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1. SARS-CoV-2 infection after vaccination in patients with inflammatory rheumatic and musculoskeletal diseases

Author: Anja Strangfeld, Ana M. Rodrigues, Loreto Carmona, Ludovic Trefond, Charalampos Papagoras, Laure Gossec, N Roux, Kimme L. Hyrich, Saskia Lawson-Tovey, Bernd Raffeiner, Elsa F Mateus, Gözde Kübra Yardımcı, Pedro Machado, Xavier Mariette, NIHR Manchester Biomedical Research Centre [Manchester] (BRC [Manchester]), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Centre for Genetics and Genomics Versus Arthritis, Centre for Epidemiology Versus Arthritis, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Instituto de Salud Musculoesqueletica (InMusc), Central Hospital of Bolzano, Faculty of Medicine [Hacettepe University], Hacettepe University = Hacettepe Üniversitesi, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Service de Médecine Interne [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Hôpital privé Robert-Schuman, Metz, France., Sociedade Portuguesa de Reumatologia [Lisboa], Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Democritus University of Thrace (DUTH), Liga Portuguesa Contra as Doenças Reumaticas (LPCDR), EULAR PARE [Zurich, Switzerland], Université Paris-Saclay, Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, University College of London [London] (UCL), NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University College London Hospitals (UCLH), London North West University Healthcare NHS Trust (LNWH), European Alliance of Associations for Rheumatology, Service de Rhumatologie [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Molé, Christine
Subjects: Male, medicine.medical_specialty, COVID-19 Vaccines, Immunology, Population, Comorbidity, General Biochemistry, Genetics and Molecular Biology, Rheumatology, Rheumatic Diseases, Internal medicine, Epidemiology, medicine, Humans, Immunology and Allergy, Registries, Adverse effect, education, Aged, Aged, 80 and over, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, education.field_of_study, business.industry, Abatacept, COVID-19, Middle Aged, vaccination, Vaccine efficacy, Vaccination, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Antirheumatic Agents, Hypertension, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, epidemiology, Rituximab, business, medicine.drug
Abstract: Patients with inflammatory rheumatic and musculoskeletal diseases (iRMDs) are often treated with immunomodulatory or immunosuppressive medications; consequently, they have been excluded alongside other immunocompromised patients from late stages of SARS-CoV-2 vaccine trials. SARS-CoV-2 vaccine efficacy in this population is unclear, though initial data are reassuring overall. However, a slightly lower SARS-CoV-2 immunogenicity of vaccines has been documented in some patients with iRMD.1 2 Some common rheumatic and musculoskeletal disease (RMD) medications have been highlighted as possible influential factors on immunogenicity, particularly rituximab (RTX), mycophenolate mofetil (MMF), methotrexate (MTX), abatacept and glucocorticoids.3–7 The European Alliance of Associations for Rheumatology (EULAR) launched a COVID-19 registry in March 2020, capturing COVID-19 outcomes in the European RMD population. Questions on reinfection and vaccination were added in January 2021. A further EULAR registry (COVAX) was launched in February 2021 to collect data on COVID-19 vaccination and related adverse events among patients with RMD. Here we describe a series of patients who contracted SARS-CoV-2 infection after COVID-19 vaccination between 19 January 2021 and 27 July 2021. The series consists of 38 adults with iRMDs, 8 from the COVID-19 registry (
Published: 2021
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2. EULAR points to consider when analysing and reporting comparative effectiveness research using observational data in rheumatology

Author: Courvoisier, Delphine Sophie, Lauper, Kim, Kedra, Joanna, de Wit, Maarten, Fautrel, Bruno, Frisell, Thomas, Hyrich, Kimme, Iannone, Florenzo, Machado, Pedro, Ørnbjerg, Lykke Midtbøll, Rotar, Ziga, Santos, Maria Jose, Stamm, Tanja, Stones, Simon, Strangfeld, Anja, Bergstra, Sytske Anne, Landewé, Robert, Finckh, Axel, Courvoisier, Delphine, Ørnbjerg, Lykke, Santos, Maria, Bergstra, Sytske, Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Université de Genève = University of Geneva (UNIGE), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), VU University Medical Center [Amsterdam], Service de Rhumatologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Karolinska Institutet [Stockholm], University of Manchester [Manchester], Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Department of Genetics [Cambridge], University of Cambridge [UK] (CAM), Center for Healthy Aging [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), University of Ljubljana, Hospital Garcia de Orta (EPE), Medizinische Universität Wien = Medical University of Vienna, University of Leeds, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Leiden University Medical Center (LUMC), Dpt of Clinical Immunology & Rheumatology [Amsterdam], Amsterdam and Atrium Medical Center, and Gestionnaire, HAL Sorbonne Université 5
Subjects: ddc:616, Comparative Effectiveness Research, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, endocrine system diseases, Epidemiology, Advisory Committees, Immunology, Health care, Reproducibility of Results, Patient reported outcome measures, health care, General Biochemistry, Genetics and Molecular Biology, Outcome assessment, Bias, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatology, patient reported outcome measures, Humans, Immunology and Allergy, epidemiology, outcome assessment
Abstract: BackgroundComparing treatment effectiveness over time in observational settings is hampered by several major threats, among them confounding and attrition bias.ObjectivesTo develop European Alliance of Associations for Rheumatology (EULAR) points to consider (PtC) when analysing and reporting comparative effectiveness research using observational data in rheumatology.MethodsThe PtC were developed using a three-step process according to the EULAR Standard Operating Procedures. Based on a systematic review of methods currently used in comparative effectiveness studies, the PtC were formulated through two in-person meetings of a multidisciplinary task force and a two-round online Delphi, using expert opinion and a simulation study. Finally, feedback from a larger audience was used to refine the PtC. Mean levels of agreement among the task force were calculated.ResultsThree overarching principles and 10 PtC were formulated, addressing, in particular, potential biases relating to attrition or confounding by indication. Building on Strengthening the Reporting of Observational Studies in Epidemiology guidelines, these PtC insist on the definition of the baseline for analysis and treatment effectiveness. They also focus on the reasons for stopping treatment as an important consideration when assessing effectiveness. Finally, the PtC recommend providing key information on missingness patterns.ConclusionTo improve the reliability of an increasing number of real-world comparative effectiveness studies in rheumatology, special attention is required to reduce potential biases. Adherence to clear recommendations for the analysis and reporting of observational comparative effectiveness studies will improve the trustworthiness of their results.
Published: 2022
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3. Safety of Vaccination against SARS-CoV-2 in People with Rheumatic and Musculoskeletal Diseases: Results from the EULAR Coronavirus Vaccine (COVAX) Physician-Reported Registry

