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1. Systemic and local evidence for complement involvement in chronic spontaneous urticaria

Author

Mehran Alizadeh Aghdam, Mignon van den Elzen, Harmieke van Os‐Medendorp, Marijke R. van Dijk, Edward F. Knol, André C. Knulst, Heike Röckmann, and Henny G. Otten

Subjects
blood, complement, omalizumab, skin, urticaria, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background The pathogenesis of chronic spontaneous urticaria (CSU), including the mechanism of action of omalizumab, remain unclear. We hypothesized complement system involvement given the often fast clinical response induced by treatment, including omalizumab. Therefore, we assessed the role of various complement factors surrounding omalizumab treatment. Methods Thirty CSU patients (median age 42 [range 21–70]; 73 % female) with a median once daily Urticaria Activity Score over 7 days (UAS7) score at baseline of 31.5 points were enrolled. Treatment consisted of six administrations of 300 mg omalizumab every 4 weeks succeeded by a follow‐up period of 12 weeks. Four punch skin biopsies were taken per patient; at baseline from lesional skin, at baseline from nonlesional skin, and after 1 and 7 days from formerly lesional skin. Complement activity, including C1q, C3, C3bc/C3, C4, C4bc/C4, C5a, and Membrane Attack Complex in peripheral blood were analyzed and complement activation in the skin was determined by the analysis of C4d deposition. Results were related to the clinical response to omalizumab. Results Fifteen patients showed a UAS7 score of 6 or lower (median 0) at Week 24, 15 patients did not (median 16). Lesional skin biopsies at baseline revealed complement deposition (C4d) in blood vessels in the papillary dermis of 53% (16/30) of the patients, which suggests involvement of immune complexes in the pathogenesis of urticaria. Moreover, indication of increased complement activation in CSU was substantiated by increased C5a levels in peripheral blood compared to healthy controls (p = 0.010). The clinical effect of omalizumab could not be linked to the variation of complement components. Conclusions Both C4d deposition in lesional skin and elevated C5a levels in peripheral blood indicate the involvement of complement activation in the pathogenesis of CSU. No correlation was found between omalizumab and activation of complement indicative of independent processes in the immunopathogenesis of CSU.

Published
2021
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2. Aged mice display altered numbers and phenotype of basophils, and bone marrow-derived basophil activation, with a limited role for aging-associated microbiota

Author

Adriaan A. van Beek, Floris Fransen, Ben Meijer, Paul de Vos, Edward F. Knol, and Huub F. J. Savelkoul

Subjects
Aging, Basophils, Immunity, Microbiota, Bone marrow, Spleen, Immunologic diseases. Allergy, RC581-607, Geriatrics, RC952-954.6
Abstract

Abstract Background The influence of age on basophils is poorly understood, as well as the effect of aging-associated microbiota on basophils. Therefore, we studied the influence of aging and aging-associated microbiota on basophil frequency and phenotype, and differentiation from basophil precursors. Results Basophils became more abundant in bone marrow (BM) and spleens of 19-month-old mice compared with 4-month-old mice. Aged basophils tended to express less CD200R3 and more CD123, both in BM and spleen. Differences in microbiota composition with aging were confirmed by 16S sequencing. Microbiota transfers from young and old mice to germ-free recipients revealed that CD11b tended to be lowered on splenic basophils by aging-associated microbiota. Furthermore, abundance of Alistipes, Oscillibacter, Bacteroidetes RC9 gut group, and S24–7 family positively correlated and CD123 expression, whereas Akkermansia abundance negatively correlated with basophils numbers. Subsequently, we purified FcεRIα+CD11c−CD117− BM-derived basophils and found that those from aged mice expressed lower levels of CD11b upon stimulation. Higher frequencies of IL-4+ basophils were generated from basophil precursors of aged mice, which could be reproduced in basophils derived from germ-free recipients of aging-associated microbiota. Conclusions Collectively, these results show the influence of aging on basophils. Furthermore, this study shows that aging-associated microbiota altered activation of BM-derived basophils in a similar fashion as observed in BM-derived basophils from aged mice.

Published
2018
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3. Sensitization to PR-10 proteins is indicative of distinctive sensitization patterns in adults with a suspected food allergy

Author

Mark A. Blankestijn, André C. Knulst, Edward F. Knol, Thuy-My Le, Heike Rockmann, Henny G. Otten, and Rob J. B. Klemans

Subjects
ImmunoCAP ISAC, Food allergy, PR-10, Specific IgE, Storage proteins, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background The extent of co-sensitization within and between food protein families in an adult population is largely unknown. This study aimed to identify the most frequently recognized components in the PR-10 and storage protein family, as well as patterns in (co-)sensitization, in a birch-endemic area. Methods Results of ImmunoCAP ISAC, performed during routine care in Dutch adult outpatients suspected of food allergy, were collected. Results A total of 305 patients were selected, aged 16–79 years (median 32 years). Sensitization to one or more PR-10 proteins was most frequent (74% of all subjects), followed by 35% to storage protein and 15% to nsLTPs. Within the PR-10 family, subjects were most often sensitized to Bet v 1 (73% of 305), Cor a 1.04 (72%) and Mal d 1 (68%). Sensitization to PR-10s from soy, celery and kiwi occurred distinctively less often ( 70%). Subjects sensitized to these ‘less common PR-10 proteins’ were sensitized to more food and inhalant components on the ISAC, compared to subjects sensitized to ‘common PR-10 proteins’ (median 22 vs 13 out of 112, p

