Andreas, Urbãne, Urzula Nora, Usman, Mariama, Valentine, Lucille, Van Aerde, Koen, Van den Berg, J M, Van den Broek, Bryan, Van der Giessen, Ilona, Van der Kuip, M, Van der Velden, Fabian, Van Furth, A M, Van Gool, Alain J, Van Leur, M, van Mierlo, G, Vázquez, Sara Ray, Vermont, Clementien, Vicente, Luisa García, Vincek, Katarina, Vito, Ortensia, Voice, Marie, Wallia, Diane, Walsh, Ben, Wang, Shih-Min, Wedderburn, Catherine, Willems, Esther, Wilson, Clare, Wood, Amanda, Woodsford, Phil, Wyss, Verena, Xagorari, Marietta, Zachariasse, Joany, Zaman, Syed M A, Zurl, Christoph, Zwerenz, Manuela, Jackson, Heather R, Hamilton, Melissa Shea, Fischer, Roman, Thorne, Adam M, Huang, Honglei, Tanck, Michael W, Jansen, Machiel H, Pollard, Andrew J, Tsolia, Maria N, Wright, Victoria J, Coin, Lachlan J M, Casals-Pascual, Climent, Herberg, Jethro A, de Jonge, Marien I, and Kuijpers, Taco W

Published
2023
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2. Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease

Author

Hendriks, T., Felderhof, M.K., Weggelaar, N.M., Filippini, L., Rozendaal, L., Groeneweg, M., Nuboer, R., Bruijn, M., Dolman, K.M., Noordzij, J.G., de Winter, J.P., Vlieger, A.M., Plötz, F.B., Delemarre, L.C., Netea, Stejara A., Biesbroek, Giske, van Stijn, Diana, Ijspeert, Hanna, van der Made, Caspar I., Jansen, Machiel H., Geissler, Judy, van den Berg, J.M. (Merlijn), van der Kuip, Martijn, Gruppen, Mariken P., Schonenberg-Meinema, Dieneke, Kapitein, Berber, van Furth, A.M. (Marceline) Tutu, Nagelkerke, Sietse Q., Pajkrt, Dasja, Plötz, Frans B., den Boer, M.E.J. (Lisette), Landman, Gijs W., van Houten, Marlies A., Goetschalckx, Ines, Toonen, Erik J.M., van de Veerdonk, Frank L., Kuipers, Irene M., Dik, Willem A., and Kuijpers, Taco W.

Published
2023
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6. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans

Author

Adhya, Zoe, Alachkar, Hana, Anantharachagan, Ariharan, Antrobus, Richard, Arumugakani, Gururaj, Bacchelli, Chiara, Baxendale, Helen, Bethune, Claire, Bibi, Shahnaz, Boardman, Barbara, Booth, Claire, Browning, Michael, Brownlie, Mary, Burns, Siobhan, Chandra, Anita, Clifford, Hayley, Cooper, Nichola, Davies, Sophie, Dempster, John, Devlin, Lisa, Doffinger, Rainer, Drewe, Elizabeth, Edgar, David, Egner, William, El-Shanawany, Tariq, Gaspar, Bobby, Ghurye, Rohit, Gilmour, Kimberley, Goddard, Sarah, Gordins, Pavel, Grigoriadou, Sofia, Hackett, Scott, Hague, Rosie, Harper, Lorraine, Hayman, Grant, Herwadkar, Archana, Hughes, Stephen, Huissoon, Aarnoud, Jolles, Stephen, Jones, Julie, Kelleher, Peter, Klein, Nigel, Kuijpers, Taco, Kumararatne, Dinakantha, Laffan, James, Lango Allen, Hana, Lear, Sara, Longhurst, Hilary, Lorenzo, Lorena, Maimaris, Jesmeen, Manson, Ania, McDermott, Elizabeth, Millar, Hazel, Mistry, Anoop, Morrisson, Valerie, Murng, Sai, Nasir, Iman, Nejentsev, Sergey, Noorani, Sadia, Oksenhendler, Eric, Ponsford, Mark, Qasim, Waseem, Quinn, Ellen, Quinti, Isabella, Richter, Alex, Samarghitean, Crina, Sargur, Ravishankar, Savic, Sinisa, Seneviratne, Suranjith, Sewall, Carrock, Shackley, Fiona, Simeoni, Ilenia, Smith, Kenneth G.C., Staples, Emily, Stauss, Hans, Steele, Cathal, Thaventhiran, James, Thomas, Moira, Thrasher, Adrian, Welch, Steve, Willcocks, Lisa, Workman, Sarita, Worth, Austen, Yeatman, Nigel, Yong, Patrick, Ashford, Sofie, Bradley, John, Fletcher, Debra, Hammerton, Tracey, James, Roger, Kingston, Nathalie, Ouwehand, Willem, Penkett, Christopher, Raymond, F Lucy, Stirrups, Kathleen, Veltman, Marijke, Young, Tim, Brown, Matthew, Clements-Brod, Naomi, Davis, John, Dewhurst, Eleanor, Erwood, Marie, Frary, Amy, Linger, Rachel, Martin, Jennifer, Papadia, Sofia, Rehnstrom, Karola, Astle, William, Attwood, Antony, Bleda, Marta, Carss, Keren, Daugherty, Louise, Deevi, Sri, Graf, Stefan, Greene, Daniel, Halmagyi, Csaba, Haimel, Matthias, Hu, Fengyuan, Matser, Vera, Meacham, Stuart, Megy, Karyn, Shamardina, Olga, Titterton, Catherine, Tuna, Salih, Turro, Ernest, Yu, Ping, von Ziegenweldt, Julie, Furnell, Abigail, Mapeta, Rutendo, Staines, Simon, Stephens, Jonathan, Whitehorn, Deborah, Rayner-Matthews, Paula, Watt, Christopher, Tuijnenburg, Paul, Burns, Siobhan O., Jansen, Machiel H., Carss, Keren J., Biasci, Daniele, Kiani-Alikhan, Sorena, Longhurst, Hilary J., Seneviratne, Suranjith L., de Bree, Godelieve J., Tool, Anton T.J., van Leeuwen, Ester M.M., Ebberink, Eduard H.T.M., Meijer, Alexander B., Thrasher, Adrian J., Thaventhiran, James E., and Kuijpers, Taco W.

