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2. Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study

Author

Maid, Pablo, Rillo, Oscar, Inderjeeth, Charles, Scheinecker, Clemens, Hermann, Josef, Marcolino, Flora Maria D'Andrea, Dias, Laiza H, Scafuto, Antonio, Bookman, Arthur AM, Fortin, Isabelle, Morin, Frederic, Goio, Elizabeth Jean Moreno, Pezo Ruiz, Ninette, Roman Zamoran, Carlos Patricio, Gonzalez Abarzua, Ivan Antonio, Elgueta, Sergio Fabian, Forero Illera, Elias Gonzalo, Marquez Herndez, Javier Dario, Garcia, Alex Echeverri, Pensec, Valerie Devauchelle, Hachulla, Eric, Mariette, Xavier, Gottenberg, Jacques-Eric, Le Guern, Veronique, Finzel, Stephanie, Schaefer, Valentin, Tony, Hans-Peter, Thomas Schmalzing, Marc, Tausche-Wunderlich, Anne-Kathrin, Tzioufas, Athanasios, Balog, Attila, Rojkovich, Bernadette, Varga, Tunde, Lidar, Merav, Rosner, Itzhak, Levy, Yair, Dagna, Lorenzo, Mosca, Marta, Quartuccio, Luca, Nishiyama, Susumu, Kodera, Masanari, Kaneko, Yuko, Okada, Masato, Ueki, Yukitaka, Hwan Park, Sung, van Daele, Paulus Leon Arthur, Bootsma, Hendrika, Duarte Barcelos, Filipe Alexandre, Crispim Romao, Vasco Madeira, Raimundo Vinagre, Filipe Manuel, Tavaresda Costa, Jose Antonio, Rednic, Simona, Duca, Liliana, Maslyanskiy, Alexey, Yakupova, Svetlana, Bugrova, Olga, Izmozherova, Nadezhda, Zotkin, Evgenyi, Nikolaevna Anoshenkova, Olga, Kvarnstrom, Marika, Tufan, Abdurrahman, Fisher, Benjamin, Yee, Chee Seng, Parker, Benjamin Joseph, Grader Beck, Thomas, Lawrence Ford, Theresa, Papas, Athena, Carsons, Steven, Thiagarajan, Saravanan, Zero, Domenick, McCoy, Sara, Sandorfi, Nora, Fisher, Benjamin A, Grader-Beck, Thomas, Ng, Wan-Fai, van Daele, P L A, Noaiseh, Ghaith, Elgueta, Sergio, McCoy, Sara S, Akpek, Esen, Bookman, Arthur, Sopala, Monika, Montecchi-Palmer, Michela, Luo, Wen-Lin, Scheurer, Cornelia, and Hueber, Wolfgang

Published
2024
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3. Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Author

Beretta, Lorenzo, Vigone, Barbara, Pers, Jacques-Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Ducreux, Julie, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Neves, Esmeralda, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Angel, Alonso, Ricardo Blanco, Martínez, Alfonso Corrales, Cervera, Ricard, Rodríguez-Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, De Langhe, Ellen, Hunzelmann, Nicolas, Belz, Doreen, Witte, Torsten, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Aguirre-Zamorano, Ma Angeles, Escudero-Contreras, Alejandro, Castro-Villegas, Ma Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Moleón, Inmaculada Jiménez, de Ramon, Enrique, Quintero, Isabel Díaz, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Maresca, Manuel Rodriguez, López-Berrio, Antonio, Aguilar-Quesada, Rocío, Navarro-Linares, Héctor, Parodis, Ioannis, Lindblom, Julius, Toro-Domínguez, Daniel, Borghi, Maria O., Castillo, Jessica, Carnero-Montoro, Elena, Enman, Yvonne, Mohan, Chandra, Alarcón-Riquelme, Marta E., Barturen, Guillermo, and Nikolopoulos, Dionysis

Published
2024
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5. Interferon and B-cell Signatures Inform Precision Medicine in Lupus Nephritis

Author

Parodis, Ioannis, primary, Lindblom, Julius, additional, Toro-Domínguez, Daniel, additional, Beretta, Lorenzo, additional, Borghi, Maria O., additional, Castillo, Jessica, additional, Carnero-Montoro, Elena, additional, Enman, Yvonne, additional, Mohan, Chandra, additional, Alarcón-Riquelme, Marta E., additional, Barturen, Guillermo, additional, Nikolopoulos, Dionysis, additional, Vigone, Barbara, additional, Pers, Jacques-Olivier, additional, Saraux, Alain, additional, Devauchelle-Pensec, Valérie, additional, Cornec, Divi, additional, Jousse-Joulin, Sandrine, additional, Lauwerys, Bernard, additional, Ducreux, Julie, additional, Maudoux, Anne-Lise, additional, Vasconcelos, Carlos, additional, Tavares, Ana, additional, Neves, Esmeralda, additional, Faria, Raquel, additional, Brandão, Mariana, additional, Campar, Ana, additional, Marinho, António, additional, Farinha, Fátima, additional, Almeida, Isabel, additional, Gonzalez-Gay Mantecón, Miguel Angel, additional, Alonso, Ricardo Blanco, additional, Martínez, Alfonso Corrales, additional, Cervera, Ricard, additional, Rodríguez-Pintó, Ignasi, additional, Espinosa, Gerard, additional, Lories, Rik, additional, De Langhe, Ellen, additional, Hunzelmann, Nicolas, additional, Belz, Doreen, additional, Witte, Torsten, additional, Baerlecken, Niklas, additional, Stummvoll, Georg, additional, Zauner, Michael, additional, Lehner, Michaela, additional, Collantes, Eduardo, additional, Ortega-Castro, Rafaela, additional, Aguirre-Zamorano, Ma Angeles, additional, Escudero-Contreras, Alejandro, additional, Castro-Villegas, Ma Carmen, additional, Ortego, Norberto, additional, Fernández Roldán, María Concepción, additional, Raya, Enrique, additional, Moleón, Inmaculada Jiménez, additional, de Ramon, Enrique, additional, Quintero, Isabel Díaz, additional, Meroni, Pier Luigi, additional, Gerosa, Maria, additional, Schioppo, Tommaso, additional, Artusi, Carolina, additional, Chizzolini, Carlo, additional, Zuber, Aleksandra, additional, Wynar, Donatienne, additional, Kovács, Laszló, additional, Balog, Attila, additional, Deák, Magdolna, additional, Bocskai, Márta, additional, Dulic, Sonja, additional, Kádár, Gabriella, additional, Hiepe, Falk, additional, Gerl, Velia, additional, Thiel, Silvia, additional, Maresca, Manuel Rodriguez, additional, López-Berrio, Antonio, additional, Aguilar-Quesada, Rocío, additional, and Navarro-Linares, Héctor, additional

Published
2024
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6. Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study