Published
2017
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4. Application of the adverse outcome pathway (AOP) concept to structure the available in vivo and in vitro mechanistic data for allergic sensitization to food proteins

Author

Jolanda H. M. van Bilsen, Edyta Sienkiewicz-Szłapka, Daniel Lozano-Ojalvo, Linette E. M. Willemsen, Celia M. Antunes, Elena Molina, Joost J. Smit, Barbara Wróblewska, Harry J. Wichers, Edward F. Knol, Gregory S. Ladics, Raymond H. H. Pieters, Sandra Denery-Papini, Yvonne M. Vissers, Simona L. Bavaro, Colette Larré, Kitty C. M. Verhoeckx, and Erwin L. Roggen

Subjects
Adverse outcome pathway, Key events, Key event relations, Food allergy, Sensitization, Mechanistic understanding, Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization. However, these events have not been organized in a sequence of related events that is plausible to result in sensitization, and useful to challenge current hypotheses. The aim of this manuscript was to collect and structure the current mechanistic understanding of sensitization induction to food proteins by applying the concept of adverse outcome pathway (AOP). Main body The proposed AOP for food sensitization is based on information on molecular and cellular mechanisms and pathways evidenced to be involved in sensitization by food and food proteins and uses the AOPs for chemical skin sensitization and respiratory sensitization induction as templates. Available mechanistic data on protein respiratory sensitization were included to fill out gaps in the understanding of how proteins may affect cells, cell–cell interactions and tissue homeostasis. Analysis revealed several key events (KE) and biomarkers that may have potential use in testing and assessment of proteins for their sensitizing potential. Conclusion The application of the AOP concept to structure mechanistic in vivo and in vitro knowledge has made it possible to identify a number of methods, each addressing a specific KE, that provide information about the food allergenic potential of new proteins. When applied in the context of an integrated strategy these methods may reduce, if not replace, current animal testing approaches. The proposed AOP will be shared at the www.aopwiki.org platform to expand the mechanistic data, improve the confidence in each of the proposed KE and key event relations (KERs), and allow for the identification of new, or refinement of established KE and KERs.

Published
2017
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5. Abstracts from the Food Allergy and Anaphylaxis Meeting 2016