Published
2018
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7. Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease

Author

Netea, Stejara A., primary, Biesbroek, Giske, additional, van Stijn, Diana, additional, Ijspeert, Hanna, additional, van der Made, Caspar I., additional, Jansen, Machiel H., additional, Geissler, Judy, additional, van den Berg, J.M. (Merlijn), additional, van der Kuip, Martijn, additional, Gruppen, Mariken P., additional, Schonenberg-Meinema, Dieneke, additional, Kapitein, Berber, additional, van Furth, A.M. (Marceline) Tutu, additional, Nagelkerke, Sietse Q., additional, Pajkrt, Dasja, additional, Plötz, Frans B., additional, den Boer, M.E.J. (Lisette), additional, Landman, Gijs W., additional, van Houten, Marlies A., additional, Goetschalckx, Ines, additional, Toonen, Erik J.M., additional, van de Veerdonk, Frank L., additional, Kuipers, Irene M., additional, Dik, Willem A., additional, Kuijpers, Taco W., additional, Hendriks, T., additional, Felderhof, M.K., additional, Weggelaar, N.M., additional, Filippini, L., additional, Rozendaal, L., additional, Groeneweg, M., additional, Nuboer, R., additional, Bruijn, M., additional, Dolman, K.M., additional, Noordzij, J.G., additional, de Winter, J.P., additional, Vlieger, A.M., additional, Plötz, F.B., additional, and Delemarre, L.C., additional

Published
2023
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8. Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome

Author

Oud, Machteld M., Tuijnenburg, Paul, Hempel, Maja, van Vlies, Naomi, Ren, Zemin, Ferdinandusse, Sacha, Jansen, Machiel H., Santer, René, Johannsen, Jessika, Bacchelli, Chiara, Alders, Marielle, Li, Rui, Davies, Rosalind, Dupuis, Lucie, Cale, Catherine M., Wanders, Ronald J.A., Pals, Steven T., Ocaka, Louise, James, Chela, Müller, Ingo, Lehmberg, Kai, Strom, Tim, Engels, Hartmut, Williams, Hywel J., Beales, Phil, Roepman, Ronald, Dias, Patricia, Brunner, Han G., Cobben, Jan-Maarten, Hall, Christine, Hartley, Taila, Le Quesne Stabej, Polona, Mendoza-Londono, Roberto, Davies, E. Graham, de Sousa, Sérgio B., Lessel, Davor, Arts, Heleen H., and Kuijpers, Taco W.

Published
2017
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10. Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease

Author

Netea, Stejara A., Biesbroek, Giske, Stijn, Diana van, Ijspeert, Hanna, Made, C.I. van der, Jansen, Machiel H., Veerdonk, F.L. van de, Dik, Willem A., Kuijpers, T.W., Netea, Stejara A., Biesbroek, Giske, Stijn, Diana van, Ijspeert, Hanna, Made, C.I. van der, Jansen, Machiel H., Veerdonk, F.L. van de, Dik, Willem A., and Kuijpers, T.W.