Author: Pedro M Machado, Saskia Lawson-Tovey, Anja Strangfeld, Elsa F Mateus, Kimme L Hyrich, Laure Gossec, Loreto Carmona, Ana Rodrigues, Bernd Raffeiner, Catia Duarte, Eric Hachulla, Eric Veillard, Eva Strakova, Gerd R Burmester, Gözde Kübra Yardımcı, Jose A Gomez-Puerta, Julija Zepa, Lianne Kearsley-Fleet, Ludovic Trefond, Maria Cunha, Marta Mosca, Martina Cornalba, Martin Soubrier, Nicolas Roux, Olivier Brocq, Patrick Durez, Richard Conway, Tiphaine Goulenok, Johannes WJ Bijlsma, Iain B McInnes, Xavier Mariette, University College London Hospitals (UCLH), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Centre for Genetics and Genomics Versus Arthritis, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Instituto de Salud Musculoesqueletica (InMusc), Central Hospital of Bolzano, Centro Hospitalar e Universitário [Coimbra], CHU Lille, Department of Rheumatology and Clinical Immunology, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Faculty of Medicine [Hacettepe University], Hacettepe University = Hacettepe Üniversitesi, Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Service de Médecine Interne [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, University of Pisa - Università di Pisa, CHU Clermont-Ferrand, Hôpital Princesse Grace [Monaco], Cliniques Universitaires Saint-Luc [Bruxelles], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center [Utrecht], Hôpital Bicêtre, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, and UCL - (SLuc) Service de rhumatologie
Subjects: Male, COVID-19 Vaccines, antirheumatic agents, Epidemiology, [SDV]Life Sciences [q-bio], Immunology, General Biochemistry, Genetics and Molecular Biology, Rheumatology, Muscular Diseases, Rheumatic Diseases, Immunology and Allergy, Humans, autoimmune diseases, Musculoskeletal Diseases, Registries, skin and connective tissue diseases, Aged, SARS-CoV-2, Vaccination, COVID-19, Middle Aged, Female, epidemiology, Rheumatologists, Immunosuppressive Agents
Abstract: ObjectivesTo describe the safety of vaccines against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal disease (I-RMD).MethodsPhysician-reported registry of I-RMD and non-inflammatory RMD (NI-RMDs) patients vaccinated against SARS-CoV-2. From 5 February 2021 to 27 July 2021, we collected data on demographics, vaccination, RMD diagnosis, disease activity, immunomodulatory/immunosuppressive treatments, flares, adverse events (AEs) and SARS-CoV-2 breakthrough infections. Data were analysed descriptively.ResultsThe study included 5121 participants from 30 countries, 90% with I-RMDs (n=4604, 68% female, mean age 60.5 years) and 10% with NI-RMDs (n=517, 77% female, mean age 71.4). Inflammatory joint diseases (58%), connective tissue diseases (18%) and vasculitis (12%) were the most frequent diagnostic groups; 54% received conventional synthetic disease-modifying antirheumatic drugs (DMARDs), 42% biological DMARDs and 35% immunosuppressants. Most patients received the Pfizer/BioNTech vaccine (70%), 17% AstraZeneca/Oxford and 8% Moderna. In fully vaccinated cases, breakthrough infections were reported in 0.7% of I-RMD patients and 1.1% of NI-RMD patients. I-RMD flares were reported in 4.4% of cases (0.6% severe), 1.5% resulting in medication changes. AEs were reported in 37% of cases (37% I-RMD, 40% NI-RMD), serious AEs in 0.5% (0.4% I-RMD, 1.9% NI-RMD).ConclusionThe safety profiles of SARS-CoV-2 vaccines in patients with I-RMD was reassuring and comparable with patients with NI-RMDs. The majority of patients tolerated their vaccination well with rare reports of I-RMD flare and very rare reports of serious AEs. These findings should provide reassurance to rheumatologists and vaccine recipients and promote confidence in SARS-CoV-2 vaccine safety in I-RMD patients.
Published: 2022
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4. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author: Lara Gibellini, Sussan Nourshargh, Susanna Cardell, Wlodzimierz Maslinski, Mar Felipo-Benavent, Florian Mair, Hans-Martin Jäck, Lilly Lopez, Klaus Warnatz, John Trowsdale, Diana Ordonez, Marcus Eich, William Hwang, Anne Cooke, Dirk Mielenz, Alberto Orfao, Winfried F. Pickl, Vladimir Benes, Alice Yue, T. Vincent Shankey, Maria Tsoumakidou, Virginia Litwin, Gelo Victoriano Dela Cruz, Andrea Cavani, Sara De Biasi, Larissa Nogueira Almeida, Jonathan J M Landry, Claudia Haftmann, Charlotte Esser, Ana Cumano, Anneke Wilharm, Francesco Dieli, Rudi Beyaert, Alessio Mazzoni, Burkhard Ludewig, Carlo Pucillo, Dirk H. Busch, Joe Trotter, Stipan Jonjić, Marc Veldhoen, Josef Spidlen, Aja M. Rieger, Dieter Adam, Srijit Khan, Todd A. Fehniger, Giuseppe Matarese, Maximilien Evrard, Christian Maueröder, Steffen Schmitt, Kristin A. Hogquist, Barry Moran, Raghavendra Palankar, Markus Feuerer, S Schmid, Susann Rahmig, Amy E. Lovett-Racke, James V. Watson, Megan K. Levings, Susanne Melzer, Dinko Pavlinic, Christopher M. Harpur, Christina Stehle, A. Graham Pockley, Toshinori Nakayama, Attila Tárnok, Juhao Yang, Michael Lohoff, Paulo Vieira, Francisco Sala-de-Oyanguren, Christian Kurts, Anastasia Gangaev, Alfonso Blanco, Hans Scherer, Regine J. Dress, Bruno Silva-Santos, Kiyoshi Takeda, Bimba F. Hoyer, Ilenia Cammarata, Daryl Grummitt, Isabel Panse, Günnur Deniz, Bianka Baying, Friederike Ebner, Esther Schimisky, Leo Hansmann, Thomas Kamradt, Edwin van der Pol, Daniel Scott-Algara, Anna Iannone, Giorgia Alvisi, Sebastian R. Schulz, Francesco Liotta, Irmgard Förster, Beatriz Jávega, Hans-Peter Rahn, Caetano Reis e Sousa, Livius Penter, Xuetao Cao, David P. Sester, Keisuke Goda, Peter Wurst, Iain B. McInnes, Ricardo T. Gazzinelli, Federica Piancone, Gerald Willimsky, Yotam Raz, Pärt Peterson, Wolfgang Fritzsche, Yvonne Samstag, Martin Büscher, Thomas Schüler, Susanne Hartmann, Robert J. Wilkinson, Anna E. S. Brooks, Steven L. C. Ketelaars, Catherine Sautès-Fridman, Anna Rubartelli, Petra Bacher, Katja Kobow, Marco A. Cassatella, Andrea Hauser, Henrik E. Mei, Kilian Schober, Silvia Della Bella, Graham Anderson, Michael D. Ward, Garth Cameron, Sebastian Lunemann, Katharina Kriegsmann, Katarzyna M. Sitnik, Brice Gaudilliere, Chantip Dang-Heine, Marcello Pinti, Paul Klenerman, Frank A. Schildberg, Joana Barros-Martins, Laura G. Rico, Hanlin Zhang, Christian Münz, Thomas Dörner, Jakob Zimmermann, Andrea M. Cooper, Jonni S. Moore, Andreas Diefenbach, Yanling Liu, Wolfgang Bauer, Tobit Steinmetz, Katharina Pracht, Leonard Tan, Peter K. Jani, Alan M. Stall, Petra Hoffmann, Christine S. Falk, Jasmin Knopf, Simon Fillatreau, Hans-Dieter Volk, Luis E. Muñoz, David L. Haviland, William W. Agace, Jonathan Rebhahn, Ljiljana Cvetkovic, Mohamed Trebak, Jordi Petriz, Mario Clerici, Diether J. Recktenwald, Anders Ståhlberg, Tristan Holland, Helen M. McGuire, Sa A. Wang, Christian Kukat, Thomas Kroneis, Laura Cook, Wan Ting Kong, Xin M. Wang, Britta Engelhardt, Pierre Coulie, Genny Del Zotto, Sally A. Quataert, Kata Filkor, Gabriele Multhoff, Bartek Rajwa, Federica Calzetti, Hans Minderman, Cosima T. Baldari, Jens Geginat, Hervé Luche, Gert Van Isterdael, Linda Schadt, Sophia Urbanczyk, Giovanna Borsellino, Liping Yu, Dale I. Godfrey, Achille Anselmo, Rachael C. Walker, Andreas Grützkau, David W. Hedley, Birgit Sawitzki, Silvia Piconese, Maria Yazdanbakhsh, Burkhard Becher, Ramon Bellmas Sanz, Michael Delacher, Hyun-Dong Chang, Immanuel Andrä, Hans-Gustaf Ljunggren, José-Enrique O'Connor, Ahad Khalilnezhad, Sharon Sanderson, Federico Colombo, Götz R. A. Ehrhardt, Inga Sandrock, Enrico Lugli, Christian Bogdan, James B. Wing, Susann Müller, Tomohiro Kurosaki, Derek Davies, Ester B. M. Remmerswaal, Kylie M. Quinn, Christopher A. Hunter, Andreas Radbruch, Timothy P. Bushnell, Anna Erdei, Sabine Adam-Klages, Pascale Eede, Van Duc Dang, Rieke Winkelmann, Thomas Korn, Gemma A. Foulds, Dirk Baumjohann, Matthias Schiemann, Manfred Kopf, Jan Kisielow, Lisa Richter, Jochen Huehn, Gloria Martrus, Alexander Scheffold, Jessica G. Borger, Sidonia B G Eckle, John Bellamy Foster, Anna Katharina Simon, Alicia Wong, Mübeccel Akdis, Gisa Tiegs, Toralf Kaiser, James McCluskey, Anna Vittoria Mattioli, Aaron J. Marshall, Hui-Fern Koay, Eva Orlowski-Oliver, Anja E. Hauser, J. Paul Robinson, Jay K. Kolls, Luca Battistini, Mairi McGrath, Jane L. Grogan, Natalio Garbi, Timothy Tree, Kingston H. G. Mills, Stefan H. E. Kaufmann, Wolfgang Schuh, Ryan R. Brinkman, Tim R. Mosmann, Vincenzo Barnaba, Andreas Dolf, Lorenzo Cosmi, Bo Huang, Andreia C. Lino, Baerbel Keller, René A. W. van Lier, Alexandra J. Corbett, Paul S. Frenette, Pleun Hombrink, Helena Radbruch, Sofie Van Gassen, Olivier Lantz, Lorenzo Moretta, Désirée Kunkel, Kirsten A. Ward-Hartstonge, Armin Saalmüller, Leslie Y. T. Leung, Salvador Vento-Asturias, Paola Lanuti, Alicia Martínez-Romero, Sarah Warth, Zhiyong Poon, Diana Dudziak, Andrea Cossarizza, Kovit Pattanapanyasat, Konrad von Volkmann, Jessica P. Houston, Agnès Lehuen, Andrew Filby, Pratip K. Chattopadhyay, Stefano Casola, Annika Wiedemann, Hannes Stockinger, Jürgen Ruland, Arturo Zychlinsky, Claudia Waskow, Katrin Neumann, Ari Waisman, Lucienne Chatenoud, Sudipto Bari, Kamran Ghoreschi, David W. Galbraith, Yvan Saeys, Hamida Hammad, Andrea Gori, Miguel López-Botet, Gabriel Núñez, Sabine Ivison, Michael Hundemer, Dorothea Reimer, Mark C. Dessing, Günter J. Hämmerling, Rudolf A. Manz, Tomas Kalina, Jonas Hahn, Holden T. Maecker, Hendy Kristyanto, Martin S. Davey, Henning Ulrich, Michael L. Dustin, Takashi Saito, Yousuke Takahama, Milena Nasi, Johanna Huber, Jürgen Wienands, Paolo Dellabona, Andreas Schlitzer, Michael D. Leipold, Kerstin H. Mair, Christian Peth, Immo Prinz, Chiara Romagnani, José M. González-Navajas, Josephine Schlosser, Marina Saresella, Matthias Edinger, Dirk Brenner, Nicole Baumgarth, Rikard Holmdahl, Fang-Ping Huang, Guadalupe Herrera, Malte Paulsen, Gergely Toldi, Luka Cicin-Sain, Reiner Schulte, Christina E. Zielinski, Thomas Winkler, Christoph Goettlinger, Philip E. Boulais, Jennie H M Yang, Antonio Celada, Heike Kunze-Schumacher, Julia Tornack, Florian Ingelfinger, Jenny Mjösberg, Andy Riddell, Leonie Wegener, Thomas Höfer, Christoph Hess, James P. Di Santo, Anna E. Oja, J. Kühne, Willem van de Veen, Mary Bebawy, Alberto Mantovani, Bart Everts, Giovanna Lombardi, Laura Maggi, Anouk von Borstel, Pia Kvistborg, Elisabetta Traggiai, A Ochel, Nima Aghaeepour, Charles-Antoine Dutertre, Matthieu Allez, Thomas Höllt, Wenjun Ouyang, Regina Stark, Maries van den Broek, Shimon Sakaguchi, Paul K. Wallace, Silvano Sozzani, Francesca LaRosa, Annette Oxenius, Malgorzata J. Podolska, Ivana Marventano, Wilhelm Gerner, Oliver F. Wirz, Britta Frehse, Gevitha Ravichandran, Martin Herrmann, Carl S. Goodyear, Gary Warnes, Helen Ferry, Stefan Frischbutter, Tim R. Radstake, Salomé LeibundGut-Landmann, Yi Zhao, Axel Schulz, Angela Santoni, Pablo Engel, Daniela C. Hernández, Andreas Acs, Cristiano Scottà, Francesco Annunziato, Thomas Weisenburger, Wolfgang Beisker, Sue Chow, Fritz Melchers, Daniel E. Speiser, Immanuel Kwok, Florent Ginhoux, Dominic A. Boardman, Natalie Stanley, Carsten Watzl, Marie Follo, Erik Lubberts, Andreas Krueger, Susanne Ziegler, Göran K. Hansson, David Voehringer, Antonia Niedobitek, Eleni Christakou, Lai Guan Ng, Sabine Baumgart, Nicholas A Gherardin, Antonio Cosma, Orla Maguire, Jolene Bradford, Daniel Schraivogel, Linda Quatrini, Stephen D. Miller, Rheumatology, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Institute of Clinical Molecular Biology, Kiel University, Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Dulbecco Telethon Institute/Department of Biology, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, European Molecular Biology Laboratory [Heidelberg] (EMBL), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Fondazione Santa Lucia (IRCCS), Department of Immunology, Chinese Academy of Medical Sciences, FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physiopatology and Transplantation, University of Milan (DEPT), University of Milan, Monash University [Clayton], Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular Pathology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biopharmacy [Bruxelles, Belgium] (Institute for Medical Immunology IMI), Université libre de Bruxelles (ULB), Charité Hospital, Humboldt-Universität zu Berlin, Agency for science, technology and research [Singapore] (A*STAR), Laboratory of Molecular Immunology and the Howard Hughes Institute, Rockefeller University [New York], Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Theodor Kocher Institute, University of Bern, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] ( IUF), Université Lumière - Lyon 2 (UL2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Edinburgh, Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Universitat de Barcelona (UB), Rheumatologie, Cell Biology, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Delft University of Technology (TU Delft), Medical Inflammation Research, Karolinska Institutet [Stockholm], Department of Photonics Engineering [Lyngby], Technical University of Denmark [Lyngby] (DTU), Dpt of Experimental Immunology [Braunschweig], Helmholtz Centre for Infection Research (HZI), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Histology and Embryology, University of Rijeka, Freiburg University Medical Center, Nuffield Dept of Clinical Medicine, University of Oxford [Oxford]-NIHR Biomedical Research Centre, Institute of Integrative Biology, Molecular Biomedicine, Berlin Institute of Health (BIH), Laboratory for Lymphocyte Differentiation, RIKEN Research Center, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Department of Surgery [Vancouver, BC, Canada] (Child and Family Research Institute), University of British Columbia (UBC)-Child and Family Research Institute [Vancouver, BC, Canada], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, King‘s College London, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brustzentrum Kantonsspital St. Gallen, Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Heinrich Pette Institute [Hamburg], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Immunology and Cell Biology, Mario Negri Institute, Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation, Institute of Translational Medicine, Klinik für Dermatologie, Venerologie und Allergologie, School of Biochemistry and Immunology, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Centre de Recherche Publique- Santé, Université du Luxembourg (Uni.lu), William Harvey Research Institute, Barts and the London Medical School, University of Michigan [Ann Arbor], University of Michigan System, Centro de Investigacion del Cancer (CSIC), Universitario de Salamanca, Molecular Pathology [Tartu, Estonia], University of Tartu, Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Monash Biomedicine Discovery Institute, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Data Mining and Modelling for Biomedicine [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, RIKEN Research Center for Allergy and Immunology, Osaka University [Osaka], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institute of Medical Immunology [Berlin, Germany], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Otto-von-Guericke University [Magdeburg] (OVGU), SUPA School of Physics and Astronomy [University of St Andrews], University of St Andrews [Scotland]-Scottish Universities Physics Alliance (SUPA), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), General Pathology and Immunology (GPI), University of Brescia, Université de Lausanne (UNIL), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Dept. Pediatric Cardiology, Universität Leipzig [Leipzig], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Cardiovascular Sciences, Albany Medical College, Dept Pathol, Div Immunol, University of Cambridge [UK] (CAM), Department of Information Technology [Gent], Universiteit Gent, Department of Plant Systems Biology, Department of Plant Biotechnology and Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Division of Molecular Immunology, Institute for Immunology, Department of Geological Sciences, University of Oregon [Eugene], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Colorado [Colorado Springs] (UCCS), FACS laboratory, Cancer Research, London, Cancer Research UK, Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], School of Computer and Electronic Information [Guangxi University], Guangxi University [Nanning], School of Materials Science and Engineering, Nanyang Technological University [Singapour], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Work in the laboratory of Dieter Adam is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 125440785 – SFB 877, Project B2.Petra Hoffmann, Andrea Hauser, and Matthias Edinger thank BD Biosciences®, San José, CA, USA, and SKAN AG, Bale, Switzerland for fruitful cooperation during the development, construction, and installation of the GMP‐compliant cell sorting equipment and the Bavarian Immune Therapy Network (BayImmuNet) for financial support.Edwin van der Pol and Paola Lanuti acknowledge Aleksandra Gąsecka M.D. for excellent experimental support and Dr. Rienk Nieuwland for textual suggestions. This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO‐TTW), research program VENI 15924.Jessica G Borger, Kylie M Quinn, Mairi McGrath, and Regina Stark thank Francesco Siracusa and Patrick Maschmeyer for providing data.Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14‐1. Rudolf A. Manz was supported by the Excellence Cluster 'Inflammation at Interfaces' (EXC 306/2).Susanne Hartmann and Friederike Ebner were supported by the German Research Foundation (GRK 2046).Hans Minderman was supported by NIH R50CA211108.This work was funded by the Deutsche Forschungsgemeinschaft through the grant TRR130 (project P11 and C03) to Thomas H. Winkler.Ramon Bellmàs Sanz, Jenny Kühne, and Christine S. Falk thank Jana Keil and Kerstin Daemen for excellent technical support. The work was funded by the Germany Research Foundation CRC738/B3 (CSF).The work by the Mei laboratory was supported by German Research Foundation Grant ME 3644/5‐1 and TRR130 TP24, the German Rheumatism Research Centre Berlin, European Union Innovative Medicines Initiative ‐ Joint Undertaking ‐ RTCure Grant Agreement 777357, the Else Kröner‐Fresenius‐Foundation, German Federal Ministry of Education and Research e:Med sysINFLAME Program Grant 01ZX1306B and KMU‐innovativ 'InnoCyt', and the Leibniz Science Campus for Chronic Inflammation (http://www.chronische-entzuendung.org).Axel Ronald Schulz, Antonio Cosma, Sabine Baumgart, Brice Gaudilliere, Helen M. McGuire, and Henrik E. Mei thank Michael D. Leipold for critically reading the manuscript.Christian Kukat acknowledges support from the ISAC SRL Emerging Leaders program.John Trowsdale received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement 695551)., European Project: 7728036(1978), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Università degli Studi di Milano = University of Milan (UNIMI), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] (IUF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universität Heidelberg [Heidelberg] = Heidelberg University, Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), University of Oxford-NIHR Biomedical Research Centre, Universität Bonn = University of Bonn, Università degli Studi di Firenze = University of Florence (UniFI), Università degli studi di Genova = University of Genoa (UniGe), Universidad de Salamanca, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Lausanne = University of Lausanne (UNIL), Universität Leipzig, Universiteit Gent = Ghent University (UGENT), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Cossarizza, A., Chang, H. -D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W., Aghaeepour, N., Akdis, M., Allez, M., Almeida, L. N., Alvisi, G., Anderson, G., Andra, I., Annunziato, F., Anselmo, A., Bacher, P., Baldari, C. T., Bari, S., Barnaba, V., Barros-Martins, J., Battistini, L., Bauer, W., Baumgart, S., Baumgarth, N., Baumjohann, D., Baying, B., Bebawy, M., Becher, B., Beisker, W., Benes, V., Beyaert, R., Blanco, A., Boardman, D. A., Bogdan, C., Borger, J. G., Borsellino, G., Boulais, P. E., Bradford, J. A., Brenner, D., Brinkman, R. R., Brooks, A. E. S., Busch, D. H., Buscher, M., Bushnell, T. P., Calzetti, F., Cameron, G., Cammarata, I., Cao, X., Cardell, S. L., Casola, S., Cassatella, M. A., Cavani, A., Celada, A., Chatenoud, L., Chattopadhyay, P. K., Chow, S., Christakou, E., Cicin-Sain, L., Clerici, M., Colombo, F. S., Cook, L., Cooke, A., Cooper, A. M., Corbett, A. J., Cosma, A., Cosmi, L., Coulie, P. G., Cumano, A., Cvetkovic, L., Dang, V. D., Dang-Heine, C., Davey, M. S., Davies, D., De Biasi, S., Del Zotto, G., Dela Cruz, G. V., Delacher, M., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Di Santo, J. P., Diefenbach, A., Dieli, F., Dolf, A., Dorner, T., Dress, R. J., Dudziak, D., Dustin, M., Dutertre, C. -A., Ebner, F., Eckle, S. B. G., Edinger, M., Eede, P., Ehrhardt, G. R. A., Eich, M., Engel, P., Engelhardt, B., Erdei, A., Esser, C., Everts, B., Evrard, M., Falk, C. S., Fehniger, T. A., Felipo-Benavent, M., Ferry, H., Feuerer, M., Filby, A., Filkor, K., Fillatreau, S., Follo, M., Forster, I., Foster, J., Foulds, G. A., Frehse, B., Frenette, P. S., Frischbutter, S., Fritzsche, W., Galbraith, D. W., Gangaev, A., Garbi, N., Gaudilliere, B., Gazzinelli, R. T., Geginat, J., Gerner, W., Gherardin, N. A., Ghoreschi, K., Gibellini, L., Ginhoux, F., Goda, K., Godfrey, D. I., Goettlinger, C., Gonzalez-Navajas, J. M., Goodyear, C. S., Gori, A., Grogan, J. L., Grummitt, D., Grutzkau, A., Haftmann, C., Hahn, J., Hammad, H., Hammerling, G., Hansmann, L., Hansson, G., Harpur, C. M., Hartmann, S., Hauser, A., Hauser, A. E., Haviland, D. L., Hedley, D., Hernandez, D. C., Herrera, G., Herrmann, M., Hess, C., Hofer, T., Hoffmann, P., Hogquist, K., Holland, T., Hollt, T., Holmdahl, R., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Huang, F. -P., Huber, J. E., Huehn, J., Hundemer, M., Hunter, C. A., Hwang, W. Y. K., Iannone, A., Ingelfinger, F., Ivison, S. M., Jack, H. -M., Jani, P. K., Javega, B., Jonjic, S., Kaiser, T., Kalina, T., Kamradt, T., Kaufmann, S. H. E., Keller, B., Ketelaars, S. L. C., Khalilnezhad, A., Khan, S., Kisielow, J., Klenerman, P., Knopf, J., Koay, H. -F., Kobow, K., Kolls, J. K., Kong, W. T., Kopf, M., Korn, T., Kriegsmann, K., Kristyanto, H., Kroneis, T., Krueger, A., Kuhne, J., Kukat, C., Kunkel, D., Kunze-Schumacher, H., Kurosaki, T., Kurts, C., Kvistborg, P., Kwok, I., Landry, J., Lantz, O., Lanuti, P., Larosa, F., Lehuen, A., LeibundGut-Landmann, S., Leipold, M. D., Leung, L. Y. T., Levings, M. K., Lino, A. C., Liotta, F., Litwin, V., Liu, Y., Ljunggren, H. -G., Lohoff, M., Lombardi, G., Lopez, L., Lopez-Botet, M., Lovett-Racke, A. E., Lubberts, E., Luche, H., Ludewig, B., Lugli, E., Lunemann, S., Maecker, H. T., Maggi, L., Maguire, O., Mair, F., Mair, K. H., Mantovani, A., Manz, R. A., Marshall, A. J., Martinez-Romero, A., Martrus, G., Marventano, I., Maslinski, W., Matarese, G., Mattioli, A. V., Maueroder, C., Mazzoni, A., Mccluskey, J., Mcgrath, M., Mcguire, H. M., Mcinnes, I. B., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Miller, S. D., Mills, K. H. G., Minderman, H., Mjosberg, J., Moore, J., Moran, B., Moretta, L., Mosmann, T. R., Muller, S., Multhoff, G., Munoz, L. E., Munz, C., Nakayama, T., Nasi, M., Neumann, K., Ng, L. G., Niedobitek, A., Nourshargh, S., Nunez, G., O'Connor, J. -E., Ochel, A., Oja, A., Ordonez, D., Orfao, A., Orlowski-Oliver, E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Pattanapanyasat, K., Paulsen, M., Pavlinic, D., Penter, L., Peterson, P., Peth, C., Petriz, J., Piancone, F., Pickl, W. F., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Poon, Z., Pracht, K., Prinz, I., Pucillo, C. E. M., Quataert, S. A., Quatrini, L., Quinn, K. M., Radbruch, H., Radstake, T. R. D. J., Rahmig, S., Rahn, H. -P., Rajwa, B., Ravichandran, G., Raz, Y., Rebhahn, J. A., Recktenwald, D., Reimer, D., Reis e Sousa, C., Remmerswaal, E. B. M., Richter, L., Rico, L. G., Riddell, A., Rieger, A. M., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Saalmuller, A., Saeys, Y., Saito, T., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sandrock, I., Santoni, A., Sanz, R. B., Saresella, M., Sautes-Fridman, C., Sawitzki, B., Schadt, L., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schimisky, E., Schlitzer, A., Schlosser, J., Schmid, S., Schmitt, S., Schober, K., Schraivogel, D., Schuh, W., Schuler, T., Schulte, R., Schulz, A. R., Schulz, S. R., Scotta, C., Scott-Algara, D., Sester, D. P., Shankey, T. V., Silva-Santos, B., Simon, A. K., Sitnik, K. M., Sozzani, S., Speiser, D. E., Spidlen, J., Stahlberg, A., Stall, A. M., Stanley, N., Stark, R., Stehle, C., Steinmetz, T., Stockinger, H., Takahama, Y., Takeda, K., Tan, L., Tarnok, A., Tiegs, G., Toldi, G., Tornack, J., Traggiai, E., Trebak, M., Tree, T. I. M., Trotter, J., Trowsdale, J., Tsoumakidou, M., Ulrich, H., Urbanczyk, S., van de Veen, W., van den Broek, M., van der Pol, E., Van Gassen, S., Van Isterdael, G., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H. -D., von Borstel, A., von Volkmann, K., Waisman, A., Walker, R. V., Wallace, P. K., Wang, S. A., Wang, X. M., Ward, M. D., Ward-Hartstonge, K. A., Warnatz, K., Warnes, G., Warth, S., Waskow, C., Watson, J. V., Watzl, C., Wegener, L., Weisenburger, T., Wiedemann, A., Wienands, J., Wilharm, A., Wilkinson, R. J., Willimsky, G., Wing, J. B., Winkelmann, R., Winkler, T. H., Wirz, O. F., Wong, A., Wurst, P., Yang, J. H. M., Yang, J., Yazdanbakhsh, M., Yu, L., Yue, A., Zhang, H., Zhao, Y., Ziegler, S. M., Zielinski, C., Zimmermann, J., Zychlinsky, A., UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, Netherlands Organization for Scientific Research, German Research Foundation, European Commission, European Research Council, Repositório da Universidade de Lisboa, CCA - Imaging and biomarkers, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, and Landsteiner Laboratory
Subjects: 0301 basic medicine, Consensus, Immunology, Consensu, Cell Separation, Biology, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Guidelines, Allergy and Immunology, medicine, Cell separation, Immunology and Allergy, Humans, guidelines, flow cytometry, immunology, medicine.diagnostic_test, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Cell sorting, Flow Cytometry, Cell selection, Data science, 3. Good health, 030104 developmental biology, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, 030215 immunology, Human
Abstract: All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).
Published: 2019
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5. Monocyte transcriptomes from patients with axial spondyloarthritis reveal dysregulated monocytopoiesis and a distinct inflammatory imprint