Author

Fisher, Benjamin A, Mariette, Xavier, Papas, Athena, Grader-Beck, Thomas, Bootsma, Hendrika, Ng, Wan-Fai, van Daele, P L A, Finzel, Stephanie, Noaiseh, Ghaith, Elgueta, Sergio, Hermann, Josef, McCoy, Sara S, Akpek, Esen, Bookman, Arthur, Sopala, Monika, Montecchi-Palmer, Michela, Luo, Wen-Lin, Scheurer, Cornelia, Hueber, Wolfgang, Maid, Pablo, Rillo, Oscar, Inderjeeth, Charles, Scheinecker, Clemens, Hermann, Josef, Marcolino, Flora Maria D'Andrea, Dias, Laiza H, Scafuto, Antonio, Bookman, Arthur AM, Fortin, Isabelle, Morin, Frederic, Goio, Elizabeth Jean Moreno, Pezo Ruiz, Ninette, Roman Zamoran, Carlos Patricio, Gonzalez Abarzua, Ivan Antonio, Elgueta, Sergio Fabian, Forero Illera, Elias Gonzalo, Marquez Herndez, Javier Dario, Garcia, Alex Echeverri, Pensec, Valerie Devauchelle, Hachulla, Eric, Mariette, Xavier, Gottenberg, Jacques-Eric, Le Guern, Veronique, Finzel, Stephanie, Schaefer, Valentin, Tony, Hans-Peter, Thomas Schmalzing, Marc, Tausche-Wunderlich, Anne-Kathrin, Tzioufas, Athanasios, Balog, Attila, Rojkovich, Bernadette, Varga, Tunde, Lidar, Merav, Rosner, Itzhak, Levy, Yair, Dagna, Lorenzo, Mosca, Marta, Quartuccio, Luca, Nishiyama, Susumu, Kodera, Masanari, Kaneko, Yuko, Okada, Masato, Ueki, Yukitaka, Hwan Park, Sung, van Daele, Paulus Leon Arthur, Bootsma, Hendrika, Duarte Barcelos, Filipe Alexandre, Crispim Romao, Vasco Madeira, Raimundo Vinagre, Filipe Manuel, Tavaresda Costa, Jose Antonio, Rednic, Simona, Duca, Liliana, Maslyanskiy, Alexey, Yakupova, Svetlana, Bugrova, Olga, Izmozherova, Nadezhda, Zotkin, Evgenyi, Nikolaevna Anoshenkova, Olga, Kvarnstrom, Marika, Tufan, Abdurrahman, Fisher, Benjamin, Yee, Chee Seng, Parker, Benjamin Joseph, Grader Beck, Thomas, Lawrence Ford, Theresa, Papas, Athena, Carsons, Steven, Thiagarajan, Saravanan, Zero, Domenick, McCoy, Sara, and Sandorfi, Nora

Abstract

Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease.

Published
2024
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7. Comparative single-cell multiplex immunophenotyping of therapy-naive patients with rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus shed light on disease-specific composition of the peripheral immune system.

Author

Balog, József Á., Zvara, Ágnes, Bukovinszki, Vivien, Puskás, László G., Balog, Attila, and Szebeni, Gábor J.

Subjects
SYSTEMIC lupus erythematosus, MONONUCLEAR leukocytes, SYSTEMIC scleroderma, IMMUNE system, RHEUMATOID arthritis, IMMUNOPHENOTYPING, AUTOIMMUNE diseases
Abstract

Introduction: Systemic autoimmune diseases (SADs) are a significant burden on the healthcare system. Understanding the complexity of the peripheral immunophenotype in SADs may facilitate the differential diagnosis and identification of potential therapeutic targets. Methods: Single-cell mass cytometric immunophenotyping was performed on peripheral blood mononuclear cells (PBMCs) from healthy controls (HCs) and therapy-naive patients with rheumatoid arthritis (RA), progressive systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). Immunophenotyping was performed on 15,387,165 CD45+ live single cells from 52 participants (13 cases/group), using an antibody panel to detect 34 markers. Results: Using the t-SNE (t-distributed stochastic neighbor embedding) algorithm, the following 17 main immune cell types were determined: CD4+/ CD57– T cells, CD4+/CD57+ T cells, CD8+/CD161– T cells, CD8+/CD161+/CD28+ T cells, CD8dim T cells, CD3+/CD4–/CD8– T cells, TCRγ/δ T cells, CD4+ NKT cells, CD8+ NKT cells, classic NK cells, CD56dim/CD98dim cells, B cells, plasmablasts, monocytes, CD11cdim/CD172dim cells, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Seven of the 17 main cell types exhibited statistically significant frequencies in the investigated groups. The expression levels of the 34 markers in the main populations were compared between HCs and SADs. In summary, 59 scatter plots showed significant differences in the expression intensities between at least two groups. Next, each immune cell population was divided into subpopulations (metaclusters) using the FlowSOM (self-organizing map) algorithm. Finally, 121 metaclusters (MCs) of the 10 main immune cell populations were found to have significant differences to classify diseases. The single-cell T-cell heterogeneity represented 64MCs based on the expression of 34 markers, and the frequency of 23 MCs differed significantly between at least twoconditions. The CD3– non-T-cell compartment contained 57 MCs with 17 MCs differentiating at least two investigated groups. In summary, we are the first to demonstrate the complexity of the immunophenotype of 34 markers over 15 million single cells in HCs vs. therapy-naive patients with RA, SSc, and SLE. Disease specific population frequencies or expression patterns of peripheral immune cells provide a single-cell data resource to the scientific community. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Comparison of humoral and cellular immune responses in hematologic diseases following completed vaccination protocol with BBIBP-CorV, or AZD1222, or BNT162b2 vaccines against SARS-CoV-2

Author

Szabó, Enikő, primary, Modok, Szabolcs, additional, Rónaszéki, Benedek, additional, Faragó, Anna, additional, Gémes, Nikolett, additional, Nagy, Lajos I., additional, Hackler, László, additional, Farkas, Katalin, additional, Neuperger, Patrícia, additional, Balog, József Á., additional, Balog, Attila, additional, Puskás, László G., additional, and Szebeni, Gabor J., additional

Published
2023
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18. Comparison of humoral and cellular immune responses in hematologic diseases following completed vaccination protocol with BBIBP-CorV, or AZD1222, or BNT162b2 vaccines against SARS-CoV-2

Author

Szabó Enikő, Modok Szabolcs, Rónaszéki Benedek, Faragó Anna, Gémes Nikolett, Nagy I. Lajos, Hackler Jr. László, Farkas Katalin, Neuperger Patrícia, Balog József Á., Balog Attila, Puskás László G., and Szebeni Gabor J.