Abstract

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Published
2023

11. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM):a multi-cohort machine learning study

Author

Jackson, Heather R., Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J., Fischer, Roman, Thorne, Adam M., Huang, Honglei, Tanck, Michael W., Jansen, Machiel H., De, Tisham, Agyeman, Philipp K.A., Von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria N., Usuf, Effua, Wright, Victoria J., Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Casals-Pascual, Climent, Cunnington, Aubrey J., Martinon-Torres, Federico, Herberg, Jethro A., de Jonge, Marien I., Levin, Michael, Kuijpers, Taco W., Kaforou, Myrsini, Jackson, Heather R., Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J., Fischer, Roman, Thorne, Adam M., Huang, Honglei, Tanck, Michael W., Jansen, Machiel H., De, Tisham, Agyeman, Philipp K.A., Von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria N., Usuf, Effua, Wright, Victoria J., Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J.M., Casals-Pascual, Climent, Cunnington, Aubrey J., Martinon-Torres, Federico, Herberg, Jethro A., de Jonge, Marien I., Levin, Michael, Kuijpers, Taco W., and Kaforou, Myrsini

Abstract

BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS:376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma sample

Published
2023

12. A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

Author

Jackson, Heather R, Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J, Fischer, Roman, Thorne, Adam M, Huang, Honglei, Tanck, Michael W, Jansen, Machiel H, De, Tisham, Agyeman, Philipp K A; https://orcid.org/0000-0002-8339-5444, von Both, Ulrich; https://orcid.org/0000-0001-8411-1071, Carrol, Enitan D, Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A, Pokorn, Marko, Pollard, Andrew J; https://orcid.org/0000-0001-7361-719X, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Tsolia, Maria N, Usuf, Effua, Wright, Victoria J; https://orcid.org/0000-0001-7826-1516, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, et al, Jackson, Heather R, Zandstra, Judith, Menikou, Stephanie, Hamilton, Melissa Shea, McArdle, Andrew J, Fischer, Roman, Thorne, Adam M, Huang, Honglei, Tanck, Michael W, Jansen, Machiel H, De, Tisham, Agyeman, Philipp K A; https://orcid.org/0000-0002-8339-5444, von Both, Ulrich; https://orcid.org/0000-0001-8411-1071, Carrol, Enitan D, Emonts, Marieke, Eleftheriou, Irini, Van der Flier, Michiel, Fink, Colin, Gloerich, Jolein, De Groot, Ronald, Moll, Henriette A, Pokorn, Marko, Pollard, Andrew J; https://orcid.org/0000-0001-7361-719X, Schlapbach, Luregn J; https://orcid.org/0000-0003-2281-2598, Tsolia, Maria N, Usuf, Effua, Wright, Victoria J; https://orcid.org/0000-0001-7826-1516, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, and et al

Abstract

Background: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. Methods: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. Findings: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS

Published
2023

15. Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations

Author

Rae, William, primary, Sowerby, John M., additional, Verhoeven, Dorit, additional, Youssef, Mariam, additional, Kotagiri, Prasanti, additional, Savinykh, Natalia, additional, Coomber, Eve L., additional, Boneparth, Alexis, additional, Chan, Angela, additional, Gong, Chun, additional, Jansen, Machiel H., additional, du Long, Romy, additional, Santilli, Giorgia, additional, Simeoni, Ilenia, additional, Stephens, Jonathan, additional, Wu, Kejia, additional, Zinicola, Marta, additional, Allen, Hana Lango, additional, Baxendale, Helen, additional, Kumararatne, Dinakantha, additional, Gkrania-Klotsas, Effrossyni, additional, Scheffler Mendoza, Selma C., additional, Yamazaki-Nakashimada, Marco Antonio, additional, Ruiz, Laura Berrón, additional, Rojas-Maruri, Cesar Mauricio, additional, Lugo Reyes, Saul O., additional, Lyons, Paul A., additional, Williams, Anthony P., additional, Hodson, Daniel J., additional, Bishop, Gail A., additional, Thrasher, Adrian J., additional, Thomas, David C., additional, Murphy, Michael P., additional, Vyse, Timothy J., additional, Milner, Joshua D., additional, Kuijpers, Taco W., additional, and Smith, Kenneth G. C., additional

Published
2022
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21. A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency

Author

Volpi, Stefano, Cicalese, Maria Pia, Tuijnenburg, Paul, Tool, Anton T.J., Cuadrado, Eloy, Abu-Halaweh, Marwan, Ahanchian, Hamid, Alzyoud, Raed, Akdemir, Zeynep Coban, Barzaghi, Federica, Blank, Alexander, Boisson, Bertrand, Bottino, Cristina, Brigida, Immacolata, Caorsi, Roberta, Casanova, Jean-Laurent, Chiesa, Sabrina, Chinn, Ivan Kingyue, Dückers, Gregor, Enders, Anselm, Erichsen, Hans Christian, Forbes, Lisa R., Gambin, Tomasz, Gattorno, Marco, Karimiani, Ehsan Ghayoor, Giliani, Silvia, Gold, Michael S., Jacobsen, Eva-Maria, Jansen, Machiel H., King, Jovanka R., Laxer, Ronald M., Lupski, James R., Mace, Emily, Marcenaro, Stefania, Maroofian, Reza, Meijer, Alexander B., Niehues, Tim, Notarangelo, Luigi D., Orange, Jordan, Pannicke, Ulrich, Pearson, Chris, Picco, Paolo, Quinn, Patrick J., Schulz, Ansgar, Seeborg, Filiz, Stray-Pedersen, Asbjørg, Tawamie, Hasan, van Leeuwen, Ester M.M., Aiuti, Alessandro, Yeung, Rae, Schwarz, Klaus, and Kuijpers, Taco W.