Author: Karow, Fabian, Smiljanovic, Biljana, Grün, J. R., Poddubnyy, Denis, Proft, Fabian, Talpin, Alice, Hue, Christophe, Boland, Anne, Deleuze, Jean François, Garchon, Henri Jean, Ergenç, Ilkay, De Craemer, Ann Sophie, Erben, Ulrike, Häupl, Thomas, Elewaut, Dirk, Breban, Maxime, Grützkau, Andreas, Syrbe, Uta, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bundesministerium für Bildung und Forschung, BMBF: 01EC1009A, Charité – Universitätsmedizin Berlin, Foundation for Research in Rheumatology, FOREUM, Funding: This work was supported by the FOREUM — Foundation for Research in Rheumatology. B.S. was supported by the German Federal Ministry of Education and Research (BMBF) with the network project ArthroMark (01EC1009A). Open Access funding enabled and organized by Projekt DEAL., Université Paris Cité (UPCité), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Ambroise Paré [AP-HP], Universiteit Gent = Ghent University (UGENT), Deutsches Rheuma-ForschungsZentrum (DRFZ), and Deutsches Rheuma-ForschungsZentrum
Subjects: Gut translocation, SUBSETS, Gene Expression Profiling, Biology and Life Sciences, ANKYLOSING-SPONDYLITIS, Diseases of the musculoskeletal system, DISEASE-ACTIVITY, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Monocytes, Transcriptomes, LIPOPOLYSACCHARIDE-BINDING PROTEIN, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, RC925-935, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], CELLS, Spondyloarthritis, Spondylarthritis, Medicine and Health Sciences, CRITERIA, Cytokines, Humans, Transcriptome, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit, GENE-EXPRESSION
Abstract: International audience; Background: In patients with axial spondyloarthritis (axSpA), monocytes show a pre-activated phenotype. Gut inflammation is a trigger of monocyte activation and may also affect their development in the bone marrow (BM). As gut inflammation is commonly observed in axSpA patients, we performed a detailed analysis of monocyte transcriptomes of axSpA patients in two cohorts and searched for signs of activation and developmental adaptations as putative imprints of gut inflammation. Methods: Transcriptomes of blood CD14+ monocytes of HLA-B27+ axSpA patients and healthy controls (HC) were generated by microarrays from cohort 1 and by RNA-sequencing from cohort 2. Differentially expressed genes from both analyses were subjected to gene set enrichment analysis (GSEA) and to co-expression analysis in reference transcriptomes from BM cells, blood cells and activated monocytes. As serological markers of translocation, 1,3 beta-glycan, intestinal fatty acid binding protein, and lipopolysaccharide binding protein (LBP) were determined by LAL and ELISA. Results: Transcriptome analysis identified axSpA-specific monocyte signatures showing an imprint of LPS/cytokine-activated monocytes, late granulopoietic BM cells, blood neutrophils, and G-CSF-mobilized blood cells, which suggests LPS/TNF activation and more prominent BM adaptation promoting a neutrophil-like phenotype. GSEA mapped axSpA upregulated genes to inflammatory responses and TNFα signaling and downregulated probe-sets to metabolic pathways. Among translocation markers, LBP levels were significantly increased in axSpA patients vs. HC (p < 0.001). Stratified analysis by disease activity and stage identified an “active disease signature” (BASDAI ≥ 4) with an imprint of LPS/cytokine-activated monocytes and CD16+ monocyte subsets. The “AS signature” (vs. non-radiographic axSpA) showed a reinforced neutrophil-like phenotype due to deprivation of dendritic cell transcripts. Conclusions: The neutrophil-like phenotype of axSpA monocytes points towards a biased monocytopoiesis from granulocyte-monocyte progenitors. This shift in monocytopoiesis and the LPS/cytokine imprint as well as the elevated LBP levels are indicators of systemic inflammation, which may result from bacterial translocation. The BM adaptation is most prominent in AS patients while disease activity appears to be linked to activation and trafficking of monocytes.
Published: 2021
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6. Evidence for tmTNF reverse signaling in vivo