Subjects
03.03. Egészségtudományok, 03.02. Klinikai orvostan
Published
2023

27. Humoral and Cellular Immunogenicity and Safety of Five Different SARS-CoV-2 Vaccines in Patients With Autoimmune Rheumatic and Musculoskeletal Diseases in Remission or With Low Disease Activity and in Healthy Controls: A Single Center Study

Author

Szebeni, Gábor J., primary, Gémes, Nikolett, additional, Honfi, Dániel, additional, Szabó, Enikő, additional, Neuperger, Patrícia, additional, Balog, József Á., additional, Nagy, Lajos I., additional, Szekanecz, Zoltán, additional, Puskás, László G., additional, Toldi, Gergely, additional, and Balog, Attila, additional

Published
2022
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29. A new molecular classification to drive precision treatment strategies in primary Sjögren’s syndrome

Author

Soret, Perrine, Le Dantec, Christelle, Desvaux, Emiko, Foulquier, Nathan, Chassagnol, Bastien, Hubert, Sandra, Christophe, Jamin, Barturen, Guillermo, Desachy, Guillaume, Devauchelle-Pensec, Valérie, Boudjeniba, Cheïma, Cornec, Divi, Saraux, Alain, Jousse-Joulin, Sandrine, Barbarroja, Nuria, Rodríguez-Pintó, Ignasi, de Langhe, Ellen, Beretta, Lorenzo, Chizzolini, Carlo, Kovács, László, Witte, Torsten, Bettacchioli, Eléonore, Buttgereit, Anne, Makowska, Zuzanna, Lesche, Ralf, Borghi, Maria Orietta, Martin, Javier, Courtade-Gaiani, Sophie, Xuereb, Laura, Guedj, Mickaël, Moingeon, Philippe, Alarcón-Riquelme, Marta, Laigle, Laurence, Pers, Jacques-Olivier, Vigone, Barbara, Lauwerys, Bernard, Maudoux, Anne-Lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Angel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega-Castro, Rafaela, Aguirre-Zamorano, Ma Angeles, Escudero-Contreras, Alejandro, Castro-Villegas, Ma Carmen, Jiménez Gómez, Yolanda, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, de Ramon, Enrique, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, Zuber, Aleksandra, Wynar, Donatienne, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Thiel, Silvia, Rodriguez Maresca, Manuel, López-Berrio, Antonio, Aguilar-Quesada, Rocío, Navarro-Linares, Héctor, Ioannou, Yiannis, Chamberlain, Chris, Marovac, Jacqueline, Alarcón Riquelme, Marta, Gomes Anjos, Tania, Marañón, Concepción, Le Lann, Lucas, Simon, Quentin, Rouvière, Bénédicte, Varela, Nieves, Muchmore, Brian, Dufour, Aleksandra, Alvarez, Montserrat, Cremer, Jonathan, Lopez-Pedrera, Chary, Gerl, Velia, Khodadadi, Laleh, Cheng, Qingyu, de Groof, Aurélie, Ducreux, Julie, Trombetta, Elena, Li, Tianlu, Alvarez-Errico, Damiana, Kniesch, Katja, Azevedo, Nancy, Neves, Esmeralda, Rao, Sambasiva, Jouve, Pierre-Emmanuel, Institut de Recherches Internationales Servier [Suresnes] (IRIS), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre for Genomics and Oncological Reearch (GENYO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Maggiore Hospital, IRCCS Foundation, Milano, Department of Pathology and Immunology [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE), University of Szeged [Szeged], Clinic for Immunology and Rhematology, Hannover Medical School, Hanover, Germany, Hôpital Morvan - CHRU de Brest (CHU - BREST ), Pharmaceuticals Division Bayer Pharma Aktiengesellschaft, Università degli Studi di Milano = University of Milan (UNIMI), Instituto de Parasitología y Biomedicina 'López-Neyra' (IPBLN), Consejo Superior de Investigaciones Científicas (CSIC), Universidad de Granada = University of Granada (UGR), and Michel, Geneviève

Subjects
MESH: Databases, Protein, MESH: Inflammation, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Flow Cytometry, MESH: Cross-Sectional Studies, MESH: DNA Methylation, MESH: Computer Simulation, cell cycle, chronic lymphocytic leukemia, liquid chromatography-tandem mass spectrometry, splicing, MESH: Autoantibodies, MESH: Interferons, MESH: RNA-Seq, MESH: Cohort Studies, MESH: Databases, Genetic, MESH: Cytokines, MESH: Humans, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH: Transcriptome, MESH: Adult, MESH: Chemokines, MESH: Male, MESH: Proteome, MESH: Sjogren's Syndrome, MESH: Genome-Wide Association Study, MESH: Biomarkers, MESH: Multigene Family, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Female, MESH: Computational Biology
Abstract

International audience; Abstract There is currently no approved treatment for primary Sjögren’s syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren’s syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials.

Published
2021

30. COVID-19: autoimmunity, multisystemic inflammation and autoimmune rheumatic patients

Author

Szekanecz, Zoltán, primary, Balog, Attila, additional, Constantin, Tamás, additional, Czirják, László, additional, Géher, Pál, additional, Kovács, László, additional, Kumánovics, Gábor, additional, Nagy, György, additional, Rákóczi, Éva, additional, Szamosi, Szilvia, additional, Szűcs, Gabriella, additional, and Vályi-Nagy, István, additional

Published
2022
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36. Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong interaction between the HLA, autoantibodies and the interferon signature