Published
2019
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25. Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans

Author

Tuijnenburg, Paul, Lango Allen, Hana, Burns, Siobhan O, Greene, Daniel, Jansen, Machiel H, Staples, Emily, Stephens, Jonathan, Carss, Keren J, Biasci, Daniele, Baxendale, Helen, Thomas, Moira, Chandra, Anita, Kiani-Alikhan, Sorena, Longhurst, Hilary J, Seneviratne, Suranjith L, Oksenhendler, Eric, Simeoni, Ilenia, De Bree, Godelieve J, Tool, Anton TJ, Van Leeuwen, Ester MM, Ebberink, Eduard HTM, Meijer, Alexander B, Tuna, Salih, Whitehorn, Deborah, Brown, Matthew, Turro, Ernest, Thrasher, Adrian J, Smith, Kenneth GC, Thaventhiran, James E, Kuijpers, Taco W, NIHR-BioResource – Rare Diseases Consortium, Lango Allen, Hana [0000-0002-7803-8688], Biasci, Daniele [0000-0003-3148-8152], Thaventhiran, James [0000-0001-8616-074X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, 03 medical and health sciences, B cells, 030104 developmental biology, 0302 clinical medicine, Common Variable Immunodeficiency, NF-κB1, 030215 immunology
Abstract

BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n=390) in the cohort. Amino-acid substitutions predicted to be pathogenic were assessed by analysis of structural protein data. Immunophenotyping, immunoblotting and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype co-segregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the non-infective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%), features prior studies correlate with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B lymphocyte differentiation. Detailed assessment of B lymphocyte numbers, phenotype and function identifies the presence of a raised CD21lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

Published
2018

27. A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Volpi, Stefano, Cicalese, Maria Pia, Tuijnenburg, Paul, Tool, Anton T J, Cuadrado, Eloy, Abu-Halaweh, Marwan, Ahanchian, Hamid, Alzyoud, Raed, Akdemir, Zeynep Coban, Barzaghi, Federica, Blank, Alexander, Boisson, Bertrand, Bottino, Cristina, Brigida, Immacolata, Caorsi, Roberta, Casanova, Jean-Laurent, Chiesa, Sabrina, Chinn, Ivan Kingyue, Dückers, Gregor, Enders, Anselm, Erichsen, Hans Christian, Forbes, Lisa R, Gambin, Tomasz, Gattorno, Marco, Karimiani, Ehsan Ghayoor, Giliani, Silvia, Gold, Michael S, Jacobsen, Eva-Maria, Jansen, Machiel H, King, Jovanka R, Laxer, Ronald M, Lupski, James R, Mace, Emily, Marcenaro, Stefania, Maroofian, Reza, Meijer, Alexander B, Niehues, Tim, Notarangelo, Luigi D, Orange, Jordan, Pannicke, Ulrich, Pearson, Chris, Picco, Paolo, Quinn, Patrick J, Schulz, Ansgar, Seeborg, Filiz, Stray-Pedersen, Asbjørg, Tawamie, Hasan, van Leeuwen, Ester M M, Aiuti, Alessandro, Yeung, Rae, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Volpi, Stefano, Cicalese, Maria Pia, Tuijnenburg, Paul, Tool, Anton T J, Cuadrado, Eloy, Abu-Halaweh, Marwan, Ahanchian, Hamid, Alzyoud, Raed, Akdemir, Zeynep Coban, Barzaghi, Federica, Blank, Alexander, Boisson, Bertrand, Bottino, Cristina, Brigida, Immacolata, Caorsi, Roberta, Casanova, Jean-Laurent, Chiesa, Sabrina, Chinn, Ivan Kingyue, Dückers, Gregor, Enders, Anselm, Erichsen, Hans Christian, Forbes, Lisa R, Gambin, Tomasz, Gattorno, Marco, Karimiani, Ehsan Ghayoor, Giliani, Silvia, Gold, Michael S, Jacobsen, Eva-Maria, Jansen, Machiel H, King, Jovanka R, Laxer, Ronald M, Lupski, James R, Mace, Emily, Marcenaro, Stefania, Maroofian, Reza, Meijer, Alexander B, Niehues, Tim, Notarangelo, Luigi D, Orange, Jordan, Pannicke, Ulrich, Pearson, Chris, Picco, Paolo, Quinn, Patrick J, Schulz, Ansgar, Seeborg, Filiz, Stray-Pedersen, Asbjørg, Tawamie, Hasan, van Leeuwen, Ester M M, Aiuti, Alessandro, and Yeung, Rae