Author: Diallo, Katy, Simons, Numa, Sayegh, Souraya, Baron, Michel, Degboé, Yannick, Boyer, Jean-Frédéric, Kruglov, Andrey, Nedospasov, Sergei, Novarino, Julien, Aloulou, Meryem, Fazilleau, Nicolas, Constantin, Arnaud, Cantagrel, Alain, Davignon, Jean-Luc, Rauwel, Benjamin, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Engelhardt Institute of Molecular Biology (ISTC), Russian Academy of Sciences [Moscow] (RAS), and Benson-Rumiz, Alicia
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cell Biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; In order to ascertain the significance of transmembrane tumor necrosis factor (tmTNF) reverse signaling in vivo, we generated a triple transgenic mouse model (3TG, TNFR1-/-, TNFR2-/-, and tmTNFKI/KI) in which all canonical tumor necrosis factor (TNF) signaling was abolished. In bone-marrow-derived macrophages harvested from these mice, various anti-TNF biologics induced the expression of genes characteristic of alternative macrophages and also inhibited the expression of pro-inflammatory cytokines mainly through the upregulation of arginase-1. Injections of TNF inhibitors during arthritis increased pro-resolutive markers in bone marrow precursors and joint cells leading to a decrease in arthritis score. These results demonstrate that the binding of anti-TNF biologics to tmTNF results in decreased arthritis severity. Collectively, our data provide evidence for the significance of tmTNF reverse signaling in the modulation of arthritis. They suggest a complementary interpretation of anti-TNF biologics effects in the treatment of inflammatory diseases and pave the way to studies focused on new arginase-1-dependent therapeutic targets.
Published: 2021
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7. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author: Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]
Subjects: Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract: Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.
Published: 2021
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8. Response to: 'Correspondence on 'Factors Associated with COVID-19-related Death in People with Rheumatic Diseases: Results from the COVID-19 Global Rheumatology Alliance Physician Reported Registry' by Mulhearn \emphet Al

Author: Anja Strangfeld, Elsa F Mateus, Martin Schäfer, Pedro Machado, Milena A. Gianfrancesco, Kimme L. Hyrich, Jinoos Yazdany, Philip Robinson, Loreto Carmona, Saskia Lawson-Tovey, Laure Gossec, Gestionnaire, Hal Sorbonne Université, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Instituto de Salud Musculoesqueletica (InMusc), University of California (UC), Service de Rhumatologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Queensland [Brisbane], and University College of London [London] (UCL)
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Population, Disease, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Internal medicine, Epidemiology, Collider (epidemiology), Health care, Immunology and Allergy, Medicine, education, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Health services research, Missing data, [SDV] Life Sciences [q-bio], 030104 developmental biology, Family medicine, business
Abstract: We thank Rosenbaum et al 1 for their correspondence on our article.2 In their reply, they largely report updated results of COVID-19 occurrence and subjective patient-reported COVID-19 severity from their patient survey of adult patients with spondyloarthritis and specifically comment that in their analysis, sulfasalazine did not ‘increase the risk to develop COVID-19’, nor did it increase the severity of those who were infected. Unfortunately, no details of the statistical methods, including any additional statistical adjustments (eg, age, sex, comorbidities and disease activity) or details of missing data, were included, and only a point estimate of risk was provided for each therapy without CIs, only p values, which therefore limits interpretation. While it is important to share reports of outcomes of COVID-19 among our populations of patients with rheumatic and musculoskeletal diseases (RMDs), it must be pointed out that the survey presented, as well as the subsequent analysis, is fundamentally different from our report on COVID-19-related mortality set within the Global Rheumatology Alliance (GRA) provider database and therefore the two outputs should not be compared , either directly or indirectly. First, the GRA database is based on physician reports of COVID-19 among patients with known rheumatic disease and therefore can only be used to look at the associations between demographic and clinical features and COVID-19 outcomes among those known to have COVID-19. The data cannot be used to look at factors associated with acquisition of SARS-CoV-2 infection or development of COVID-19 disease, which is the focus of the report presented in the correspondence. These factors should not be compared since restricting the analysis to patients with an existing COVID-19 diagnosis may cause relationships between any variables that relate to COVID-19 acquisition to be distorted compared with a more general population, due to collider bias.3 Indeed, factors associated with …
Published: 2021
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9. Analysing and reporting of observational data: a systematic review informing the EULAR points to consider when analysing and reporting comparative effectiveness research with observational data in rheumatology

Author: Lykke Midtbøll Ørnbjerg, Tanja Stamm, Pedro Machado, Anja Strangfeld, Delphine S. Courvoisier, Ziga Rotar, Robert Landewé, Joanna Kedra, Kimme L. Hyrich, Thomas Frisell, Sytske Anne Bergstra, Maria José Santos, Simon Stones, Axel Finckh, Kim Lauper, Maarten de Wit, Bruno Fautrel, Florenzo Iannone, University of Geneva [Switzerland], University of Manchester [Manchester], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), European League Against Rheumatism (EULAR), Karolinska Institutet [Stockholm], Università degli studi di Bari Aldo Moro (UNIBA), University College of London [London] (UCL), Copenhagen Center for Arthritis Research,Copenhagen (Center for Rheumatology and Spine Diseases), University of Ljubljana, Faculdade de Medicina [Lisboa], Universidade de Lisboa (ULISBOA), Hospital Garcia de Orta (EPE), University of Vienna [Vienna], Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, University of Amsterdam [Amsterdam] (UvA), Zuyderland Hospital [Heerlen, The Netherlands], Leiden University Medical Center (LUMC), HAL-SU, Gestionnaire, Université de Genève = University of Geneva (UNIGE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), and Universidade de Lisboa = University of Lisbon (ULISBOA)
Subjects: medicine.medical_specialty, Comparative Effectiveness Research, antirheumatic agents, Epidemiology, Immunology, Comparative effectiveness research, Bivariate analysis, 03 medical and health sciences, 0302 clinical medicine, Bias, Rheumatology, Immunology and Allergy, Medicine, Humans, 030212 general & internal medicine, Imputation (statistics), 10. No inequality, 030203 arthritis & rheumatology, ddc:616, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Arthritis, Confounding, Missing data, Antirheumatic agents, 3. Good health, Systematic review, arthritis, Family medicine, Observational study, epidemiology, Systematic Review, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: ObjectivesTo evaluate the analysis and reporting of comparative effectiveness research with observational data in rheumatology, informing European Alliance of Associations for Rheumatology points to consider.MethodsWe performed a systematic literature review searching Ovid MEDLINE for original articles comparing drug effectiveness in longitudinal observational studies, published in key rheumatology journals between 2008 and 2019. The extracted information focused on reporting and types of analyses. We evaluated if year of publication impacted results.ResultsFrom 9969 abstracts reviewed, 211 articles fulfilled the inclusion criteria. Ten per cent of studies did not adjust for confounding factors. Some studies did not explain how they chose covariates for adjustment (9%), used bivariate screening (21%) and/or stepwise selection procedures (18%). Only 33% studies reported the number of patients lost to follow-up and 25% acknowledged attrition (drop-out or treatment cessation). To account for attrition, studies used non-responder imputation, followed by last observation carried forward (LOCF) and complete case (CC) analyses. Most studies did not report the number of missing data on covariates (83%), and when addressed, 49% used CC and 11% LOCF. Date of publication did not influence the results.ConclusionMost studies did not acknowledge missing data and attrition, and a tenth did not adjust for any confounding factors. When attempting to account for them, several studies used methods which potentially increase bias (LOCF, CC analysis, bivariate screening…). This study shows that there is no improvement over the last decade, highlighting the need for recommendations for the assessment and reporting of comparative drug effectiveness in observational data in rheumatology.
Published: 2021
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10. Prevention, screening, assessing and managing of non-adherent behaviour in people with rheumatic and musculoskeletal diseases:systematic reviews informing the 2020 EULAR points to consider