Author

Teruel, María, Barturen, Guillermo, Martínez Bueno, Manuel, Castellini Pérez, Olivia, Barroso Gil, Miguel, Povedano, Elena, Kerick, Martin, Català Moll, Francesc, Makowska, Zuzanna, Buttgereit, Anne, Beretta, Lorenzo, Chizzolini, Carlo, Zuber, Aleksandra, Wynar, Donatienne, Kovács, Laszló, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, Hiepe, Falk, Gerl, Velia, Thiel, Silvia, Rodriguez Maresca, Manuel, López Berrio, Antonio, Aguilar Quesada, Rocío, Navarro Linares, Héctor, Alvarez, Montserrat, Álvarez Errico, Damiana, Azevedo, Nancy, Barbarroja, Nuria, Cheng, Qingyu, Cremer, Jonathan, Groof, Aurélie de, Langhe, Ellen de, Ducreux, Julie, Dufour, Aleksandra, Hernández Fuentes, María, Khodadadi, Laleh, Kniesch, Katja, Li, Tianlu, López Pedrera, Chary, Marañón, Concepción, Muchmore, Brian, Neves, Esmeralda, Rouvière, Bénédicte, Simon, Quentin, Trombetta, Elena, Varela, Nieves, Witte, Torsten, Pers, Jacques-olivier, Ballestar, Esteban, Martin, Javier, Carnero Montoro, Elena, Alarcón Riquelme, Marta, Precisesads Clinical Consortium, Precisesads Flow Cytometry Study Group, Vigone, Barbara, Pers, Jacques Olivier, Saraux, Alain, Devauchelle-Pensec, Valérie, Cornec, Divi, Jousse-Joulin, Sandrine, Lauwerys, Bernard, Maudoux, Anne-lise, Vasconcelos, Carlos, Tavares, Ana, Faria, Raquel, Brandão, Mariana, Campar, Ana, Marinho, António, Farinha, Fátima, Almeida, Isabel, Gonzalez-Gay Mantecón, Miguel Ángel, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Cervera, Ricard, Rodríguez Pintó, Ignasi, Espinosa, Gerard, Lories, Rik, Hunzelmann, Nicolas, Belz, Doreen, Baerlecken, Niklas, Stummvoll, Georg, Zauner, Michael, Lehner, Michaela, Collantes, Eduardo, Ortega Castro, Rafaela, Aguirre Zamorano, Mª Angeles, Escudero Contreras, Alejandro, Castro Villegas, Mª Carmen, Ortego, Norberto, Fernández Roldán, María Concepción, Raya, Enrique, Jiménez Moleón, Inmaculada, Ramon, Enrique de, Díaz Quintero, Isabel, Meroni, Pier Luigi, Gerosa, Maria, Schioppo, Tommaso, Artusi, Carolina, PRECISESADS Clinical Consortium, PRECISESADS Flow Cytometry Study Group, [Teruel,M, Barturen,G, Martínez-Bueno,M, Castellini-Pérez,O, Barroso-Gil,M, Povedano,E, Marañón,C, Carnero-Montoro,E, Alarcón-Riquelme,ME] GENYO, Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government, Granada, Spain. [Kerick,M, Martin,J] IPBLN-CSIC, Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científcas, Granada, Spain. [Català-Moll,F, Ballestar,E] Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), Badalona, Barcelona, Spain. [Català-Moll,F, Ballestar,E] IDIBELL, Bellvitge Biomedical Research Institute L’Hospitalet de Llobregat, Barcelona, Spain. [Makowska,Z, Buttgereit,A] Pharmaceuticals Division, Bayer Pharma Aktiengesellschaft, Berlin, Germany. [Pers,JO] Université de Brest, INSERM, Labex IGO, CHU de Brest, Brest, France.[Alarcón-Riquelme,ME] Institute for Environmental Medicine, Karolinska Institutet, Solna, Sweden., and Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement nº 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies’ in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucía (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuró for design support.

Subjects
Epigenomics, Male, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], Autoimmune diseases, Gene Expression, Quantitative trait, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Interferons [Medical Subject Headings], 0302 clinical medicine, Rheumatic diseases, HLA Antigens, Genetics, Regulation of gene expression, 0303 health sciences, education.field_of_study, Multidisciplinary, Malalties autoimmunitàries, Molecular medicine, Epigenetic, Autoanticuerpos, Genomics, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics::Epigenomics [Medical Subject Headings], 3. Good health, Sjogren's Syndrome, DNA methylation, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::DNA Methylation [Medical Subject Headings], Medicine, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::HLA Antigens [Medical Subject Headings], Epigenetics, Female, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Extracellular matrix organization, Science, Population, Check Tags::Male [Medical Subject Headings], Human leukocyte antigen, Biology, Variación genética, Article, 03 medical and health sciences, Rheumatology, Enfermedades autoinmunes, Diseases::Immune System Diseases::Autoimmune Diseases [Medical Subject Headings], Immunogenetics, Diseases::Immune System Diseases::Autoimmune Diseases::Arthritis, Rheumatoid::Sjogren's Syndrome [Medical Subject Headings], Humans, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies [Medical Subject Headings], education, Gene, 030304 developmental biology, Autoantibodies, 030203 arthritis & rheumatology, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic [Medical Subject Headings], Genetic Variation, DNA Methylation, Epigenètica, Check Tags::Female [Medical Subject Headings], Gene Expression Regulation, Epigenómica, Síndrome de Sjögren, Interferons, Expresión génica
Abstract

Funding for the preparation of this manuscript has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115,565, resources composed of the financial contribution from the European Union's Seventh Framework Program (FP7/2007-2013) and the EFPIA companies' in kind contribution. MT is supported by a Spanish grant from Health Department, Junta de Andalucia (PI/0017/2016) and through the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806975. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA. EC-M was funded by the Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness (FJCI_2014_20652). We thank Ralf Lesche for the production of RNASeq data and Marc Torres Ciuro for design support., Primary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population., Innovative Medicines Initiative Joint Undertaking from the European Union's Seventh Framework Program (FP7/2007-2013) 115,565, EFPIA companies, Junta de Andalucia PI/0017/2016, Innovative Medicines Initiative 2 Joint Undertaking 806975 European Union's Horizon 2020 research and innovation programme, EFPIA, Postdoctoral Training Subprogramme Juan de la Cierva-Ministry of Economy and Competitiveness FJCI_2014_20652

Published
2021

37. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

Barturen, Guillermo, Babaei, Sepideh, Catala-Moll, Francesc, Martinez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugan, Jordi, Carmona-Saez, Pedro, Toro-Dominguez, Daniel, Carnero-Montoro, Elena, Teruel, Maria, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodriguez-Ubreva, Javier, Garcia-Gomez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Maranon, Concepcion, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocio, Garrancho, Francisco Javier, Lopez-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Hector, Almeida, Isabel, Azevedo, Nancy, Brandao, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fatima, Marinho, Antonio, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martinez, Alfonso, Genre, Fernanda, Lopez Mejias, Raquel, Gonzalez-Gay, Miguel A., Remuzgo, Sara, Ubilla Garcia, Begona, Cervera, Ricard, Espinosa, Gerard, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Diaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernandez Roldan, Maria Concepcion, Jimenez Gomez, Yolanda, Jimenez Moleon, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurelie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valerie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouviere, Benedicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, Dufour, Aleksandra, Wynar, Donatienne, Balog, Attila, Bocskai, Marta, Deak, Magdolna, Dulic, Sonja, Kadar, Gabriella, Kovacs, Laszlo, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegard, Johan, Martin, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, Alarcon-Riquelme, Marta E., Barturen, Guillermo, Babaei, Sepideh, Catala-Moll, Francesc, Martinez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugan, Jordi, Carmona-Saez, Pedro, Toro-Dominguez, Daniel, Carnero-Montoro, Elena, Teruel, Maria, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodriguez-Ubreva, Javier, Garcia-Gomez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Maranon, Concepcion, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocio, Garrancho, Francisco Javier, Lopez-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Hector, Almeida, Isabel, Azevedo, Nancy, Brandao, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fatima, Marinho, Antonio, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martinez, Alfonso, Genre, Fernanda, Lopez Mejias, Raquel, Gonzalez-Gay, Miguel A., Remuzgo, Sara, Ubilla Garcia, Begona, Cervera, Ricard, Espinosa, Gerard, Rodriguez-Pinto, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Diaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernandez Roldan, Maria Concepcion, Jimenez Gomez, Yolanda, Jimenez Moleon, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurelie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valerie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouviere, Benedicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, Dufour, Aleksandra, Wynar, Donatienne, Balog, Attila, Bocskai, Marta, Deak, Magdolna, Dulic, Sonja, Kadar, Gabriella, Kovacs, Laszlo, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Benschop, Robert J., Chamberlain, Chris, Dow, Ernst R., Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegard, Johan, Martin, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, and Alarcon-Riquelme, Marta E.