Published
2019

28. Activated neutrophils exert myeloid-derived suppressor cell activity damaging T cells beyond repair

Author

Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Aarts, Cathelijn E M, Hiemstra, Ida H, Béguin, Eelke P, Hoogendijk, Arjan J, Bouchmal, Souhailla, van Houdt, Michel, Tool, Anton T J, Mul, Erik, Jansen, Machiel H, Janssen, Hans, van Alphen, Floris P J, de Boer, Jan-Paul, Zuur, Charlotte L, Meijer, Alexander B, van den Berg, Timo K, Kuijpers, Taco W, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Aarts, Cathelijn E M, Hiemstra, Ida H, Béguin, Eelke P, Hoogendijk, Arjan J, Bouchmal, Souhailla, van Houdt, Michel, Tool, Anton T J, Mul, Erik, Jansen, Machiel H, Janssen, Hans, van Alphen, Floris P J, de Boer, Jan-Paul, Zuur, Charlotte L, Meijer, Alexander B, van den Berg, Timo K, and Kuijpers, Taco W

Published
2019

30. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans

Author

Tuijnenburg, Paul, primary, Lango Allen, Hana, additional, Burns, Siobhan O., additional, Greene, Daniel, additional, Jansen, Machiel H., additional, Staples, Emily, additional, Stephens, Jonathan, additional, Carss, Keren J., additional, Biasci, Daniele, additional, Baxendale, Helen, additional, Thomas, Moira, additional, Chandra, Anita, additional, Kiani-Alikhan, Sorena, additional, Longhurst, Hilary J., additional, Seneviratne, Suranjith L., additional, Oksenhendler, Eric, additional, Simeoni, Ilenia, additional, de Bree, Godelieve J., additional, Tool, Anton T.J., additional, van Leeuwen, Ester M.M., additional, Ebberink, Eduard H.T.M., additional, Meijer, Alexander B., additional, Tuna, Salih, additional, Whitehorn, Deborah, additional, Brown, Matthew, additional, Turro, Ernest, additional, Thrasher, Adrian J., additional, Smith, Kenneth G.C., additional, Thaventhiran, James E., additional, Kuijpers, Taco W., additional, Adhya, Zoe, additional, Alachkar, Hana, additional, Anantharachagan, Ariharan, additional, Antrobus, Richard, additional, Arumugakani, Gururaj, additional, Bacchelli, Chiara, additional, Bethune, Claire, additional, Bibi, Shahnaz, additional, Boardman, Barbara, additional, Booth, Claire, additional, Browning, Michael, additional, Brownlie, Mary, additional, Burns, Siobhan, additional, Clifford, Hayley, additional, Cooper, Nichola, additional, Davies, Sophie, additional, Dempster, John, additional, Devlin, Lisa, additional, Doffinger, Rainer, additional, Drewe, Elizabeth, additional, Edgar, David, additional, Egner, William, additional, El-Shanawany, Tariq, additional, Gaspar, Bobby, additional, Ghurye, Rohit, additional, Gilmour, Kimberley, additional, Goddard, Sarah, additional, Gordins, Pavel, additional, Grigoriadou, Sofia, additional, Hackett, Scott, additional, Hague, Rosie, additional, Harper, Lorraine, additional, Hayman, Grant, additional, Herwadkar, Archana, additional, Hughes, Stephen, additional, Huissoon, Aarnoud, additional, Jolles, Stephen, additional, Jones, Julie, additional, Kelleher, Peter, additional, Klein, Nigel, additional, Kuijpers, Taco, additional, Kumararatne, Dinakantha, additional, Laffan, James, additional, Lear, Sara, additional, Longhurst, Hilary, additional, Lorenzo, Lorena, additional, Maimaris, Jesmeen, additional, Manson, Ania, additional, McDermott, Elizabeth, additional, Millar, Hazel, additional, Mistry, Anoop, additional, Morrisson, Valerie, additional, Murng, Sai, additional, Nasir, Iman, additional, Nejentsev, Sergey, additional, Noorani, Sadia, additional, Ponsford, Mark, additional, Qasim, Waseem, additional, Quinn, Ellen, additional, Quinti, Isabella, additional, Richter, Alex, additional, Samarghitean, Crina, additional, Sargur, Ravishankar, additional, Savic, Sinisa, additional, Seneviratne, Suranjith, additional, Sewall, Carrock, additional, Shackley, Fiona, additional, Stauss, Hans, additional, Steele, Cathal, additional, Thaventhiran, James, additional, Thrasher, Adrian, additional, Welch, Steve, additional, Willcocks, Lisa, additional, Workman, Sarita, additional, Worth, Austen, additional, Yeatman, Nigel, additional, Yong, Patrick, additional, Ashford, Sofie, additional, Bradley, John, additional, Fletcher, Debra, additional, Hammerton, Tracey, additional, James, Roger, additional, Kingston, Nathalie, additional, Ouwehand, Willem, additional, Penkett, Christopher, additional, Raymond, F Lucy, additional, Stirrups, Kathleen, additional, Veltman, Marijke, additional, Young, Tim, additional, Clements-Brod, Naomi, additional, Davis, John, additional, Dewhurst, Eleanor, additional, Erwood, Marie, additional, Frary, Amy, additional, Linger, Rachel, additional, Martin, Jennifer, additional, Papadia, Sofia, additional, Rehnstrom, Karola, additional, Astle, William, additional, Attwood, Antony, additional, Bleda, Marta, additional, Carss, Keren, additional, Daugherty, Louise, additional, Deevi, Sri, additional, Graf, Stefan, additional, Halmagyi, Csaba, additional, Haimel, Matthias, additional, Hu, Fengyuan, additional, Matser, Vera, additional, Meacham, Stuart, additional, Megy, Karyn, additional, Shamardina, Olga, additional, Titterton, Catherine, additional, Yu, Ping, additional, von Ziegenweldt, Julie, additional, Furnell, Abigail, additional, Mapeta, Rutendo, additional, Staines, Simon, additional, Rayner-Matthews, Paula, additional, and Watt, Christopher, additional