Author: Fernando Estévez-López, Peter Böhm, Andréa Marques, Emma Dures, J. Bijlsma, Tanja Stamm, Marieke Voshaar, Bart J F van den Bemt, Laure Gossec, Kirsten K. Viktil, E. Moholt, Michal Nudel, Annamaria Iagnocco, Loreto Carmona, Daniel Aletaha, José B Negrón, Razvan Dragoi, Valentin Ritschl, Annette de Thurah, Conni Skrubbeltrang, Child and Adolescent Psychiatry / Psychology, Psychology, Health & Technology, Medizinische Universität Wien = Medical University of Vienna, Utrecht University [Utrecht], Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, West University of Timișoara [Roumanie] (WUT), University of the West of England [Bristol] (UWE Bristol), Erasmus University Rotterdam, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Torino (UNITO), Universidad de Puerto Rico - UPR (PUERTO RICO), University of Puerto Rico (UPR), University of Haifa [Haifa], Centro Hospitalar e Universitário [Coimbra], Dpt of Rheumatology [Oslo], Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway, Aalborg University [Denmark] (AAU), Nijmegen Medical Centre [Nijmegen], Oslo University Hospital [Oslo], University of Twente [Netherlands], Instituto de Salud Musculoesqueletica (InMusc), Aarhus University Hospital, Gestionnaire, HAL Sorbonne Université 5, Service de Rhumatologie [CHU Pitié Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Torino = University of Turin (UNITO), and University of Twente
Subjects: medicine.medical_specialty, Epidemiology, media_common.quotation_subject, Immunology, Psychological intervention, lcsh:Medicine, Health services research, Patient Care Team, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Rheumatology, medicine, Immunology and Allergy, Humans, Quality (business), 030212 general & internal medicine, Musculoskeletal Diseases, Exercise, media_common, 030203 arthritis & rheumatology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, business.industry, Gold standard, lcsh:R, Evidence-based medicine, 3. Good health, Systematic review, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Family medicine, Patient Compliance, business, Delivery of Health Care, Patient education, Systematic Reviews as Topic
Abstract: ObjectiveTo analyse how non-adherence to prescribed treatments might be prevented, screened, assessed and managed in people with rheumatic and musculoskeletal diseases (RMDs).MethodsAn overview of systematic reviews (SR) was performed in four bibliographic databases. Research questions focused on: (1) effective interventions or strategies, (2) associated factors, (3) impact of shared decision making and effective communication, (4) practical things to prevent non-adherence, (5) effect of non-adherence on outcome, (6) screening and assessment tools and (7) responsible healthcare providers. The methodological quality of the reviews was assessed using AMSTAR-2. The qualitative synthesis focused on results and on the level of evidence attained from the studies included in the reviews.ResultsAfter reviewing 9908 titles, the overview included 38 SR on medication, 29 on non-pharmacological interventions and 28 on assessment. Content and quality of the included SR was very heterogeneous. The number of factors that may influence adherence exceed 700. Among 53 intervention studies, 54.7% showed a small statistically significant effect on adherence, and all three multicomponent interventions, including different modes of patient education and delivered by a variety of healthcare providers, showed a positive result in adherence to medication. No single assessment provided a comprehensive measure of adherence to either medication or exercise.ConclusionsThe results underscore the complexity of non-adherence, its changing pattern and dependence on multi-level factors, the need to involve all stakeholders in all steps, the absence of a gold standard for screening and the requirement of multi-component interventions to manage it.
Published: 2020
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11. c-FLIP is crucial for IL-7/IL-15-dependent NKp46+ ILC development and protection from intestinal inflammation in mice

Author: Bank, Ute, Deiser, Katrin, Plaza-Sirvent, Carlos, Osbelt, Lisa, Witte, Amelie, Knop, Laura, Labrenz, Rebecca, Jänsch, Robert, Richter, Felix, Biswas, Aindrila, Zenclussen, Ana C., Vivier, Eric, Romagnani, Chiara, Kühl, Anja A., Dunay, Ildiko R., Strowig, Till, Schmitz, Ingo, Schüler, Thomas, Otto-von-Guericke University [Magdeburg] (OVGU), Helmholtz Centre for Infection Research (HZI), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service d'Immunologie [Marseille], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Innate Pharma Research Labs [Marseille], Innate Pharma, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), This work was supported by the Deutsche Forschungsgemeinschaft Sonderforschungsbereich SFB854 (project A22) and DFG priority program 1937 (project SCHU 2326/2-1)., HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Bodescot, Myriam, Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Science, T-Lymphocytes, CASP8 and FADD-Like Apoptosis Regulating Protein, Innate lymphoid cells, Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Article, Inflammatory bowel disease, Mice, STAT5 Transcription Factor, Animals, Antigens, Ly, Phosphorylation, lcsh:Science, skin and connective tissue diseases, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Interleukin-15, Mice, Knockout, B-Lymphocytes, Natural Cytotoxicity Triggering Receptor 1, Interleukins, Interleukin-7, Colitis, Killer Cells, Natural, body regions, Mucosal immunology, lcsh:Q
Abstract: NKp46+ innate lymphoid cells (ILC) modulate tissue homeostasis and anti-microbial immune responses. ILC development and function are regulated by cytokines such as Interleukin (IL)−7 and IL-15. However, the ILC-intrinsic pathways translating cytokine signals into developmental programs are largely unknown. Here we show that the anti-apoptotic molecule cellular FLICE-like inhibitory protein (c-FLIP) is crucial for the generation of IL-7/IL-15-dependent NKp46+ ILC1, including conventional natural killer (cNK) cells, and ILC3. Cytokine-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) precedes up-regulation of c-FLIP, which protects developing NKp46+ ILC from TNF-induced apoptosis. NKp46+ ILC-specific inactivation of c-FLIP leads to the loss of all IL-7/IL-15-dependent NKp46+ ILC, thereby inducing early-onset chronic colitis and subsequently microbial dysbiosis; meanwhile, the depletion of cNK, but not NKp46+ ILC1/3, aggravates experimental colitis. In summary, our data demonstrate a non-redundant function of c-FLIP for the generation of NKp46+ ILC, which protect T/B lymphocyte-sufficient mice from intestinal inflammation., Innate lymphoid cells (ILC) are important immune cells for maintaining the gut homeostasis. Here the authors show that c-FLIP, an anti-apoptotic molecule, is important for the development of NKP46+ ILC1, including conventional natural killer (cNK) cells, and ILC3, with cNK being more critical for ameliorating intestinal inflammation.
Published: 2020
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12. In situ maturation and tissue adaptation of type 2 innate lymphoid cell progenitors

Author: Remi Doucet-Ladeveze, Dominic Grün, Georg Gasteiger, David Voehringer, Daniela C. Hernández, Nina Peltokangas, Richard M. Locksley, Agnieszka M. Kabat, Josip S. Herman, Cornelia Symowski, Patrice Zeis, Rebecca Gentek, Alexander Y. Rudensky, Christin Friedrich, Marc Bajénoff, Konrad Knöpper, Mi Lian, Shlomo Elias, Xiying Fan, Chiara Romagnani, Bajenoff, Marc, Max Planck Institute of Immunobiology and Epigenetics (MPI-IE), Max-Planck-Gesellschaft, Julius-Maximilians-Universität Würzburg (JMU), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of Freiburg [Freiburg], University of California [San Francisco] (UC San Francisco), University of California (UC), Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Howard Hughes Medical Institute (HHMI)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), University of California [San Francisco] (UCSF), University of California, and Institute for Virology and Immunobiology [Würzburg, Germany]
Subjects: 0301 basic medicine, Ontogeny, [SDV]Life Sciences [q-bio], Cell, single cell atlas, Inbred C57BL, ILC2, Mice, 0302 clinical medicine, T Cell Transcription Factor 1, Immunology and Allergy, Innate, Promyelocytic Leukemia Zinc Finger Protein, Lymphocytes, skin and connective tissue diseases, Lung, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Cultured, single-cell RNA-seq, Innate lymphoid cell, Cell Differentiation, Lymphoid Progenitor Cells, Phenotype, ILCP, Nippostrongylus Brasiliensis, Cell biology, Infectious Diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Single-Cell Analysis, Interleukin-18 Receptor alpha Subunit, Signal Transduction, bone marrow, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cells, Immunology, Innate lymphoid cells, Biology, Article, 03 medical and health sciences, Innate lymphoid cells (ILC), medicine, Genetics, Animals, Humans, Progenitor cell, Transcription factor, Progenitor, progenitors, Immunity, immune system development, Stem Cell Research, Immunity, Innate, tissue immunity, Mice, Inbred C57BL, body regions, 030104 developmental biology, Bone marrow, Transcription Factors
Abstract: Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2- ILCPs to Il18r- ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.
Published: 2020
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13. Origin of Public Memory B Cell Clones in Fish After Antiviral Vaccination

Author: Magadan, Susana, Jouneau, Luc, Puelma Touzel, Maximilian, Marillet, Simon, Chara, Wahiba, Six, Adrien, Quillet, Edwige, Mora, Thierry, Walczak, Aleksandra, Cazals, Frédéric, Sunyer, Oriol, Fillatreau, Simon, Boudinot, Pierre, Unité de recherche Virologie et Immunologie Moléculaires (VIM), Institut National de la Recherche Agronomique (INRA), Laboratoire de Physique Théorique de l'ENS (LPTENS), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, Biology, Structure (ABS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Immunologie - Immunopathologie - Immunothérapie (I3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Génétique Animale et Biologie Intégrative (GABI), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Laboratoire de Physique Statistique de l'ENS (LPS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of Pathobiology [Philadelphia], University of Pennsylvania [Philadelphia], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Universités (COMUE), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), University of Pennsylvania, European Commission under the Work Programme 2012 of the 7th Framework Programme for Research and Technological Development of the European Union [306312, 600391], FishRNAVax [ANR-16-CE20-0002-01], INRA-INRIA contract Young scientist, NIH [R01-GM085207-08], NSF [IOS-1457282], ANR-16-CE20-0002,Fish-RNAvax,Vaccins ARN éco-compatibles pour l'induction de réponses immunitaires protectrices chez le poisson d'élevage(2016), European Project: 311993,EC:FP7:KBBE,FP7-KBBE-2012-6-singlestage,TARGETFISH(2012), ProdInra, Migration, Targeted disease prophylaxis in European fish farming - TARGETFISH - - EC:FP7:KBBE2012-10-01 - 2017-09-30 - 311993 - VALID, Laboratoire de Physique Théorique de l'ENS [École Normale Supérieure] (LPTENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Immunology, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, [INFO.INFO-CG]Computer Science [cs]/Computational Geometry [cs.CG], Novirhabdovirus, Hemorrhagic Septicemia, Viral, Animals, antibodies, comparative immunology, ComputingMilieux_MISCELLANEOUS, Original Research, B-Lymphocytes, B cells, [SDV.GEN]Life Sciences [q-bio]/Genetics, RepSeq, Vaccination, Fishes, repertoire, Viral Vaccines, V(D)J Recombination, Clone Cells, [SDV] Life Sciences [q-bio], public response, fish immunology, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Immunoglobulin M, Immunologic Memory
Abstract: International audience; Vaccination induces "public" antibody clonotypes common to all individuals of a species, that may mediate universal protection against pathogens. Only few studies tried to trace back the origin of these public B-cell clones. Here we used Illumina sequencing and computational modeling to unveil the mechanisms shaping the structure of the fish memory antibody response against an attenuated Viral Hemorrhagic Septicemia rhabdovirus. After vaccination, a persistent memory response with a public VH5JH5 IgM component was composed of dominant antibodies shared among all individuals. The rearrangement model showed that these public junctions occurred with high probability indicating that they were already favored before vaccination due to the recombination process, as shown inmammals. In addition, these clonotypes were in the naive repertoire associated with larger similarity classes, composed of junctions differing only at one or two positions by amino acids with comparable properties. The model showed that this property was due to selective processes exerted between the recombination and the naive repertoire. Finally, our results showed that public clonotypes greatly expanded after vaccination displayed several VDJ junctions differing only by one or two amino acids with similar properties, highlighting a convergent response. The fish public memory antibody response to a virus is therefore shaped at three levels: by recombination biases, by selection acting on the formation of the pre-vaccination repertoire, and by convergent selection of functionally similar clonotypes during the response. We also show that naive repertoires of IgM and IgT have different structures and sharing between individuals, due to selection biases. In sum, our comparative approach identifies three conserved features of the antibody repertoire associated with public memory responses. These features were already present in the last common ancestors of fish and mammals, while other characteristics may represent species-specific solutions.
Published: 2018
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14. Prevalence and Gene Characteristics of Antibodies with Cofactor-induced HIV-1 Specificity