Abstract

Objective Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. Methods Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. Results Four clusters were identified and validated. Three were pathologic, representing inflammatory, lymphoid, and interferon patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. Conclusion Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Published
2021

38. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.

Author

UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Alarcón-Riquelme, Marta E, Benschop, Robert J, Balog, Attila, Bocskai, Márta, Deák, Magdolna, Dulic, Sonja, Kádár, Gabriella, Kovács, László, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Chamberlain, Chris, Dufour, Aleksandra, Dow, Ernst R, Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegård, Johan, Martín, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, Wynar, Donatienne, Barturen, Guillermo, Babaei, Sepideh, Català-Moll, Francesc, Martínez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugán, Jordi, Carmona-Sáez, Pedro, Toro-Domínguez, Daniel, Carnero-Montoro, Elena, Teruel, María, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodríguez-Ubreva, Javier, García-Gómez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Marañón, Concepción, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocío, Garrancho, Francisco Javier, López-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Héctor, Almeida, Isabel, Azevedo, Nancy, Brandão, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fátima, Marinho, António, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Genre, Fernanda, López Mejías, Raquel, Gonzalez-Gay, Miguel A, Remuzgo, Sara, Ubilla Garcia, Begoña, Cervera, Ricard, Espinosa, Gerard, Rodríguez-Pintó, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Díaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernández Roldán, María Concepción, Jiménez Gómez, Yolanda, Jiménez Moleón, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurélie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valérie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouvière, Bénédicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, Chizzolini, Carlo, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Alarcón-Riquelme, Marta E, Benschop, Robert J, Balog, Attila, Bocskai, Márta, Deák, Magdolna, Dulic, Sonja, Kádár, Gabriella, Kovács, László, Cheng, Qingyu, Gerl, Velia, Hiepe, Falk, Khodadadi, Laleh, Thiel, Silvia, de Rinaldis, Emanuele, Rao, Sambasiva, Chamberlain, Chris, Dufour, Aleksandra, Dow, Ernst R, Ioannou, Yiannis, Laigle, Laurence, Marovac, Jacqueline, Wojcik, Jerome, Renaudineau, Yves, Borghi, Maria Orietta, Frostegård, Johan, Martín, Javier, Beretta, Lorenzo, Ballestar, Esteban, McDonald, Fiona, Pers, Jacques-Olivier, Wynar, Donatienne, Barturen, Guillermo, Babaei, Sepideh, Català-Moll, Francesc, Martínez-Bueno, Manuel, Makowska, Zuzanna, Martorell-Marugán, Jordi, Carmona-Sáez, Pedro, Toro-Domínguez, Daniel, Carnero-Montoro, Elena, Teruel, María, Kerick, Martin, Acosta-Herrera, Marialbert, Le Lann, Lucas, Jamin, Christophe, Rodríguez-Ubreva, Javier, García-Gómez, Antonio, Kageyama, Jorge, Buttgereit, Anne, Hayat, Sikander, Mueller, Joerg, Lesche, Ralf, Hernandez-Fuentes, Maria, Juarez, Maria, Rowley, Tania, White, Ian, Marañón, Concepción, Gomes Anjos, Tania, Varela, Nieves, Aguilar-Quesada, Rocío, Garrancho, Francisco Javier, López-Berrio, Antonio, Rodriguez Maresca, Manuel, Navarro-Linares, Héctor, Almeida, Isabel, Azevedo, Nancy, Brandão, Mariana, Campar, Ana, Faria, Raquel, Farinha, Fátima, Marinho, António, Neves, Esmeralda, Tavares, Ana, Vasconcelos, Carlos, Trombetta, Elena, Montanelli, Gaia, Vigone, Barbara, Alvarez-Errico, Damiana, Li, Tianlu, Thiagaran, Divya, Blanco Alonso, Ricardo, Corrales Martínez, Alfonso, Genre, Fernanda, López Mejías, Raquel, Gonzalez-Gay, Miguel A, Remuzgo, Sara, Ubilla Garcia, Begoña, Cervera, Ricard, Espinosa, Gerard, Rodríguez-Pintó, Ignasi, De Langhe, Ellen, Cremer, Jonathan, Lories, Rik, Belz, Doreen, Hunzelmann, Nicolas, Baerlecken, Niklas, Kniesch, Katja, Witte, Torsten, Lehner, Michaela, Stummvoll, Georg, Zauner, Michael, Aguirre-Zamorano, Maria Angeles, Barbarroja, Nuria, Castro-Villegas, Maria Carmen, Collantes-Estevez, Eduardo, de Ramon, Enrique, Díaz Quintero, Isabel, Escudero-Contreras, Alejandro, Fernández Roldán, María Concepción, Jiménez Gómez, Yolanda, Jiménez Moleón, Inmaculada, Lopez-Pedrera, Rosario, Ortega-Castro, Rafaela, Ortego, Norberto, Raya, Enrique, Artusi, Carolina, Gerosa, Maria, Meroni, Pier Luigi, Schioppo, Tommaso, De Groof, Aurélie, Ducreux, Julie, Lauwerys, Bernard, Maudoux, Anne-Lise, Cornec, Divi, Devauchelle-Pensec, Valérie, Jousse-Joulin, Sandrine, Jouve, Pierre-Emmanuel, Rouvière, Bénédicte, Saraux, Alain, Simon, Quentin, Alvarez, Montserrat, and Chizzolini, Carlo