Published
2018
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31. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans

Author

Tuijnenburg, Paul, Lango Allen, Hana, Burns, Siobhan O, Greene, Daniel, Jansen, Machiel H, Staples, Emily, Stephens, Jonathan, Carss, Keren J, Biasci, Daniele, Baxendale, Helen, Thomas, Moira, Chandra, Anita, Kiani-Alikhan, Sorena, Longhurst, Hilary J, Seneviratne, Suranjith L, Oksenhendler, Eric, Simeoni, Ilenia, de Bree, Godelieve J, Tool, Anton T J, van Leeuwen, Ester M M, Ebberink, Eduard H T M, Meijer, Alexander B, Tuna, Salih, Whitehorn, Deborah, Brown, Matthew, Turro, Ernest, Thrasher, Adrian J, Smith, Kenneth G C, Thaventhiran, James E, Kuijpers, Taco W, Tuijnenburg, Paul, Lango Allen, Hana, Burns, Siobhan O, Greene, Daniel, Jansen, Machiel H, Staples, Emily, Stephens, Jonathan, Carss, Keren J, Biasci, Daniele, Baxendale, Helen, Thomas, Moira, Chandra, Anita, Kiani-Alikhan, Sorena, Longhurst, Hilary J, Seneviratne, Suranjith L, Oksenhendler, Eric, Simeoni, Ilenia, de Bree, Godelieve J, Tool, Anton T J, van Leeuwen, Ester M M, Ebberink, Eduard H T M, Meijer, Alexander B, Tuna, Salih, Whitehorn, Deborah, Brown, Matthew, Turro, Ernest, Thrasher, Adrian J, Smith, Kenneth G C, Thaventhiran, James E, and Kuijpers, Taco W

Published
2018

33. High‐throughput compound screen reveals mTOR inhibitors as potential therapeutics to reduce (auto)antibody production by human plasma cells.

Author

Tuijnenburg, Paul, aan de Kerk, Daan J., Jansen, Machiel H., Morris, Ben, Lieftink, Cor, Beijersbergen, Roderick L., Leeuwen, Ester M.M., and Kuijpers, Taco W.

Subjects
ANTIBODY formation, PLASMA cells, MTOR inhibitors, PLASMA production, INTERLEUKIN-21, PROTEIN kinase inhibitors, PHOSPHOINOSITIDES
Abstract

Antibody production by the B cell compartment is a crucial part of the adaptive immune response. Dysregulated antibody production in the form of autoantibodies can cause autoimmune disease. To date, B‐cell depletion with anti‐CD20 antibodies is commonly applied in autoimmunity, but pre‐existing plasma cells are not eliminated in this way. Alternative ways of more selective inhibition of antibody production would add to the treatment of these autoimmune diseases. To explore novel therapeutic targets in signaling pathways essential for plasmablast formation and/or immunoglobulin production, we performed a compound screen of almost 200 protein kinase inhibitors in a robust B‐cell differentiation culture system. This study yielded 35 small cell‐permeable compounds with a reproducible inhibitory effect on B‐cell activation and plasmablast formation, among which was the clinically applied mammalian target of rapamycin (mTOR) inhibitor rapamycin. Two additional compounds targeting the phosphoinositide 3‐kinase‐AKT‐mTOR pathway (BKM120 and WYE‐354) did not affect proliferation and plasmablast formation, but specifically reduced the immunoglobulin production. With this compound screen we successfully applied a method to investigate therapeutic targets for B‐cell differentiation and identified compounds in the phosphoinositide 3‐kinase‐AKT‐mTOR pathway that could specifically inhibit immunoglobulin production only. These drugs may well be explored to be of value in current B‐cell‐depleting treatment regimens in autoimmune disorders. [ABSTRACT FROM AUTHOR]