Author

Guillaume Pouessel, Claire Claverie, Julien Labreuche, Jean-Marie Renaudin, Aimée Dorkenoo, Mireille Eb, Anne Moneret-Vautrin, Antoine Deschildre, Stephane Leteurtre, Linus Grabenhenrich, Margitta Worm, Sabine Dölle, Kathrin Scherer, Isidor Hutteger, Morten Christensen, Carsten Bindslev-Jensen, Charlotte Mortz, Esben Eller, Henrik Fomsgaard Kjaer, Leonor Carneiro-Leão, Jenny Badas, Alice Coimbra, Dikla Pivko Levy, Moshe Ben-Shoshan, Ayelet Rimon, Shira Benor, Nicolette J. T. Arends, Nikki Edelbroek, Hans de Groot, Joyce A. M. Emons, H. Kim A. Brand, Dirk Verhoeven, Leonieke N. van Veen, Nicolette W. de Jong, Geunwoong Noh, Eun Ha Jang, Mariona Pascal, Olga Dominguez, Mònica Piquer, Montserrat Alvaro, Rosa Jimenez-Feijoo, Jaime Lozano, Adriana Machinena, Maria del Mar Folqué, Maria Teresa Giner, Ana María Plaza, Paul Turner, Nandinee Patel, Marta Vazquez-Ortiz, Sarah Lindsley, Lucy Walker, Simon Rosenberg, Adriano Mari, Claudia Alessandri, Ivana Giangrieco, Lisa Tuppo, Chiara Rafaiani, Georg Mitterer, Michela Ciancamerla, Rosetta Ferrara, Maria Livia Bernardi, Danila Zennaro, Maurizio Tamburrini, Maria Antonetta Ciardiello, Christian Harwanegg, Antonio Fernandez, Regina Selb, Philippe Egenmann, Michelle Epstein, Karin Hoffmann-Sommergruber, Frits Koning, Martinus Lovik, E. N. Clare Mills, Javier Moreno, Henk van Loveren, Jean-Michel Wal, Susanne Diesner, Cornelia Bergmayr, Barbara Pfitzner, Vera Elisabeth Assmann, Philipp Starkl, David Endesfelder, Thomas Eiwegger, Zsolt Szepfalusi, Heinz Fehrenbach, Erika Jensen-Jarolim, Anton Hartmann, Isabella Pali-Schöll, Eva Untersmayr, Soren Wille, Peter Meyer, Caroline Klingebiel, Jonas Lidholm, Angelica Ehrenberg, Jonas Östling, Isabelle Cleach, Jean-Louis Mège, Joana Vitte, Roberta Aina, Pawel Dubiela, Sabine Pfeifer, Merima Bublin, Christian Radauer, Piotr Humeniuk, Stefan Kabasser, Riccardo Asero, Gador Bogas, Francisca Gomez, Paloma Campo, Maria Salas, Inmaculada Doña, Esther Barrionuevo, Maria Auxiliadora Guerrero, Cristobalina Mayorga, Ana Prieto, Domingo Barber, Maria Jose Torres, Annette Jamin, Andrea Wangorsch, Barbara Ballmer, Stefan Vieths, Stephan Scheurer, Danijela Apostolovic, Jelena Mihailovic, Maja Krstic, Maria Starkhammar, Tanja Cirkovic Velickovic, Carl Hamsten, Marianne van Hage, Francine C. van Erp, Edward F. Knol, Hannah M. Kansen, Bo Pontoppidan, Yolanda Meijer, Cornelis K. van der Ent, André C. Knulst, Rebekah Sayers, Helen Brown, Adnan Custovic, Angela Simpson, Claire Mills, Juliane Schulz, Network for Online Registration of Anaphylaxis (NORA), Jaap Akkerdaas, Muriel Totis, Annabelle Capt, Corinne Herouet-Guicheney, Ronald van Ree, Tushar Banerjee, Antima Banerjee, Mathilde Claude, Grégory Bouchaud, Roberta Lupi, Laure Castan, Olivier Tranquet, Sandra Denery-Papini, Marie Bodinier, Chantal Brossard, Rosella De Poi, Elisa Gritti, Emiliano De Dominicis, Bert Popping, Patrizia Polverino de Laureto, Kati Palosuo, Anna Kaarina Kukkonen, Anna Pelkonen, Mika Mäkelä, Nanju Alice Lee, Johanna Rost, Sridevi Muralidharan, Dianne Campbell, Sam Mehr, Catherine Nock, Joseph Baumert, Steve Taylor, Carla Mastrorilli, Salvatore Tripodi, Carlo Caffarelli, Serena Perna, Andrea Di Rienzo Businco, Ifigenia Sfika, Arianna Dondi, Annamaria Bianchi, Carlotta Povesi Dascola, Giampaolo Ricci, Francesca Cipriani, Nunzia Maiello, Michele Miraglia del Giudice, Tullio Frediani, Simone Frediani, Francesco Macrì, Chiara Pistoletti, Iride Dello Iacono, Maria Francesca Patria, Elena Varin, Diego Peroni, Pasquale Comberiati, Loredana Chini, Viviana Moschese, Sandra Lucarelli, Roberto Bernardini, Giuseppe Pingitore, Umberto Pelosi, Roberta Olcese, Matteo Moretti, Anastasia Cirisano, Diego Faggian, Alessandro Travaglini, Mario Plebani, Maria Carmen Verga, Mauro Calvani, Paolo Giordani, Paolo Maria Matricardi, Noe Ontiveros, Francisco Cabrera-Chavez, Julie Galand, Etienne Beaudouin, The Anaphylaxis Working Group of the French Allergology SocietyThe Anaphylaxis Working Group of the French Allergology Society, Florence Pineau, Shinobu Sakai, Kayoko Matsunaga, Reiko Teshima, Colette Larré, Sandra Denery, Sebastian Tschirner, Valérie Trendelenburg, Gabriele Schulz, Bodo Niggemann, Kirsten Beyer, Youcef Bouferkas, Younes Belabbas, Djamel Saidi, Omar