Abstract

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Published
2021

39. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

Barturen, Guillermo, primary, Babaei, Sepideh, additional, Català‐Moll, Francesc, additional, Martínez‐Bueno, Manuel, additional, Makowska, Zuzanna, additional, Martorell‐Marugán, Jordi, additional, Carmona‐Sáez, Pedro, additional, Toro‐Domínguez, Daniel, additional, Carnero‐Montoro, Elena, additional, Teruel, María, additional, Kerick, Martin, additional, Acosta‐Herrera, Marialbert, additional, Le Lann, Lucas, additional, Jamin, Christophe, additional, Rodríguez‐Ubreva, Javier, additional, García‐Gómez, Antonio, additional, Kageyama, Jorge, additional, Buttgereit, Anne, additional, Hayat, Sikander, additional, Mueller, Joerg, additional, Lesche, Ralf, additional, Hernandez‐Fuentes, Maria, additional, Juarez, Maria, additional, Rowley, Tania, additional, White, Ian, additional, Marañón, Concepción, additional, Gomes Anjos, Tania, additional, Varela, Nieves, additional, Aguilar‐Quesada, Rocío, additional, Garrancho, Francisco Javier, additional, López‐Berrio, Antonio, additional, Rodriguez Maresca, Manuel, additional, Navarro‐Linares, Héctor, additional, Almeida, Isabel, additional, Azevedo, Nancy, additional, Brandão, Mariana, additional, Campar, Ana, additional, Faria, Raquel, additional, Farinha, Fátima, additional, Marinho, António, additional, Neves, Esmeralda, additional, Tavares, Ana, additional, Vasconcelos, Carlos, additional, Trombetta, Elena, additional, Montanelli, Gaia, additional, Vigone, Barbara, additional, Alvarez‐Errico, Damiana, additional, Li, Tianlu, additional, Thiagaran, Divya, additional, Blanco Alonso, Ricardo, additional, Corrales Martínez, Alfonso, additional, Genre, Fernanda, additional, López Mejías, Raquel, additional, Gonzalez‐Gay, Miguel A., additional, Remuzgo, Sara, additional, Ubilla Garcia, Begoña, additional, Cervera, Ricard, additional, Espinosa, Gerard, additional, Rodríguez‐Pintó, Ignasi, additional, De Langhe, Ellen, additional, Cremer, Jonathan, additional, Lories, Rik, additional, Belz, Doreen, additional, Hunzelmann, Nicolas, additional, Baerlecken, Niklas, additional, Kniesch, Katja, additional, Witte, Torsten, additional, Lehner, Michaela, additional, Stummvoll, Georg, additional, Zauner, Michael, additional, Aguirre‐Zamorano, Maria Angeles, additional, Barbarroja, Nuria, additional, Castro‐Villegas, Maria Carmen, additional, Collantes‐Estevez, Eduardo, additional, Ramon, Enrique, additional, Díaz Quintero, Isabel, additional, Escudero‐Contreras, Alejandro, additional, Fernández Roldán, María Concepción, additional, Jiménez Gómez, Yolanda, additional, Jiménez Moleón, Inmaculada, additional, Lopez‐Pedrera, Rosario, additional, Ortega‐Castro, Rafaela, additional, Ortego, Norberto, additional, Raya, Enrique, additional, Artusi, Carolina, additional, Gerosa, Maria, additional, Meroni, Pier Luigi, additional, Schioppo, Tommaso, additional, De Groof, Aurélie, additional, Ducreux, Julie, additional, Lauwerys, Bernard, additional, Maudoux, Anne‐Lise, additional, Cornec, Divi, additional, Devauchelle‐Pensec, Valérie, additional, Jousse‐Joulin, Sandrine, additional, Jouve, Pierre‐Emmanuel, additional, Rouvière, Bénédicte, additional, Saraux, Alain, additional, Simon, Quentin, additional, Alvarez, Montserrat, additional, Chizzolini, Carlo, additional, Dufour, Aleksandra, additional, Wynar, Donatienne, additional, Balog, Attila, additional, Bocskai, Márta, additional, Deák, Magdolna, additional, Dulic, Sonja, additional, Kádár, Gabriella, additional, Kovács, László, additional, Cheng, Qingyu, additional, Gerl, Velia, additional, Hiepe, Falk, additional, Khodadadi, Laleh, additional, Thiel, Silvia, additional, Rinaldis, Emanuele, additional, Rao, Sambasiva, additional, Benschop, Robert J., additional, Chamberlain, Chris, additional, Dow, Ernst R., additional, Ioannou, Yiannis, additional, Laigle, Laurence, additional, Marovac, Jacqueline, additional, Wojcik, Jerome, additional, Renaudineau, Yves, additional, Borghi, Maria Orietta, additional, Frostegård, Johan, additional, Martín, Javier, additional, Beretta, Lorenzo, additional, Ballestar, Esteban, additional, McDonald, Fiona, additional, Pers, Jacques‐Olivier, additional, and Alarcón‐Riquelme, Marta E., additional

Published
2021
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41. Kynurenic Acid Analog Attenuates the Production of Tumor Necrosis Factor-α, Calgranulins (S100A 8/9 and S100A 12), and the Secretion of HNP1–3 and Stimulates the Production of Tumor Necrosis Factor-Stimulated Gene-6 in Whole Blood Cultures of Patients With Rheumatoid Arthritis

Author

Balog, Attila, primary, Varga, Borisz, additional, Fülöp, Ferenc, additional, Lantos, Ildikó, additional, Toldi, Gergely, additional, Vécsei, László, additional, and Mándi, Yvette, additional

Published
2021
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42. TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis

Author

Clanchy, Felix I.L., primary, Borghese, Federica, additional, Bystrom, Jonas, additional, Balog, Attila, additional, Penn, Henry, additional, Hull, Dobrina N., additional, Wells, Graham M.A., additional, Kiriakidis, Serafim, additional, Taylor, Peter C., additional, Sacre, Sandra M., additional, Williams, Lynn M., additional, Stone, Trevor W., additional, Mageed, Rizgar A., additional, and Williams, Richard O., additional

Published
2021
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43. IgM antibodies against malondialdehyde and phosphorylcholine in different systemic rheumatic diseases

Author

Thiagarajan, Divya, Oparina, Nina, Lundström, Susanna, Zubarev, Roman, Sun, Jitong, PRECISESADS, Clinical Consortium, Alarcón-Riquelme, Marta, Frostegård, Johan, Kovács, László, Balog, Attila, Deák, Magdolna, Bocskai, Márta, Dulic, Sonja, Kádár, Gabriella, The PRECISESADS Clinical Consortium, [Thiagarajan,D, Oparina,N, Sun,J, Alarcon-Riquelme,M, Frostegård,J] Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. [Lundström,S, Zubarev,R] Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. [Alarcon-Riquelme,M] GENYO, Center for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Government, Parque tecnolуgico de la salud, Granada, Spain., and PRECISESADS Clinical Consortium Members: Te research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115565, resources of which are composed of fnancial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies in kind contribution. Swedish Heart Lung foundation and Swedish Rheumatism Association also contributed to fnancing. Open access funding provided by Karolinska Institute.