Author: Srinivas V. Kaveri, Anastas Pashov, Claudia Berek, Annaelle Jarossay, Cyril Planchais, Sébastien Lacroix-Desmazes, Maxime Lecerf, Jordan D. Dimitrov, Stéphane Mesnage, Delphine Ohayon, Tobias Scheel, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Bulgarian Academy of Sciences (BAS), University of Sheffield [Sheffield], and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: animal diseases, [SDV]Life Sciences [q-bio], Immunology, Immunoglobulin Variable Region, chemical and pharmacologic phenomena, Heme, Adaptive Immunity, HIV Antibodies, HIV Envelope Protein gp120, Biochemistry, chemistry.chemical_compound, Immune system, Antigen, medicine, Humans, Molecular Biology, Gene, Antibody, Binding selectivity, B cell, B-Lymphocytes, Human Immunodeficiency Virus (HIV), biology, Cofactors, Cell Biology, biochemical phenomena, metabolism, and nutrition, Acquired immune system, Molecular biology, 3. Good health, gp120, medicine.anatomical_structure, chemistry, HIV-1, Immunoglobulin G (IgG), biology.protein, bacteria, Cloning
Abstract: The healthy immune repertoire contains a fraction of antibodies that bind to various biologically relevant cofactors, including heme. Interaction of heme with some antibodies results in induction of new antigen binding specificities and acquisition of binding polyreactivity. In vivo, extracellular heme is released as a result of hemolysis or tissue damage; hence the post-translational acquisition of novel antigen specificities might play an important role in the diversification of the immunoglobulin repertoire and host defense. Here, we demonstrate that seronegative immune repertoires contain antibodies that gain reactivity to HIV-1 gp120 upon exposure to heme. Furthermore, a panel of human recombinant antibodies was cloned from different B cell subpopulations, and the prevalence of antibodies with cofactor-induced specificity for gp120 was determined. Our data reveal that upon exposure to heme, ∼24% of antibodies acquired binding specificity for divergent strains of HIV-1 gp120. Sequence analyses reveal that heme-sensitive antibodies do not differ in their repertoire of variable region genes and in most of the molecular features of their antigen-binding sites from antibodies that do not change their antigen binding specificity. However, antibodies with cofactor-induced gp120 specificity possess significantly lower numbers of somatic mutations in their variable region genes. This study contributes to the understanding of the significance of cofactor-binding antibodies in immunoglobulin repertoires and of the influence that the tissue microenvironment might have in shaping adaptive immune responses.
Published: 2015
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15. Anti-interleukin-6 signalling therapy rebalances the disrupted cytokine production of B cells from patients with active rheumatoid arthritis

Author: Alix Lhéritier, Frédéric Cazals, Sarah J. Fleischer, Ping Shen, Stefanie Ries, Thomas Dörner, Gerd R Burmester, Simon Fillatreau, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Algorithms, Biology, Structure (ABS), Inria Sophia Antipolis - Méditerranée (CRISAM), and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)
Subjects: 0301 basic medicine, medicine.medical_treatment, Chemokine CXCL1, Immunology, B-cell receptor, medicine.disease_cause, [INFO.INFO-CG]Computer Science [cs]/Computational Geometry [cs.CG], Antibodies, Monoclonal, Humanized, Autoimmunity, Arthritis, Rheumatoid, TNF-Related Apoptosis-Inducing Ligand, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Tocilizumab, Antigen, Nerve Growth Factor, medicine, Immunology and Allergy, Humans, Interleukin 6, Chemokine CCL4, B cell, 030203 arthritis & rheumatology, B-Lymphocytes, biology, business.industry, Interleukin-6, Interleukin-8, Interleukin, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Cytokine, chemistry, biology.protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business
Abstract: Rheumatoid arthritis (RA) is associated with abnormal B cell functions implicating antibody-dependent and -independent mechanisms. B cells have emerged as important cytokine-producing cells, and cytokines are well-known drivers of RA pathogenesis. To identify novel cytokine-mediated B cell functions in RA, we comprehensively analysed the capacity of B cells from RA patients with an inadequate response to disease modifying anti-rheumatic drugs to produce cytokines in comparison with healthy donors (HD). RA B cells displayed a constitutively higher production of the pathogenic factors interleukin (IL)-8 and Gro-α, while their production of several cytokines upon activation via the B cell receptor for antigen (BCR) was broadly suppressed, including a loss of the expression of the protective factor TRAIL, compared to HD B cells. These defects were partly erased after treatment with the IL-6-signalling inhibitor tocilizumab, indicating that abnormal IL-6 signalling contributed to these abnormalities. Noteworthy, the clinical response of individual patients to tocilizumab therapy could be predicted using the amounts of MIP-1β and β-NGF produced by these patients’ B cells before treatment. Taken together, our study highlights hitherto unknown abnormal B cell functions in RA patients, which are related to the unbalanced cytokine network, and are potentially relevant for RA pathogenesis and treatment. This article is protected by copyright. All rights reserved
Published: 2017
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16. Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage

Author: Bhattacharya, Anannya, Hegazy, Ahmed N., Deigendesch, Nikolaus, Kosack, Lindsay, Cupovic, Jovana, Kandasamy, Richard K., Hildebrandt, Andrea, Merkler, Doron, Kühl, Anja A., Vilagos, Bojan, Schliehe, Christopher, Panse, Isabel, Khamina, Kseniya, Baazim, Hatoon, Arnold, Isabelle, Flatz, Lukas, Xu, Haifeng C., Lang, Philipp A., Aderem, Alan, Takaoka, Akinori, Superti-Furga, Giulio, Colinge, Jacques, Ludewig, Burkhard, Löhning, Max, Bergthaler, Andreas, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of Oxford [Oxford], Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Brustzentrum Kantonsspital St. Gallen, University of Geneva [Switzerland], Computer Science [Heinrich Heine University], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Hokkaido University [Sapporo, Japan], Medizinische Universität Wien = Medical University of Vienna, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), and CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Transcription, Genetic, T-Lymphocytes, Immunology, SOD1, ddc:616.07, medicine.disease_cause, Antioxidants, Article, Superoxide dismutase, Mice, Superoxide Dismutase-1, Downregulation and upregulation, Interferon, medicine, Animals, Immunology and Allergy, Inflammation, Hepatitis, biology, Superoxide Dismutase, medicine.disease, Immunity, Innate, 3. Good health, Killer Cells, Natural, Mice, Inbred C57BL, Oxidative Stress, Hepatocytes, Oxidative Damage, Infectious Diseases, Liver, Hepatitis, Viral, Animal, Interferon Type I, biology.protein, Cancer research, Viral hepatitis, Oxidation-Reduction, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Interferon type I, Oxidative stress, Signal Transduction, medicine.drug
Abstract: Summary Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1−/− mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1−/− and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage. Video Abstract, Graphical Abstract, Highlights • Viral infection leads to redox dysregulation including the downregulation of SOD1 • Sod1−/− mice exhibit aggravated viral hepatitis, which is rescued by antioxidants • IFN-I signaling via STAT1 drives SOD1 downregulation and early liver damage • Ablation of IFN-I signaling ameliorates viral hepatitis in Sod1−/− and WT mice, Bergthaler and colleagues show that superoxide dismutase 1 protects the liver from type I interferon-driven oxidative damage in viral hepatitis. Liver damage was mediated by hepatocyte-intrinsic IFNAR1-STAT1 signaling.
Published: 2015
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17. TLR-activated B cells suppress T cell-mediated autoimmunity

Author: Toralf Roch, Yi Hao, Stephen M. Anderton, Kai Hoehlig, Patricia Neves, Claire H. Sweenie, Antonio A. Freitas, Elisabeth Calderón Gómez, Vicky Lampropoulou, Simon Fillatreau, Ulrich Steinhoff, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, School of medical sciences, University of Edinburgh, Biologie des Populations Lymphocytaires, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Signal Transduction, MESH: Mycobacterium tuberculosis, MESH: Interleukin-10, T-Lymphocytes, Autoimmunity, medicine.disease_cause, Lymphocyte Activation, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Immunology and Allergy, MESH: Animals, Mice, Knockout, 0303 health sciences, B-Lymphocytes, MESH: Dendritic Cells, biology, Experimental autoimmune encephalomyelitis, Toll-Like Receptors, 3. Good health, Interleukin-10, Interleukin 10, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, MESH: Toll-Like Receptors, MESH: Myeloid Differentiation Factor 88, Signal Transduction, Encephalomyelitis, Autoimmune, Experimental, T cell, Immunology, Inflammation, 03 medical and health sciences, Immune system, MESH: Mice, Inbred C57BL, MESH: B-Lymphocytes, MESH: Autoimmunity, medicine, Animals, MESH: Lymphocyte Activation, MESH: Encephalomyelitis, Autoimmune, Experimental, MESH: Mice, 030304 developmental biology, Autoimmune disease, CD40, Dendritic Cells, Mycobacterium tuberculosis, medicine.disease, Mice, Inbred C57BL, MESH: T-Lymphocytes, Myeloid Differentiation Factor 88, biology.protein, 030215 immunology
Abstract: TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.
Published: 2008
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18. The Role of Glycocalyx Diversity and Thickness for Nanoparticle Internalization in M1-/M2-like Macrophages.

Author: Liu Y, He Y, Xu H, Remmo A, Wiekhorst F, Heymann F, Liu H, Schellenberger E, Häckel A, Hauptmann R, Taupitz M, Shen Y, Yilmaz EY, Müller DN, Heidemann L, Schmidt R, and Savic LJ
Abstract: Very small superparamagnetic iron oxide nanoparticles (VSOPs) show diagnostic value in multiple diseases as a promising MRI contrast agent. Macrophages predominantly ingest VSOPs, but the mechanism remains unclear. This study identifies differences in VSOP uptake between pro-inflammatory M1 and anti-inflammatory M2 macrophages and explores the role of the pericellular glycocalyx. Glycosaminoglycans (GAG) synthesis activities and the pericellular glycocalyx for M1/M2-like macrophages were assessed by RT-qPCR, Click-iT reaction, and WGA-FITC staining. The uptake of europium-VSOP and Synomag by the two subtypes was measured using Prussian blue staining, fluorescent microscopy, and magnetic particle spectroscopy. The findings revealed that M2-like macrophages had higher GAG synthesis activity, a thicker glycocalyx, and increased nanoparticle uptake compared to M1-like macrophages. Enzymatic glycocalyx degradation significantly decreased nanoparticle uptake. This study demonstrates a positive correlation between glycocalyx and nanoparticle uptake that could be exploited for imaging and targeted therapy, particularly in cancer, where macrophage subtypes play distinct roles.
Published: 2024
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19. Dysregulation of immune checkpoint molecules as a characteristic of autoimmune congenital heart block.