Kheroua, Kamel Eddine El Mecherfi, Malika Guendouz, Abir Haddi, Hanane Kaddouri, Luis Amaral, Ana Pereira, Susana Rodrigues, Mareen Datema, Laurian Jongejan, Michael Clausen, Andre Knulst, Nikolaos Papadopoulos, Marek Kowalski, Frédéric de Blay, Aeilko Zwinderman, Karin Hoffman-Sommergruber, Barbara Ballmer-Weber, Montserrat Fernandez-Rivas, Shan Deng, Jia Yin, Charlotte Eisenmann, Maria Nassiri, Rabea Reinert, Johanna P. M. van der Valk, Roy Gerth van Wijk, Yvonne Vergouwe, Ewout W. Steyerberg, Marit Reitsma, Harry J. Wichers, Huub F. J. Savelkoul, Berber Vlieg-Boerstra, Anthony E. J. Dubois, Fabrícia Carolino, Ana Rodolfo, Josefina Cernadas, Dasha Roa-Medellín, Ana Rodriguez-Fernandez, Joaquín Navarro, Vicente Albendiz, María Luisa Baeza, Sonsoles Intente-Herrero, Andrea Mikkelsen, Kirsten Mehlig, Lauren Lissner, Linda Verrill, Stefano Luccioli, Jolanda van Bilsen, Frieke Kuper, André Wolterbeek, Tanja Rouhani Rankouhi, Lars Verschuren, Hilde Cnossen, Prescilla Jeurink, Johan Garssen, Léon Knippels, Jossie Garthoff, Geert Houben, Winfried Leeman, M. Eleonore Pettersson, Afke M. M. Schins, Gerard H. Koppelman, Boudewjin J. Kollen, Svitlana Zubchenko, Sarah Kuntz, Pablo Mérida, Montserrat Álvaro, Monica Piquer, Carmen Riggioni, Juan Heber Castellanos, Rosa Jimenez, Melanie Cap, Elodie Drumez, Stéphanie Lejeune, Caroline Thumerelle, Clémence Mordacq, Véronique Nève, Sonia Ricò, Margherita Varini, Rita Nocerino, Linda Cosenza, Antonio Amoroso, Margherita Di Costanzo, Carmen Di Scala, Giorgio Bedogni, Roberto Berni Canani, Paul J. Turner, Paloma Poza-Guedes, Ruperto González-Pérez, Inmaculada Sánchez-Machín, Victor Matheu-Delgado, Erik Wambre, Anne-Sofie Ballegaard, Charlotte Madsen, Juliane Gregersen, Katrine Lindholm Bøgh, Philippe Aubert, Michel Neunlist, Antoine Magnan, Daniel Lozano-Ojalvo, Alba Pablos-Tanarro, Leticia Pérez-Rodríguez, Elena Molina, Rosina López-Fandiño, Akila Rekima, Patricia Macchiaverni, Mathilde Turfkruyer, Sebastien Holvoet, Lénaïck Dupuis, Nour Baiz, Isabella Annesi-Maesano, Annick Mercenier, Sophie Nutten, Valérie Verhasselt, Ines Mrakovcic-Sutic, Srdan Banac, Ivana Sutic, Zdenka Baricev-Novakovic, Ingrid Sutic, Valentino Pavisic, Rosa Muñoz-Cano, Teodoríkez Jiménez-Rodríguez, Daniel Corbacho, Jordi Roca-Ferrer, Joan Bartra, Aleksandar Bulog, Vladimir Micovic, Lidia Markiewicz, Agata Szymkiewicz, Anna Szyc, Barbara Wróblewska, Bryan M. Harvey, Lucien F. Harthoorn, A. Wesley Burks, Georgios Rentzos, Anna-Lena Bramstång Björk, Ulf Bengtsson, Colin Barber, Chrystyna Kalicinsky, Christine Breynaert, Lieve Coorevits, Cornelia Jansen, Erna Van Hoeyveld, Kristin Verbeke, Anne-Marie Kochuyt, Rik Schrijvers, Diana Deleanu, Adriana Muntean, Maria Konstantakopoulou, Maria Pasioti, Anastasia Papadopoulou, Anna Iliopoulou, Nikolaos Mikos, Evangelia Kompoti, Eunice Dias de Castro, Borja Bartalomé, Kok Loong Ue, Elizabeth Griffiths, Stephen Till, Kate Grimshaw, Graham Roberts, Anna Selby, Indre Butiene, Jose Ignacio Larco, Ruta Dubakiene, Ana Fiandor, Alessandro Fiocchi, Nikos Papadopoulos, Sigurveig Sigurdardottir, Aline Sprikkelman, Anne-Fleur Schoemaker, Paraskevi Xepapadaki, Thomas Keil, Zizi Cojocariu, Beatriz Secades Barbado, Vasti Iancu, Esozia Arroabarren, Marta Goñi Esarte, Miren Arteaga, Mayra Coutinho Andrade, Denise Borges, Jorge Kalil, Pedro Giavina Bianchi, Rosana Camara Agondi, Rinkesh Kumar Gupta, Akanksha Sharma, Kriti Gupta, Mukul Das, Premendra Dwivedi, Rusudan Karseladze, Liana Jorjoliani, Lali Saginadze, Mariam Tskhakaia, Katia Basello, Gabriele Piuri, Attilio Francesco Speciani, Michela Carola Speciani, Carla Camerotto, Francesco Zinno, Olga Pakholchuk, Svitlana Nedelska, Stefano Pattini, Maria Teresa Costantino, Silvia Peveri, Danilo Villalta, Eleonora Savi, Andrea Costanzi, Vera A. Revyakina, Marina A. Kiseleva, Elena D. Kuvshinova, Inna A. Larkova, Anton A. Shekhetov, Diana Silva, André Moreira, José Plácido, Hanneke van der Kleij, Esther van Twuijver, Robbert Sutorius, Pieter-Jan de Kam, Jenny van Odijk, Helen Lindqvist, Elin Lustig, Amyra Ali Azamar Jácome, Karla Leversia Borjas Aguilar, Miguel García Domínguez, David Alejandro Mendoza Hernández, Cristiano Caruso, Cono Casale, Gian Lodovico Rapaccini, Antonino Romano, Italo De Vitis, Renata