Subjects
Male, Proteomics, lcsh:Medicine, Malondialdehído, 030204 cardiovascular system & hematology, Inmunoglobulina M, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, 0302 clinical medicine, Mixed connective tissue disease, Rheumatic diseases, Malondialdehyde, lcsh:Science, skin and connective tissue diseases, Chemicals and Drugs::Organic Chemicals::Aldehydes::Malondialdehyde [Medical Subject Headings], Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Aged, 80 and over, Multidisciplinary, biology, medicine.diagnostic_test, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Undifferentiated connective tissue disease, Fosforilcolina, Enfermedades reumáticas, Middle Aged, Diseases::Musculoskeletal Diseases::Rheumatic Diseases [Medical Subject Headings], Female, Antibody, Persons::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Serum Globulins::Immunoglobulins::Antibodies::Autoantibodies [Medical Subject Headings], Adult, IgM, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biochemistry::Proteomics [Medical Subject Headings], Phosphorylcholine, Check Tags::Male [Medical Subject Headings], Immunoglobulins, Artritis reumatoide, Article, Flow cytometry, 03 medical and health sciences, Young Adult, Rheumatology, Rheumatic Diseases, medicine, Humans, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Serum Globulins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin M [Medical Subject Headings], Rheumatoid arthritis, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Aged, Autoantibodies, 030203 arthritis & rheumatology, business.industry, lcsh:R, Autoantibody, Case-control study, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], medicine.disease, Proteómica, chemistry, Check Tags::Female [Medical Subject Headings], Immunoglobulin M, Persons::Persons::Age Groups::Adult::Aged::Aged, 80 and over [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Amines::Quaternary Ammonium Compounds::Trimethyl Ammonium Compounds::Choline::Phosphorylcholine [Medical Subject Headings], Case-Control Studies, Immunology, biology.protein, lcsh:Q, business, Immunoglobulines
Abstract

IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. Anti-PC and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective tissue disease (MCTD, 77), Systemic sclerosis (SSc, 331), Sjögren’s syndrome (SjS, 324), primary antiphospholipid syndrome (PAPs, 65), undifferentiated connective tissue disease (UCTD, 118) and 515 matched healthy controls (HC). Cardiovascular score (CV) was broadly defined based on clinical disease symptoms. Anti-PC and anti-MDA peptide/protein characterization were compared using a proteomics de novo sequencing approach. anti-MDA and anti-PC were extracted from total IgM. The proportion of Treg cells was determined by flow cytometry. The maximal difference between cases and controls was shown for MCTD: significantly lower IgM Anti-PC but not anti-MDA among patients (median 49.3RU/ml vs 70.4 in healthy controls, p(t-test) = 0.0037). IgM low levels were more prevalent in MCTD, SLE, SjS, SSc and UCTD. IgM anti-PC variable region profiles were different from and more homologous than anti-MDA. Anti-PC but not anti-MDA were significantly negatively correlated with CV in the whole patient group. In contrast to IgM anti-PC, anti-MDA did not promote polarization of Tregs. Taken together, Anti-PC is decreased in MCTD and also in SLE, SjS and SSc but not in other studied diseases. Anti-PC may thus differentiate between these. In contrast, anti-MDA did not show these differences between diseases studied. Anti-PC level is negatively correlated with CV in the patient group cohort. In contrast to anti-PC, anti-MDA did not promote Treg polarization. These findings could have both diagnostic and therapeutic implications, one possibility being active or passive immunization with PC in some rheumatic conditions.

Published
2020

44. COVID-19: a citokinviharon innen és túl

Author

Szekanecz Zoltán, Bálint Péter Vince, Balog Attila, Barta Zsolt, Czirják László, Géher Pál, Kovács László, Kumánovics Gábor, Nagy György, Rákóczi Éva, Szamosi Szilvia, Szűcs Gabriella, Vályi-Nagy István, Várkonyi István, and Constantin Tamás

Published
2020

45. Standardization procedure for flow cytometry data harmonization in prospective multicenter studies

Author

Lann, Le, Lucas, Jouve, Pierre-Emmanuel, Alarcón-Riquelme, Marta, Jamin, Christophe, PRECISESADS, Flow Cytometry Study Group, PRECISESADS, Clinical Consortium, Balog, Attila, Bocskai, Márta, Deák, Magdolna, Dulic, Sonja, Kádár, Gabriella, and Kovács, László

Abstract

One of the most challenging objective for clinical cytometry in prospective multicenter immunomonitoring trials is to compare frequencies, absolute numbers of leukocyte populations and further the mean fluorescence intensities of cell markers, especially when the data are generated from different instruments. Here, we describe an innovative standardization workflow to compare all data to carry out any large-scale, prospective multicentric flow cytometry analysis whatever the duration, the number or type of instruments required for the realization of such projects.

Published
2020

48. O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases

Author

Barturen, Guillermo, primary, Babaei, Sepideh, additional, Català-Moll, Francesc, additional, Martínez-Bueno, Manuel, additional, Makowska, Zuzanna, additional, Martorell-Marugán, Jordi, additional, Carmona-Sáez, Pedro, additional, Toro-Domínguez, Daniel, additional, Carnero-Montoro, Elena, additional, Kerick, Martin, additional, Acosta-Herrera, Marialbert, additional, Lann, Lucas Le, additional, Jamin, Christophe, additional, Rodríguez-Ubreva, Javier, additional, García-Gómez, Antonio, additional, Kageyama, Jorge, additional, Buttgereit, Anne, additional, Hayat, Sikander, additional, Mueller, Joerg, additional, Lesche, Ralf, additional, Hernandez-Fuentes, Maria, additional, Juarez, Maria, additional, Rowley, Tania, additional, White, Ian, additional, Marañón, Concepción, additional, Anjos, Tania Gomes, additional, Varela, Nieves, additional, Aguilar-Quesada, Rocío, additional, Garrancho, Francisco Javier, additional, López-Berrio, Antonio, additional, Maresca, Manuel Rodriguez, additional, Navarro-Linares, Héctor, additional, Almeida, Isabel, additional, Azevedo, Nancy, additional, Brandão, Mariana, additional, Campar, Ana, additional, Faria, Raquel, additional, Farinha, Fátima, additional, Marinho, António, additional, Neves, Esmeralda, additional, Tavares, Ana, additional, Vasconcelos, Carlos, additional, Trombetta, Elena, additional, Montanelli, Gaia, additional, Vigone, Barbara, additional, Alvarez-Errico, Damiana, additional, Li, Tianlu, additional, Alonso, Ricardo Blanco, additional, Martínez, Alfonso Corrales, additional, Genre, Fernanda, additional, Mejías, Raquel López, additional, Gonzalez-Gay, Miguel A, additional, Remuzgo, Sara, additional, Garcia, Begoña Ubilla, additional, Cervera, Ricard, additional, Espinosa, Gerard, additional, Rodríguez-Pintó, Ignasi, additional, Langhe, Ellen De, additional, Cremer, Jonathan, additional, Lories, Rik, additional, Belz, Doreen, additional, Hunzelmann, Nicolas, additional, Baerlecken, Niklas, additional, Kniesch, Katja, additional, Witte, Torsten, additional, Lehner, Michaela, additional, Stummvoll, Georg, additional, Zauner, Michael, additional, Aguirre-Zamorano, Maria Angeles, additional, Barbarroja, Nuria, additional, Castro-Villegas, Maria Carmen, additional, Collantes-Estevez, Eduardo, additional, Ramon, Enrique de, additional, Quintero, Isabel Díaz, additional, Escudero-Contreras, Alejandro, additional, Roldán, María Concepción Fernández, additional, Gómez, Yolanda Jiménez, additional, Moleón, Inmaculada Jiménez, additional, Lopez-Pedrera, Rosario, additional, Ortega-Castro, Rafaela, additional, Ortego, Norberto, additional, Raya, Enrique, additional, Artusi, Carolina, additional, Gerosa, Maria, additional, Meroni, Pier Luigi, additional, Schioppo, Tommaso, additional, Groof, Aurélie De, additional, Ducreux, Julie, additional, Lauwerys, Bernard, additional, Maudoux, Anne-Lise, additional, Cornec, Divi, additional, Devauchelle-Pensec, Valérie, additional, Jousse-Joulin, Sandrine, additional, Jouve, Pierre-Emmanuel, additional, Rouvière, Bénédicte, additional, Saraux, Alain, additional, Simon, Quentin, additional, Alvarez, Montserrat, additional, Chizzolini, Carlo, additional, Dufour, Aleksandra, additional, Wynar, Donatienne, additional, Balog, Attila, additional, Bocskai, Márta, additional, Deák, Magdolna, additional, Dulic, Sonja, additional, Kádár, Gabriella, additional, Kovács, László, additional, Cheng, Qingyu, additional, Gerl, Velia, additional, Hiepe, Falk, additional, Khodadadi, Laleh, additional, Thiel, Silvia, additional, Rinaldis, Emanuele de, additional, Rao, Sambasiva, additional, Benschop, Robert J, additional, Chamberlain, Chris, additional, Dow, Ernst R, additional, Ioannou, Yiannis, additional, Laigle, Laurence, additional, Marovac, Jacqueline, additional, Wojcik, Jerome, additional, Renaudineau, Yves, additional, Borghi, Maria Orietta, additional, Frostegård, Johan, additional, Martín, Javier, additional, Beretta, Lorenzo, additional, Ballestar, Esteban, additional, McDonald, Fiona, additional, Pers, Jacques-Olivier, additional, and Alarcón-Riquelme, Marta E, additional