Published
2020
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35. Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release

Author

Cuadrado, Eloy, Michailidou, Iliana, Van Bodegraven, Emma J., Jansen, Machiel H., Sluijs, Jacqueline A., Geerts, Dirk, Couraud, Pierre Olivier, Filippis, Lidia De, Vescovi, Angelo L., Kuijpers, Taco W., Hol, Elly M., Cuadrado, Eloy, Michailidou, Iliana, Van Bodegraven, Emma J., Jansen, Machiel H., Sluijs, Jacqueline A., Geerts, Dirk, Couraud, Pierre Olivier, Filippis, Lidia De, Vescovi, Angelo L., Kuijpers, Taco W., and Hol, Elly M.

Published
2015

36. Aicardi-Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies

Author

TN groep Hol, Brain, Cuadrado, Eloy, Vanderver, Adeline, Brown, Kristy J., Sandza, Annie, Takanohashi, Asako, Jansen, Machiel H., Anink, Jasper, Herron, Brian, Orcesi, Simona, Olivieri, Ivana, Rice, Gillian I., Aronica, Eleonora, Lebon, Pierre, Crow, Yanick J., Hol, Elly M., Kuijpers, Taco W., TN groep Hol, Brain, Cuadrado, Eloy, Vanderver, Adeline, Brown, Kristy J., Sandza, Annie, Takanohashi, Asako, Jansen, Machiel H., Anink, Jasper, Herron, Brian, Orcesi, Simona, Olivieri, Ivana, Rice, Gillian I., Aronica, Eleonora, Lebon, Pierre, Crow, Yanick J., Hol, Elly M., and Kuijpers, Taco W.

Published
2015

37. Phenotypic variation in Aicardi-Goutières syndrome explained by cell-specific IFN-stimulated gene response and cytokine release

Author

TN groep Hol, Brain, Cuadrado, Eloy, Michailidou, Iliana, Van Bodegraven, Emma J., Jansen, Machiel H., Sluijs, Jacqueline A., Geerts, Dirk, Couraud, Pierre Olivier, Filippis, Lidia De, Vescovi, Angelo L., Kuijpers, Taco W., Hol, Elly M., TN groep Hol, Brain, Cuadrado, Eloy, Michailidou, Iliana, Van Bodegraven, Emma J., Jansen, Machiel H., Sluijs, Jacqueline A., Geerts, Dirk, Couraud, Pierre Olivier, Filippis, Lidia De, Vescovi, Angelo L., Kuijpers, Taco W., and Hol, Elly M.

Published
2015

38. ADAR1 Facilitates HIV-1 Replication in Primary CD4+ T Cells

Author

Cuadrado, Eloy, primary, Booiman, Thijs, additional, van Hamme, John L., additional, Jansen, Machiel H., additional, van Dort, Karel A., additional, Vanderver, Adeline, additional, Rice, Gillian I., additional, Crow, Yanick J., additional, Kootstra, Neeltje A., additional, and Kuijpers, Taco W., additional

Published
2015
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39. Phenotypic Variation in Aicardi–Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release

Author

Cuadrado, Eloy, primary, Michailidou, Iliana, additional, van Bodegraven, Emma J., additional, Jansen, Machiel H., additional, Sluijs, Jacqueline A., additional, Geerts, Dirk, additional, Couraud, Pierre-Olivier, additional, De Filippis, Lidia, additional, Vescovi, Angelo L., additional, Kuijpers, Taco W., additional, and Hol, Elly M., additional

Published
2015
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42. Aicardi–Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies

Author

Cuadrado, Eloy, primary, Vanderver, Adeline, additional, Brown, Kristy J, additional, Sandza, Annie, additional, Takanohashi, Asako, additional, Jansen, Machiel H, additional, Anink, Jasper, additional, Herron, Brian, additional, Orcesi, Simona, additional, Olivieri, Ivana, additional, Rice, Gillian I, additional, Aronica, Eleonora, additional, Lebon, Pierre, additional, Crow, Yanick J, additional, Hol, Elly M, additional, and Kuijpers, Taco W, additional

Published
2014
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45. ADAR1 Facilitates HIV-1 Replication in Primary CD4+ T Cells.

Author

Cuadrado, Eloy, Booiman, Thijs, van Hamme, John L., Jansen, Machiel H., van Dort, Karel A., Vanderver, Adeline, Rice, Gillian I., Crow, Yanick J., Kootstra, Neeltje A., and Kuijpers, Taco W.