R. Cocco, Carolina Aranda, Marcia C. Mallozi, Jackeline F. Motta, Lilian Moraes, Antonio Pastorino, Nelson Rosario, Ekaterini Goudouris, Arnaldo Porto, Neusa F. Wandalsen, Emanuel Sarinho, Flavio Sano, Dirceu Solé, Constantinos Pitsios, Maria Petrodimopoulou, Ekaterini Papadopoulou, Maria Passioti, Meropi Kontogianni, Nino Adamia, Ekaterina Khaleva, Ana Prieto del Prado, George Du Toit, Edyta Krzych, Urszula Samolinska-Zawisza, Konrad Furmanczyk, Aneta Tomaszewska, Filip Raciborski, Agnieszka Lipiec, Piotr Samel-Kowalik, Artur Walkiewicz, Jacek Borowicz, Boleslaw Samolinski, Aimee Lou Nano, Marysia Recto, Maria Luisa Somoza, Natalia Blanca López, Diana Pérez Alzate, Francisco Javier Ruano, Maria Isabel Garcimartín, Elisa Haroun, Maria Vázquez de la Torre, Antonia Rojas, Montserrat López Onieva, Gabriela Canto, Alexandra Rodrigues, Andreia Forno, António Jorge Cabral, Rute Gonçalves, Ilya Vorozhko, Tatyana Sentsova, Olga Chernyak, Svetlana Denisova, Lidia Ilènko, Valery Muhortnich, Caroline Zimmermann, Alexander Rohrbach, Faisal R. Bakhsh, Kollen Boudewijn, Anne-Marie Oomkes-Pilon, Dorien Van Ginkle, Mira Šilar, Anja Jeverica, Tina Vesel, Tadej Avčin, Peter Korošec, Johanna van der Valk, Irene Berends, Nicolette Arends, Maurits van Maaren, Harry Wichers, Joyce Emons, Anthony Dubois, Nicolette de Jong, Oksana Matsyura, Lesya Besh, Chung-Hsiung Huang, Tong-Rong Jan, Gary Stiefel, Jean Tratt, Kerrie Kirk, Fabricia Carolino, Stefania Arasi, Lucia Caminiti, Giuseppe Crisafulli, Chiara Fiamingo, Jlenia Fresta, Giovanni Pajno, Ben Remington, Astrid Kruizinga, W. Marty Blom, Joost Westerhout, Sabina Bijlsma, Joe Baumert, Mark Blankestijn, Henny Otten, Rob Klemans, Anouska D. Michelsen-Huisman, Harmieke van Os-Medendorp, Astrid G. Kruizinga, Astrid Versluis, Gert van Duijn, H. Mary-Lene de Zeeuw-Brouwer, Jacqueline J. M. Castenmiller, Hub P. J. M. Noteborn, Geert F. Houben, Kristian Bravin, David Luyt, Bushra Javed, Phil Couch, Christopher Munro, Phil Padfield, Matt Sperrin, Aideen Byrne, Lizalet Oosthuizen, Carina Kelleher, Fiona Ward, Niamh Brosnan, Graham King, Eva Corbet, Josué Alejandro Huertas Guzmán, Montserrat Bosque García, Oscar Asensio, Laura Valdesoiro Navarrete, Helena Larramona, Xavier Domingo Miró, Katarzyna Pyrz, Moira Austin, Yanne Boloh, Philip Couch, Deirdre Galloway, Pilar Hernandez, Jonathan O’B. Hourihane, Fiona Kenna, Barbara Majkowska-Wojciechowska, Lynne Regent, Marina Themisb, Sabine Schnadt, Aida Semic-Jusufagic, Audrey Dunn Galvin, Tiina Kauppila, Mikael Kuitunen, Nikolaos A. Kitsioulis, Nikolaos Douladiris, Sofia Kostoudi, Ioanna Manolaraki, Dimitris Mitsias, Emmanouil Manousakis, Nikolaos G. Papadopoulos, Rebecca Knibb, Jennifer Hammond, Richard Cooke, Jaakko Yrjänä, Anna-Maija Hanni, Päivi Vähäsarja, Oona Mustonen, Teija Dunder, Petri Kulmala, Eva Lasa, Carmen D’Amelio, Sara Martínez, Alejandro Joral, Gabriel Gastaminza, Maria Jose Goikoetxea, David C. A. Candy, Marleen T. J. Van Ampting, Manon M. Oude Nijhuis, Assad M. Butt, Diego G. Peroni, Adam T. Fox, Jan Knol, Louise J. Michaelis, Ines Padua, Patricia Padrao, Pedro Moreira, Renata Barros, Hanan Sharif, Manzoor Ahmed, Nehad Gomaa, Joris Mens, Koen Smit, Frans Timmermans, Tomaž Poredoš, Anja Koren Jeverica, Marjeta Sedmak, Evgen Benedik, Meta Accetto, Mirjana Zupančič, Glauce Yonamine, Gustavo Soldateli, Bruna Aquilante, Antonio Carlos Pastorino, Cleonir Lui de Moraes Beck, Andrea Keiko Gushken, Mayra de Barros Dorna, Cristiane Nunes dos Santos, Ana Paula Moschione Castro, Abdulhadi Al-Qahtani, Rand Arnaout, Agha Rehan Khaliq, Rashid Amin, Farrukh Sheikh, Jorge Alvarez, Marta Anda, Miriam Palacios, Montserrat De Prada, Carmen Ponce, Bianca Balbino, Riccardo Sibilano, Thomas Marichal, Nicolas Gaudenzio, Hajime Karasuyama, Pierre Bruhns, Mindy Tsai, Laurent L. Reber, Stephen J. Galli, Ana Reis Ferreira, Josefina R. Cernadas, Aida del Campo García, Sara Pereiro Fernández, Nerea Sarmiento Carrera, Fernando Bandrés Sánchez-Cruz, José Ramón Fernández Lorenzo, Stephanie Claus, Claudia Pföhler, Franziska Ruëff, Regina Treudler, Mercedes Escarrer Jaume, Agustin Madroñero, Maria Teresa Guerra Perez, Juan Carlos Julia, Charlotte Hands Plovdiv, Lee Gethings, Jim Langridge, Karine Adel-Patient, Hervé Bernard, Ivona