Author: Stefanski AL, Rincon-Arevalo H, Dressler-Steinbach I, Nomovi N, Mackert A, Aue A, Ritter J, Wiedemann A, Szelinski F, Schrezenmeier E, Kühl AA, Lino AC, Henrich W, and Dörner T
Abstract: Competing Interests: Competing interests: None declared.
Published: 2024
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20. Pre-assembled ECMO: Enhancing efficiency and reducing stress in refractory cardiac arrest care.

Author: Thevathasan T, Lech S, Diefenbach A, Bechthold E, Gaßmann T, Fester S, Girke G, Knie W, Lukusa BT, Kühn S, Desch S, Landmesser U, and Skurk C
Abstract: Aim: Extracorporeal cardiopulmonary resuscitation (ECPR) by veno-arterial extracorporeal membrane oxygenation (VA-ECMO) during refractory cardiac arrest presents significant medical and psychological challenges for healthcare providers. Beyond managing cardiac arrest and preparing for potential coronary angiography, the ECMO circuit must be assembled and primed under strictly sterile conditions, contributing to additional psychological stress and potential delays in ECMO cannulation. This pragmatic study thought to evaluate whether pre-assembled and pre-primed ECMO circuits (pre-primed group) maintain sterility over a 21-day period, expedite ECMO initiation in ECPR patients and alleviate the psychological burden on the ECPR team, compared to newly assembled and primed ECMO circuits (on-demand group)., Methods: In a prospective manner, ECMO circuits were either pre-assembled and pre-primed under sterile conditions, maintained for 21 days with culture samples taken every seventh day, or newly assembled and primed during the acute emergency situation. The transition from on-demand assembly and priming of ECMO circuits to pre-primed ECMO circuits occurred on January 1st, 2021. The interval between patients' arrival in the cardiac catheterization laboratory and the initiation of ECMO was recorded and retrospectively compared between the two treatment groups. The ECPR team, comprising experienced cardiologists and nurses, was prospectively surveyed using the modified Perceived Stress Questionnaire (PSQ-20)., Results: All aseptically pre-assembled and pre-primed ECMO circuits demonstrated sterile cultures for aerobic and anaerobic microorganisms as well as fungal agents over the 21-day period: 0/120 positive cultures (0 %, 95 % CI for binomial probability 0-0.03). The time to ECMO initiation was significantly reduced in the pre-primed group compared to the on-demand group: 13 [IQR 9-17] versus 31 [IQR 27-44] minutes, P < 0.001. Responses from ECPR physicians and nurses on the PSQ-20 were similar across all items. With the use of pre-primed ECMO circuits, all ECPR professionals reported a greater sense of settled inner feeling, considerably less psychological tension, fewer worries and insecurities, as well as more effective ICU shifts with improved personal goal achievement. However, treating ECPR patients with pre-primed ECMO circuits did not lead to increased job satisfaction or higher physical energy levels., Conclusion: Aseptically pre-assembled and pre-primed ECMO circuits maintain sterility for multiple weeks, significantly reducing ECMO initiation times and alleviating psychological strain on the ECPR team. Consequently, implementing these circuits in ECPR centers could enhance both patient outcomes and healthcare provider well-being., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)
Published: 2024
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21. Retention of ES cell-derived 129S genome drives NLRP1 hypersensitivity and transcriptional deregulation in Nlrp3 tm1Flv mice.

Author: Weiss FD, Alvarez Y, Shakeri F, Sahu A, Leka P, Dernst A, Rollheiser J, Vasconcelos M, Geraci A, Duthie F, Stahl R, Lee HE, Gellner AK, Buness A, Latz E, and Meissner F
Abstract: Immune response genes are highly polymorphic in humans and mice, with heterogeneity amongst loci driving strain-specific host defence responses. The inadvertent retention of polymorphic loci can introduce confounding phenotypes, leading to erroneous conclusions, and impeding scientific advancement. In this study, we employ a combination of RNAseq and variant calling analyses to identify a substantial region of 129S genome, including the highly polymorphic Nlrp1 locus, proximal to Nlrp3, in one of the most commonly used mouse models of NLRP3 deficiency (Nlrp3 tm1Flv ). We show that the presence of the Nlrp1 129S locus leads to an increase in NLRP1B protein expression, and a sensitising of Nlrp3 tm1Flv macrophages to NLRP1 inflammasome activation, independent of NLRP3 deficiency. Retention of 129S genome further leads to protein sequence differences and altered gene regulation across multiple cell types, including of the key tissue-resident macrophage marker, TIM4. Using alternative models of NLRP3 deficiency, including a previously undescribed conditional Nlrp3 allele enabling precise temporal and cell-type specific control over Nlrp3 deletion, we further show that NLRP3 contributes to Talabostat-driven IL-1β release. Our study also establishes a generic framework to identify functionally relevant SNPs and assess genomic contamination in transgenic mice using RNAseq data. This allows for unambiguous attribution of phenotypes to the target gene and advances the precision and reliability of research in the field of host defence responses., (© 2024. The Author(s).)
Published: 2024
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22. The Role of Chimeric Antigen Receptor T-Cell Therapy in Immune-Mediated Neurological Diseases.

Author: Brittain G, Roldan E, Alexander T, Saccardi R, Snowden JA, Sharrack B, and Greco R
Subjects: Humans, Nervous System Diseases therapy, Nervous System Diseases immunology, Receptors, Chimeric Antigen immunology, Immunotherapy, Adoptive methods, Immunotherapy, Adoptive adverse effects
Abstract: Despite the use of 'high efficacy' disease-modifying therapies, disease activity and clinical progression of different immune-mediated neurological diseases continue for some patients, resulting in accumulating disability, deteriorating social and mental health, and high economic cost to patients and society. Although autologous hematopoietic stem cell transplant is an effective treatment modality, it is an intensive chemotherapy-based therapy with a range of short- and long-term side-effects. Chimeric antigen receptor T-cell therapy (CAR-T) has revolutionized the treatment of B-cell and other hematological malignancies, conferring long-term remission for otherwise refractory diseases. However, the toxicity of this treatment, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and the complexity of production necessitate the need for a high level of specialization at treating centers. Early-phase trials of CAR-T therapies in immune-mediated B cell driven conditions, such as systemic lupus erythematosus, neuromyelitis optica spectrum disorder and myasthenia gravis, have shown dramatic clinical response with few adverse events. Based on the common physiopathology, CAR-T therapy in other immune-mediated neurological disease, including multiple sclerosis, chronic inflammatory polyradiculopathy, autoimmune encephalitis, and stiff person syndrome, might be an effective option for patients, avoiding the need for long-term immunosuppressant medications. It may prove to be a more selective immunoablative approach than autologous hematopoietic stem cell transplant, with potentially increased efficacy and lower adverse events. In this review, we present the state of the art and future directions of the use of CAR-T in such conditions. ANN NEUROL 2024;96:441-452., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
Published: 2024
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23. High-dimensional single-cell analysis of human natural killer cell heterogeneity.

Author: Rebuffet L, Melsen JE, Escalière B, Basurto-Lozada D, Bhandoola A, Björkström NK, Bryceson YT, Castriconi R, Cichocki F, Colonna M, Davis DM, Diefenbach A, Ding Y, Haniffa M, Horowitz A, Lanier LL, Malmberg KJ, Miller JS, Moretta L, Narni-Mancinelli E, O'Neill LAJ, Romagnani C, Ryan DG, Sivori S, Sun D, Vagne C, and Vivier E
Subjects: Humans, Transcriptome, Neoplasms immunology, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism, Palatine Tonsil immunology, Palatine Tonsil cytology, Gene Expression Profiling, Lung immunology, Cytokines metabolism, Single-Cell Analysis methods, Killer Cells, Natural immunology
Abstract: Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons., (© 2024. The Author(s).)
Published: 2024
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24. NLRP3 inflammasome signalling in Alzheimer's disease.

Author: McManus RM and Latz E
Subjects: Animals, Humans, Brain metabolism, Brain immunology, Alzheimer Disease metabolism, Alzheimer Disease immunology, Alzheimer Disease drug therapy, Inflammasomes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, NLR Family, Pyrin Domain-Containing 3 Protein antagonists & inhibitors, Signal Transduction physiology, Signal Transduction drug effects
Abstract: Every year, 10 million people develop dementia, the most common of which is Alzheimer's disease (AD). To date, there is no way to prevent cognitive decline and therapies are limited. This review provides a neuroimmunological perspective on the progression of AD, and discusses the immune-targeted therapies that are in preclinical and clinical trials that may impact the development of this disease. Specifically, we look to the role of the NLRP3 inflammasome, its triggers in the brain and how its activation can contribute to the progression of dementia. We summarise the range of inhibitors targeting the NLRP3 inflammasome and its downstream pathways that are under investigation, and discuss future therapeutic perspectives for this devastating condition., Competing Interests: Declaration of competing interest E.L. is a Co-founder and adviser at IFM Therapeutics, Dioscure Therapeutics, a ‘Stealth’ Biotech and Odyssey Therapeutics. R.M.M. has no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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25. Immune-mediated inflammatory diseases (IMIDs) in children: key research questions and some answers.

Author: Kallinich T and Mall MA
Published: 2024
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26. MarShie: a clearing protocol for 3D analysis of single cells throughout the bone marrow at subcellular resolution.

Author: Mertens TF, Liebheit AT, Ehl J, Köhler R, Rakhymzhan A, Woehler A, Katthän L, Ebel G, Liublin W, Kasapi A, Triantafyllopoulou A, Schulz TJ, Niesner RA, and Hauser AE
Subjects: Mice, Animals, Hematopoietic Stem Cells, Hematopoiesis, Stromal Cells, Bone Marrow, Bone Marrow Cells metabolism
Abstract: Analyzing immune cell interactions in the bone marrow is vital for understanding hematopoiesis and bone homeostasis. Three-dimensional analysis of the complete, intact bone marrow within the cortex of whole long bones remains a challenge, especially at subcellular resolution. We present a method that stabilizes the marrow and provides subcellular resolution of fluorescent signals throughout the murine femur, enabling identification and spatial characterization of hematopoietic and stromal cell subsets. By combining a pre-processing algorithm for stripe artifact removal with a machine-learning approach, we demonstrate reliable cell segmentation down to the deepest bone marrow regions. This reveals age-related changes in the marrow. It highlights the interaction between CX 3 CR1 + cells and the vascular system in homeostasis, in contrast to other myeloid cell types, and reveals their spatial characteristics after injury. The broad applicability of this method will contribute to a better understanding of bone marrow biology., (© 2024. The Author(s).)
Published: 2024
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27. UNC93B1 variants underlie TLR7-dependent autoimmunity.

Author: Wolf C, Lim EL, Mokhtari M, Kind B, Odainic A, Lara-Villacanas E, Koss S, Mages S, Menzel K, Engel K, Dückers G, Bernbeck B, Schneider DT, Siepermann K, Niehues T, Goetzke CC, Durek P, Minden K, Dörner T, Stittrich A, Szelinski F, Guerra GM, Massoud M, Bieringer M, de Oliveira Mann CC, Beltrán E, Kallinich T, Mashreghi MF, Schmidt SV, Latz E, Klughammer J, Majer O, and Lee-Kirsch MA
Subjects: Mice, Animals, Humans, Autoimmunity genetics, Toll-Like Receptor 9 metabolism, Toll-Like Receptor 8, Toll-Like Receptor 3 metabolism, Membrane Transport Proteins, Toll-Like Receptor 7 genetics, Lupus Erythematosus, Systemic genetics
Abstract: UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.
Published: 2024
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28. Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry.