Subjects
HIV infections, ADENOSINE deaminase, CD4 antigen, VIRAL replication, T cells, DISEASE susceptibility
Abstract

Unlike resting CD4+ T cells, activated CD4+T cells are highly susceptible to infection of human immunodeficiency virus 1 (HIV-1). HIV-1 infects T cells and macrophages without activating the nucleic acid sensors and the anti-viral type I interferon response. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that displays antiviral activity against several RNA viruses. Mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutieères syndrome (AGS). This disease is characterized by an inappropriate activation of the interferon-stimulated gene response. Here we show that HIV-1 replication, in ADAR1-deficient CD4+T lymphocytes from AGS patients, is blocked at the level of protein translation. Furthermore, viral protein synthesis block is accompanied by an activation of interferon-stimulated genes. RNA silencing of ADAR1 in Jurkat cells also inhibited HIV-1 protein synthesis. Our data support that HIV-1 requires ADAR1 for efficient replication in human CD4+T cells. [ABSTRACT FROM AUTHOR]

Published
2015
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46. Identification of B Cell Defects Using Age-Defined Reference Ranges for In Vivo and In Vitro B Cell Differentiation.

Author

de Kerk, Daan J. aan, Jansen, Machiel H., ten Berge, Ineke J. M., van Leeuwen, Ester M. M., and Kuijpers, Taco W.

Subjects
*B cells, *IMMUNODEFICIENCY, *B cell differentiation, *T cells, *IMMUNOPHENOTYPING, *PLASMA cells, *IMMUNOGLOBULIN G, *CD20 antigen, *DIAGNOSIS, *DISEASES
Abstract

Primary immunodeficiencies consist to a large extent of B cell defects, as indicated by inadequate Ab levels or response upon immunization. Many B cell defects have not yet been well characterized. Our objective was to create reliable in vivo and in vitro assays to routinely analyze human B cell differentiation, proliferation, and Ig production and to define reference ranges for different age categories. The in vitro assays were applied to classify the developmental and/or functional B cell defects in patients previously diagnosed with common variable immunodeficiency. Apart from standard immunophenotyping of circulating human B cell subsets, an in vitro CFSE dilution assay was used for the assessment of proliferative capacity comparing T cell-dependent and T cell-independent B cell activation. Plasmablast/plasma cell differentiation was assessed by staining for CD20, CD38, and CD138, and measurement of in vitro Ig secretion. At young age, B cells proliferate upon in vitro activation, but neither differentiate nor produce IgG. These latter functions reached adult levels at 5 and 10 y of age for T cell-dependent versus T cell-independent stimulations, respectively. The capacity of B cells to differentiate into plasmablasts and to produce IgG appeared to be contained within the switched memory B cell pool. Using these assays, we could categorize common variable immunodeficiency patients into subgroups and identified a class-switch recombination defect caused by an UNG mutation in one of the patients. We defined age-related reference ranges for human B cell differentiation. Our findings indicate that in vivo B cell functionality can be tested in vitro and helps to diagnose suspected B cell defects. [ABSTRACT FROM AUTHOR]

Published
2013
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47. Idiopathic CD4+T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations

Author

Kuijpers, Taco W., Ijspeert, Hanna, van Leeuwen, Ester M.M., Jansen, Machiel H., Hazenberg, Mette D., Weijer, Kees C., van Lier, Rene A.W., and van der Burg, Mirjam

Abstract

A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo proliferation. Patient-derived CD34+hematopoietic stem cells could not repopulate RAG2−/−IL2Rγc−/−mice, indicating the lymphoid origin of the defect. We identified 2 novel missense mutations in RAG1(p.Arg474Cys and p.Leu506Phe) resulting in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAGmutations from severe immune defects to an almost normal condition.

Published
2011
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49. A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells.

Author

Kuijpers TW, van Leeuwen EM, Barendregt BH, Klarenbeek P, aan de Kerk DJ, Baars PA, Jansen MH, de Vries N, van Lier RA, and van der Burg M

Subjects
CD8-Positive T-Lymphocytes pathology, Cell Proliferation, Child, Humans, Interleukin Receptor Common gamma Subunit physiology, Lymphocyte Count, Male, Pedigree, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency pathology, CD8-Positive T-Lymphocytes physiology, Interleukin Receptor Common gamma Subunit genetics, Mutation genetics, Severe Combined Immunodeficiency genetics
Abstract

Mutations in the common gamma chain (γc, CD132, encoded by the IL2RG gene) can lead to B(+)T(-)NK(-) X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8(+) T cells and increased over time. Only the revertant CD8(+) T cells showed normal expression of CD132 and the various CD8(+) T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ(+) T cells and differentiated CD4(+)CD27(-) effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8(+) T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells.

Published
2013
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