Barcievic-Jones, Raditsa Sokolova, Rumyana Yankova, Mariya Ivanovska, Marianna Murdjeva, Tatyana Popova, Svetlan Dermendzhiev, Martin Karjalainen, Ulrike Lehnigk, Duncan Brown, Julie C. Locklear, Julie Locklear, Ioana Maris, Jonathan Hourihane, Cristina Ornelas, Joana Caiado, Manuel Branco Ferreira, Manuel Pereira-Barbosa, Yolanda Puente, Juan Carlos Daza, Francisco Javier Monteseirin, Natalia Ukleja-Sokolowska, Ewa Gawronska-Ukleja, Magdalena Zbikowska-Gotz, Zbigniew Bartuzi, Lukasz Sokolowski, Aine Adams, Bernard Mahon, Karen English, Nelly Gourdon-Dubois, Laetitia Sellam, Bruno Pereira, Elodie Michaud, Khaled Messaoudi, Bertrand Evrard, Jean-Luc Fauquert, Francisca Palomares, Gador Gomez, Maria Jose Rodriguez, Luisa Galindo, Ana Molina, Lorella Paparo, Maurizio Mennini, Rosita Aitoro, Adam Wawrzeńczyk, Michał Przybyszewski, Anna Wawrzeńczyk, Hulya Ercan Sarıcoban, Meltem Ugras, Zerrin Yalvac, Bertine M. J. Flokstra-de Blok, J. L. van der Velde, Andrea Vereda, Clara Ippolito, Amaranta Traversa, Daniela Adriano, Daniela Manila Bianchi, Silvia Gallina, Lucia Decastelli, Melina Makatsori, Anne Miles, Sonja Posega Devetak, Iztok Devetak, Soraya Ainad Tabet, Jeanette Fisker Trandbohus, Pernille Winther, Hans-Jørgen Malling, Kirsten Skamstrup Hansen, Lene Heise Garvey, Chia-Chi Wang, Yin-Hua Cheng, Chun-Wei Tung, Mariola Dietrich, Ingo Marenholz, Birgit Kalb, Sarah Grosche, Katharina Blümchen, Rupert Schlags, Mareike Price, Sylke Rietz, Jorge Esparza-Gordillo, Susanne Lau, Young-Ae Lee, Ali Almontasheri, Mohammad Al Bahkali, Sahar Elshorbagi, Abdullah Alfhaid, Mashary Altamimi, Eman Madbouly, Hassan Al-Dhekri, Rand K. Arnaout, Maria Basagaña, Sira Miquel, Borja Bartolomé, Bettina Brix, Stefanie Rohwer, Sandra Brandhoff, Alena Berger, Waltraud Suer, Alf Weimann, Cristina Bueno, Laura Martín-Pedraza, Sara Abián, Pablo San Segundo-Acosta, Juan Carlos López-Rodríguez, Rodrigo Barderas, Eva Batanero, Javier Cuesta-Herranz, María Teresa Villalba, Magna Correia, Filipe Benito-Garcia, Cristina Arêde, Susana Piedade, Mário Morais-Almeida, James Hindley, Ross Yarham, Anna Kuklinska-Pijanka, David Gillick, Karine Patient, Martin D. Chapman, Katrine L. Bøgh, Ana Miranda, Eugénia Matos, Anna Sokolova, Huan Rao, Ivona Baricevic-Jones, Frances Smith, Wentong Xue, Helga Magnusdottir, Anna G. Vidarsdottir, Sigrun Lund, Anders Blom Jensen, Bjorn R. Ludviksson, Reyna Simon, Robert Elfont, Sean Bennett, Robert Voyksner, Maria de Lurdes Torre, Songül Yürek, Margaretha A. Faber, Annick Bastiaensen, Evelyne Mangodt, Athina van Gasse, Ine Decuyper, Vito Sabato, Margo M. Hagendorens, Chris H. Bridts, Luc S. De Clerck, Didier Ebo, Susanne Schwarz, Mandy Ziegert, Saskia Albroscheit, Christian Schwager, Skadi Kull, Jochen Behrends, Niels Röckendorf, Frauke Schocker, Andreas Frey, Arne Homann, Wolf-Meinhard Becker, Uta Jappe, Nesrine Zaabat, Sylvia Osscini, Chantal Agabriel, Benoît Sterling, Ania Carsin, Valérie Liabeuf, Monica Maćków, Alina Zbróg, Monica Bronkowska, Justine Courtois, Romy Gadisseur, Catherine Bertholet, Pierre Lukas, Etienne Cavalier, Philippe Delahaut, Birgit Quinting, Margareta Brandt Gertmo, Ewa Ternesten Hasseus, Vladyslava Barzylovych, Júlio Oliveira, Luis F. Ensina, Carolina S. Aranda, Leire Dopazo, Rebeca Lopez, Raquel Perez, Laura Santos-Diez, Agurtzane Bilbao, Juan Miguel Garcia, Ignacio García Núñez, María Ángeles Algaba Mármol, María José Barasona Villarejo, José Antonio Bácter Martos, Marina Suárez Vergara, José María Ignacio García, Agata Michalska, Grzegorz Sergiejko, Robert Zacniewski, Ileana-Maria Ghiordanescu, Cristina Deaconu, Mihaela Popescu, Roxana Silvia Bumbacea, Alkerta Ibranji, Elida Nikolla, Gjustina Loloci, Nanna Juel-Berg, Lau Fabricius Larsen, Lars Kjaergaard Poulsen, João Marcelino, Ricardo Prata, Ana Célia Costa, Fátima Duarte, Marta Neto, Jennifer Santos, Luís Câmara Pestana, Daniel Sampaio, Paola Minale, Paola Dignetti, Donatella Bignardi, Irena Nedelea, Florin-Dan Popescu, Mariana Vieru, Florin-Adrian Secureanu, Carmen Saviana Ganea, Miguel Vieira, José Pedro Moreira Silva, Timothy Watts, Sophia Watts, Marta Lomikovska, Marina Peredelskaya, Natalia Nenasheva, Ivana Filipovic, Zorica Zivkovic, Djordje Filipovic, Jennette Higgs, Amena Warner, and Carla Jones