Published
2020
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49. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Author

Barturen, Guillermo, primary, Babaei, Sepideh, additional, Català-Moll, Francesc, additional, Martínez-Bueno, Manuel, additional, Makowska, Zuzanna, additional, Martorell-Marugán, Jordi, additional, Carmona-Sáez, Pedro, additional, Toro-Domínguez, Daniel, additional, Carnero-Montoro, Elena, additional, Teruel, María, additional, Kerick, Martin, additional, Acosta-Herrera, Marialbert, additional, Lann, Lucas Le, additional, Jamin, Christophe, additional, Rodríguez-Ubreva, Javier, additional, García-Gómez, Antonio, additional, Kageyama, Jorge, additional, Buttgereit, Anne, additional, Hayat, Sikander, additional, Mueller, Joerg, additional, Lesche, Ralf, additional, Hernandez-Fuentes, Maria, additional, Juarez, Maria, additional, Rowley, Tania, additional, White, Ian, additional, Marañón, Concepción, additional, Anjos, Tania Gomes, additional, Varela, Nieves, additional, Aguilar-Quesada, Rocío, additional, Garrancho, Francisco Javier, additional, López-Berrio, Antonio, additional, Maresca, Manuel Rodriguez, additional, Navarro-Linares, Héctor, additional, Almeida, Isabel, additional, Azevedo, Nancy, additional, Brandão, Mariana, additional, Campar, Ana, additional, Faria, Raquel, additional, Farinha, Fátima, additional, Marinho, António, additional, Neves, Esmeralda, additional, Tavares, Ana, additional, Vasconcelos, Carlos, additional, Trombetta, Elena, additional, Montanelli, Gaia, additional, Vigone, Barbara, additional, Alvarez-Errico, Damiana, additional, Li, Tianlu, additional, Alonso, Ricardo Blanco, additional, Martínez, Alfonso Corrales, additional, Genre, Fernanda, additional, López Mejías, Raquel, additional, Gonzalez-Gay, Miguel A., additional, Remuzgo, Sara, additional, Garcia, Begoña Ubilla, additional, Cervera, Ricard, additional, Espinosa, Gerard, additional, Rodríguez-Pintó, Ignasi, additional, De Langhe, Ellen, additional, Cremer, Jonathan, additional, Lories, Rik, additional, Belz, Doreen, additional, Hunzelmann, Nicolas, additional, Baerlecken, Niklas, additional, Kniesch, Katja, additional, Witte, Torsten, additional, Lehner, Michaela, additional, Stummvoll, Georg, additional, Zauner, Michael, additional, Aguirre-Zamorano, Maria Angeles, additional, Barbarroja, Nuria, additional, Castro-Villegas, Maria Carmen, additional, Collantes-Estevez, Eduardo, additional, de Ramon, Enrique, additional, Díaz Quintero, Isabel, additional, Escudero-Contreras, Alejandro, additional, Fernández Roldán, María Concepción, additional, Jiménez Gómez, Yolanda, additional, Jiménez Moleón, Inmaculada, additional, Lopez-Pedrera, Rosario, additional, Ortega-Castro, Rafaela, additional, Ortego, Norberto, additional, Raya, Enrique, additional, Artusi, Carolina, additional, Gerosa, Maria, additional, Meroni, Pier Luigi, additional, Schioppo, Tommaso, additional, De Groof, Aurélie, additional, Ducreux, Julie, additional, Lauwerys, Bernard, additional, Maudoux, Anne-Lise, additional, Cornec, Divi, additional, Devauchelle-Pensec, Valérie, additional, Jousse-Joulin, Sandrine, additional, Jouve, Pierre-Emmanuel, additional, Rouvière, Bénédicte, additional, Saraux, Alain, additional, Simon, Quentin, additional, Alvarez, Montserrat, additional, Chizzolini, Carlo, additional, Dufour, Aleksandra, additional, Wynar, Donatienne, additional, Balog, Attila, additional, Bocskai, Márta, additional, Deák, Magdolna, additional, Dulic, Sonja, additional, Kádár, Gabriella, additional, Kovács, László, additional, Cheng, Qingyu, additional, Gerl, Velia, additional, Hiepe, Falk, additional, Khodadadi, Laleh, additional, Thiel, Silvia, additional, de Rinaldis, Emanuele, additional, Rao, Sambasiva, additional, J.Benschop, Robert, additional, Chamberlain, Chris, additional, Dow, Ernst R., additional, Ioannou, Yiannis, additional, Laigle, Laurence, additional, Marovac, Jacqueline, additional, Wojcik, Jerome, additional, Renaudineau, Yves, additional, Borghi, Maria Orietta, additional, Frostegård, Johan, additional, Martín, Javier, additional, Beretta, Lorenzo, additional, Ballestar, Esteban, additional, McDonald, Fiona, additional, Pers, Jacques-Olivier, additional, and Alarcón-Riquelme, Marta E., additional

Published
2020
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