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2017
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6. Non-Digestible Oligosaccharides Can Suppress Basophil Degranulation in Whole Blood of Peanut-Allergic Patients

Author

Simone M. Hayen, Constance F. den Hartog Jager, André C. Knulst, Edward F. Knol, Johan Garssen, Linette E. M. Willemsen, and Henny G. Otten

Subjects
basophil degranulation, food allergy, galectin-9, immunomodulation, non-digestible oligosaccharides, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundDietary non-digestible oligosaccharides (NDOs) have a protective effect against allergic manifestations in children at risk. Dietary intervention with NDOs promotes the colonization of beneficial bacteria in the gut and enhances serum galectin-9 levels in mice and atopic children. Next to this, NDOs also directly affect immune cells and low amounts may reach the blood. We investigated whether pre-incubation of whole blood from peanut-allergic patients with NDOs or galectin-9 can affect basophil degranulation.MethodsHeparinized blood samples from 15 peanut-allergic adult patients were pre-incubated with a mixture of short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides (scGOS/lcFOS), scFOS/lcFOS, or galectin-9 (1 or 5 µg/mL) at 37°C in the presence of IL-3 (0.75 ng/mL). After 2, 6, or 24 h, a basophil activation test was performed. Expression of FcεRI on basophils, plasma cytokine, and chemokine concentrations before degranulation were determined after 24 h.ResultsPre-incubation with scGOS/lcFOS, scFOS/lcFOS, or galectin-9 reduced anti-IgE-mediated basophil degranulation. scFOS/lcFOS or 5 µg/mL galectin-9 also decreased peanut-specific basophil degranulation by approximately 20%, mainly in whole blood from female patients. Inhibitory effects were not related to diminished FcεRI expression on basophils. Galectin-9 was increased in plasma after pre-incubation with scGOS/lcFOS, and both NDOs and 5 µg/mL galectin-9 increased MCP-1 production.Conclusion and clinical relevanceThe prebiotic mixture scFOS/lcFOS and galectin-9 can contribute to decreased degranulation of basophils in vitro in peanut-allergic patients. The exact mechanism needs to be elucidated, but these NDOs might be useful in reducing allergic symptoms.

Published
2018
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7. The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

Author

Suzanne van Dorp, Henrike Resemann, Liane te Boome, Floor Pietersma, Debbie van Baarle, Frits Gmelig-Meyling, Roel de Weger, Eefke Petersen, Monique Minnema, Henk Lokhorst, Saskia Ebeling, Scott J.P. Beijn, Edward F. Knol, Marijke van Dijk, Ellen Meijer, and Jürgen Kuball

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8+ T cells, suggesting that host B cells play a role in maintaining pathological CD8+ T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42).

Published
2011
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8. Transforming growth factor-β inhibits human antigen-specific CD4+ T cell proliferation without modulating the cytokine response.

Author

Machteld M. Tiemessen, Steffen Kunzmann, Carsten B. Schmidt-Weber, Johan Garssen, Carla A. F. M. Bruijnzeel-Koomen, Edward F. Knol, and Els Van Hoffen

Subjects
TRANSFORMING growth factors, IMMUNE response, IMMUNE system, T cells
Abstract

Transforming growth factor (TGF)-β has been demonstrated to play a key role in the regulation of the immune response, mainly by its suppressive function towards cells of the immune system. In humans, the effect of TGF-β on antigen-specific established memory T cells has not been investigated yet. In this study antigen-specific CD4+ T cell clones (TCC) were used to determine the effect of TGF-β on antigen-specific proliferation, the activation status of the T cells and their cytokine production. This study demonstrates that TGF-β is an adequate suppressor of antigen-specific T cell proliferation, by reducing the cell-cycle rate rather than induction of apoptosis. Addition of TGF-β resulted in increased CD69 expression and decreased CD25 expression on T cells, indicating that TGF-β is able to modulate the activation status of in vivo differentiated T cells. On the contrary, the antigen-specific cytokine production was not affected by TGF-β. Although TGF-β was suppressive towards the majority of the T cells, insensitivity of a few TCC towards TGF-β was also observed. This could not be correlated to differential expression of TGF-β signaling molecules such as Smad3, Smad7, SARA (Smad anchor for receptor activation) and Hgs (hepatocyte growth factor-regulated tyrosine kinase substrate). In summary, TGF-β has a pronounced inhibitory effect on antigen-specific T cell proliferation without modulating their cytokine production. [ABSTRACT FROM AUTHOR]

Published
2003

9. Seeking diagnostic and prognostic biomarkers for childhood bacterial pneumonia in sub-Saharan Africa: study protocol for an observational study

Author

Julio Ramírez, Quique Bassat, Wilco de Jager, Patricia L Hibberd, Grant A Mackenzie, Umberto D’Alessandro, Clarissa Valim, Yekin Ajauoi Olatunji, Yasir Shitu Isa, Rasheed Salaudeen, Sarwar Golam, Edward F Knol, Sheriffo Kanyi, Abdoulie Jammeh, Alejandro A Diaz, Roger C Wiegand, and Marsha A Moses

Subjects
Medicine
Abstract

Introduction Clinically diagnosed pneumonia in children is a leading cause of paediatric hospitalisation and mortality. The aetiology is usually bacterial or viral, but malaria can cause a syndrome indistinguishable from clinical pneumonia. There is no method with high sensitivity to detect a bacterial infection in these patients and, as result, antibiotics are frequently overprescribed. Conversely, unrecognised concomitant bacterial infection in patients with malarial infections occur with omission of antibiotic therapy from patients with bacterial infections. Previously, we identified two combinations of blood proteins with 96% sensitivity and 86% specificity for detecting bacterial disease. The current project aimed to validate and improve these combinations by evaluating additional biomarkers in paediatric patients with clinical pneumonia. Our goal was to describe combinations of a limited number of proteins with high sensitivity and specificity for bacterial infection to be incorporated in future point-of-care tests. Furthermore, we seek to explore signatures to prognosticate clinical pneumonia.Methods and analysis Patients (n=900) aged 2–59 months presenting with clinical pneumonia at two Gambian hospitals will be enrolled and classified according to criteria for definitive bacterial aetiology (based on microbiological tests and chest radiographs). We will measure proteins at admission using Luminex-based immunoassays in 90 children with definitive and 160 with probable bacterial aetiology, and 160 children classified according to the prognosis of their disease. Previously identified diagnostic signatures will be assessed through accuracy measures. Moreover, we will seek new diagnostic and prognostic signatures through machine learning methods, including support vector machine, penalised regression and classification trees.Ethics and dissemination Ethics approval has been obtained from the Gambia Government/Medical Research Council Unit The Gambia Joint Ethics Committee (protocol 1616) and the institutional review board of Boston University Medical Centre (STUDY00000958). Study results will be disseminated to the staff of the study hospitals, in scientific seminars and meetings, and in publications.Trial registration number H-38462.

Published
2021
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10. The immune cell composition in Barrett's metaplastic tissue resembles that in normal duodenal tissue.

Author

Alexandra Lind, Peter D Siersema, Johannes G Kusters, Jan A M Van der Linden, Edward F Knol, and Leo Koenderman

Subjects
Medicine, Science
Abstract

Background and objectiveBarrett's esophagus (BE) is characterized by the transition of squamous epithelium into columnar epithelium with intestinal metaplasia. The increased number and types of immune cells in BE have been indicated to be due to a Th2-type inflammatory process. We tested the alternative hypothesis that the abundance of T-cells in BE is caused by a homing mechanism that is found in the duodenum.Patients and methodsBiopsies from BE and duodenal tissue from 30 BE patients and duodenal tissue from 18 controls were characterized by immmunohistochemistry for the presence of T-cells and eosinophils(eos). Ex vivo expanded T-cells were further phenotyped by multicolor analysis using flowcytometry.ResultsThe high percentage of CD4(+)-T cells (69±3% (mean±SEM/n = 17, by flowcytometry)), measured by flowcytometry and immunohistochemistry, and the presence of non-activated eosinophils found in BE by immunohistochemical staining, were not different from that found in duodenal tissue. Expanded lymphocytes from these tissues had a similar phenotype, characterized by a comparable but low percentage of αE(CD103) positive CD4(+)cells (44±5% in BE, 43±4% in duodenum of BE and 34±7% in duodenum of controls) and a similar percentage of granzyme-B(+)CD8(+) cells(44±5% in BE, 33±6% in duodenum of BE and 36±7% in duodenum of controls). In addition, a similar percentage of α4β7(+) T-lymphocytes (63±5% in BE, 58±5% in duodenum of BE and 62±8% in duodenum of controls) was found. Finally, mRNA expression of the ligand for α4β7, MAdCAM-1, was also similar in BE and duodenal tissue. No evidence for a Th2-response was found as almost no IL-4(+)-T-cells were seen.ConclusionThe immune cell composition (lymphocytes and eosinophils) and expression of intestinal adhesion molecule MAdCAM-1 is similar in BE and duodenum. This supports the hypothesis that homing of lymphocytes to BE tissue is mainly caused by intestinal homing signals rather than to an active inflammatory response.

Published
2012
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