Author: Kuemmerle-Deschner JB, Kallinich T, Henes J, Kortus-Götze B, Oommen PT, Rech J, Krickau T, Weller-Heinemann F, Horneff G, Janda A, Foeldvari I, Schuetz C, Dressler F, Borte M, Hufnagel M, Meier F, Fiene M, Andreica I, Weber-Arden J, and Blank N
Subjects: Adult, Humans, Child, Female, Adolescent, Male, Prospective Studies, Quality of Life, Registries, Familial Mediterranean Fever drug therapy, Cryopyrin-Associated Periodic Syndromes diagnosis, Cryopyrin-Associated Periodic Syndromes drug therapy, Mevalonate Kinase Deficiency drug therapy, Mevalonate Kinase Deficiency etiology, Antibodies, Monoclonal, Humanized
Abstract: Objective: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS)., Methods: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit., Results: At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout., Conclusion: Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS., Competing Interests: Competing interests: JBK-D has received grant/research support from Novartis, AbbVie, Sobi and is a consultant of Novartis, AbbVie, Sobi. TKa received research support from Novartis. JH has received grant/research support from Novartis, Roche, SOBI and is a consultant of Novartis and has contributed to a speakers bureau with AbbVie, AstraZeneca, BMS, Boehringer-Ingelheim, Chugai, Janssen, Novartis, Pfizer, GSK, Sobi, Roche and UCB. BK-G is a consultant of Novartis. PTO has received study support from Novartis. JR has received grants from Novartis and Sobi; speaker fees from AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi and UCB; and consultancy for AbbVie, Biogen, BMS, Chugai, GSK, Janssen, Lilly, MSD, Mylan, Novartis, Roche, Sanofi, Sobi and UCB. FW-H has no disclosures. GH has received grant/research support from AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer and Roche and contributed to speakers bureau with AbbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer and Roche. AJ has received study support from Novartis. IF is a consultant of Novartis. CS has received study support from Novartis. FD has received study support from Novartis and is a consultant of AbbVie, Mylan, Novartis and Pfizer. MB has received grant/research support from Pfizer and Shire. MH has received study support from Novartis. FM has received honoraria from Novartis. MF has received support from AbbVie, Novartis, Pfizer, Galapagos and Amgen. TK has received study support, speaker fees and consultancy fees from Novartis. IA has contributed to a speakers bureau with AbbVie, Chugai, Novartis, UCB, MSD, Lilly, Sobi, AstraZeneca, Amgen, Pfizer and Gilead; received consultant fees from AstraZeneca and UCB; is a consultant for AbbVie, Chugai, Novartis, UCB, Galapagos, Takeda, AstraZeneca, Lilly, Boehringer Ingelheim, Amgen and Sobi. JW-A is an employee of Novartis. NB has received grant/research support from Novartis and Sobi; is a consultant of Novartis, Sobi, Lilly, Pfizer, AbbVie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim and Roche., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2024
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29. An atlas of cells in the human tonsil.

Author: Massoni-Badosa R, Aguilar-Fernández S, Nieto JC, Soler-Vila P, Elosua-Bayes M, Marchese D, Kulis M, Vilas-Zornoza A, Bühler MM, Rashmi S, Alsinet C, Caratù G, Moutinho C, Ruiz S, Lorden P, Lunazzi G, Colomer D, Frigola G, Blevins W, Romero-Rivero L, Jiménez-Martínez V, Vidal A, Mateos-Jaimez J, Maiques-Diaz A, Ovejero S, Moreaux J, Palomino S, Gomez-Cabrero D, Agirre X, Weniger MA, King HW, Garner LC, Marini F, Cervera-Paz FJ, Baptista PM, Vilaseca I, Rosales C, Ruiz-Gaspà S, Talks B, Sidhpura K, Pascual-Reguant A, Hauser AE, Haniffa M, Prosper F, Küppers R, Gut IG, Campo E, Martin-Subero JI, and Heyn H
Subjects: Humans, Adult, Palatine Tonsil, B-Lymphocytes metabolism
Abstract: Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil., Competing Interests: Declaration of interests H.H. is co-founder of Omniscope, SAB member of Nanostring and MiRXES, and consultant to Moderna and Singularity. J.C.N. is consultant to Omniscope., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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30. Spatial analyses: Focusing on immune-stromal interactions to understand immunity in the tissue context.

Author: Hauser AE
Subjects: Humans, Immunity, Innate, Fibrosis, Lymphocytes, Pulmonary Fibrosis
Abstract: Immune cells perform their tasks in tissues, thus, they are highly dependent on their microenvironment. This means that the tissue context should be considered to fully understand their function. For a long time, it has been difficult to quantify these complex interrelationships in tissues and to spatially map the diversity of cell types involved. In recent years, several methods have become available that allow comprehensive profiling of immune cells and their microenvironment, at both the protein and transcriptional levels. We have used multiplex immunofluorescence histology in combination with machine-learning based cell segmentation and annotation to identify even rare immune cell populations, namely innate lymphoid cells, in various human tissues and found that they preferentially localize in fibrovascular niches. Those niches are located around blood vessels, enriched in stromal cells and extracellular matrix, and represent a location for innate lymphoid cells across various organs. By combining multiplexed histology and spatial transcriptomics on serial sections, we further identified those tissue areas as seed points for COVID-19 induced lung fibrosis and pin-pointed a pro-fibrotic macrophage population as driver of this process, leading to an expansion of the niches. At later disease stages, these areas were populated by lymphocytes, promoting the formation of tertiary lymphoid structures. Whether similar mechanisms apply to other diseases associated with fibrosis, such as autoimmune conditions, awaits further investigation., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 Elsevier Inc. All rights reserved.)
Published: 2024
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31. Tissue niches and immunopathology through the lens of spatial tissue profiling techniques.

Author: Pascual-Reguant A, Kroh S, and Hauser AE
Subjects: Humans, Pandemics, Disease Progression, Gene Expression Profiling, Autoimmune Diseases, COVID-19
Abstract: Spatial organization plays a fundamental role in biology, influencing the function of biological structures at various levels. The immune system, in particular, relies on the orchestrated interactions of immune cells with their microenvironment to mount protective or pathogenic immune responses. The COVID-19 pandemic has underscored the significance of studying immunity within target organs to understand disease progression and severity. To achieve this, multiplex histology and spatial transcriptomics have proven indispensable in providing a spatial context to protein and gene expression patterns. By combining these techniques, researchers gain a more comprehensive understanding of the complex interactions at the cellular and molecular level in distinct tissue niches, key functional units modulating health and disease. In this review, we discuss recent advances in spatial tissue profiling techniques, highlighting their advantages over traditional histopathology studies. The insights gained from these approaches have the potential to revolutionize the diagnosis and treatment of various diseases including cancer, autoimmune disorders, and infectious diseases. However, we also acknowledge their challenges and limitations. Despite these, spatial tissue profiling offers promising opportunities to improve our understanding of how tissue niches direct regional immunity, and their relevance in tissue immunopathology, as a basis for novel therapeutic strategies and personalized medicine., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
Published: 2024
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32. [Society for Pediatric and Adolescent Rheumatology (GKJR) diagnosis and treatment optimization board-New ways to the diagnosis and treatment of complex diseases : An analysis after 2 years testing in practice].

Author: Hospach T, Kallinich T, Rietschel C, Hufnagel M, Freudenhammer J, Rücklová K, and Oommen PT
Subjects: Humans, Adolescent, Child, Rheumatology, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic therapy
Abstract: With the diagnosis and treatment optimization board, the Society for Pediatric and Adolescent Rheumatology (GKJR) has developed a new format for expert-based discussion of rare and complex diseases. So far, 32 cases, predominantly from the areas of hyperinflammation, systemic lupus erythematosus, myositis and nonbacterial osteomyelitis, could be discussed in 8 conferences. The digital format enabled a high number of participants and the involvement of national and international experts. Rare diseases increasingly present modern medicine with challenges, which the GKJR meets with the new format., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
Published: 2024
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33. HSCT for systemic autoimmune diseases with neurologic involvement.

Author: Alexander T and Arnold R
Subjects: Humans, Nervous System Diseases therapy, Nervous System Diseases etiology, Hematopoietic Stem Cell Transplantation methods, Autoimmune Diseases therapy
Abstract: Over the past 25 years, hematopoietic stem cell transplantation (HSCT) has been evolving as specific treatment for patients with severe and refractory systemic autoimmune diseases, where mechanistic studies have provided evidence for a profound immune renewal facilitating the observed beneficial responses. In addition to autoimmune neurologic diseases, such as multiple sclerosis (MS) or neuromyelitis optica (NMO), rheumatic diseases with central or peripheral nervous system involvement and insufficient response to conventional immunosuppressive or biologic therapies represent a growing indication for autologous HSCT. They most commonly include connective tissue diseases, such as systemic lupus erythematosus (SLE), vasculitides, or rarer diseases from the autoinflammatory spectrum, such as Behçet's disease, where neurologic manifestations may represent the greatest disease burden. Neurologic manifestations may resemble those of MS, including myelitis optic neuropathy, stroke, or seizures. Outcomes of such manifestations are variable after autologous HSCT but most frequently improve or even resolve with the underlying disease, especially in SLE. This article will provide the current evidence and summarize the outcomes of HSCT for rheumatic autoimmune diseases with neurologic manifestations., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
Published: 2024
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34. Daratumumab for autoimmune diseases: a systematic review.

Author: Holzer MT, Ruffer N, Huber TB, Kötter I, Ostendorf L, and Krusche M
Subjects: Humans, Rituximab, Autoantibodies, Antibodies, Monoclonal adverse effects, Autoimmune Diseases drug therapy, Autoimmune Diseases chemically induced
Abstract: Objective: Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases., Methods: A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome., Results: 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%)., Conclusion: Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Published: 2023
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35. Phagocytic cell death leads to enhanced release of pro-inflammatory S100A12 in familial Mediterranean fever.

Author: Varga G, Schleifenbaum S, Koenig U, Waldkirch J, Hinze C, Kessel C, Geluk W, Pap T, Lainka E, Kallinich T, Foell D, and Wittkowski H
Abstract: Background: Familial Mediterranean fever (FMF) is a prototypical autoinflammatory syndrome associated with phagocytic cell activation. Pyrin mutations are the genetic basis of this disease, and its expression has been shown in monocytes, granulocytes, dendritic cells, and synovial fibroblasts. Pyrin functions as a cytosolic pattern recognition receptor and forms a distinct pyrin inflammasome. The phagocyte-specific protein S100A12 is predominantly expressed in granulocytes and belongs to the group of damage associated molecular patterns (DAMP). S100A12 can be detected at massively elevated levels in the serum of FMF patients, even in clinically inactive disease. Whether this is crucial for FMF pathogenesis is as yet unknown, and we therefore investigated the mechanisms of S100A12 release from granulocytes of FMF patients presenting clinically inactive., Results: We demonstrate that FMF neutrophils from patients in clinical inactive disease possess an intrinsic activity leading to cell death even in exogenously unstimulated neutrophils. Cell death resembles NETosis and is dependent on ROS and pore forming protein gasdermin D (GSDMD), as inhibitors for both are capable of completely block cell death and S100A12 release. When pyrin-activator TcdA (Clostridium difficile toxin A) is used to stimulate, neutrophilic cell death and S100A12 release are significantly enhanced in neutrophils from FMF patients compared to neutrophils from HC., Conclusions: We are able to demonstrate that activation threshold of neutrophils from inactive FMF patients is decreased, most likely by pre-activated pyrin. FMF neutrophils present with intrinsically higher ROS production, when cultured ex vivo. This higher baseline ROS activity leads to increased GSDMD cleavage and subsequent release of, e.g., S100A12, and to increased cell death with features of NETosis and pyroptosis. We show for the first time that cell death pathways in neutrophils of inactive FMF patients are easily triggered and lead to ROS- and GSDMD-dependent activation mechanisms and possibly pathology. This could be therapeutically addressed by blocking ROS or GSDMD cleavage to decrease inflammatory outbreaks when becoming highly active., (© 2023. The Author(s).)
Published: 2023
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36. The miR-221/222 cluster regulates hematopoietic stem cell quiescence and multipotency by suppressing both Fos/AP-1/IEG pathway activation and stress-like differentiation to granulocytes.

Author: Jani PK, Petkau G, Kawano Y, Klemm U, Guerra GM, Heinz GA, Heinrich F, Durek P, Mashreghi MF, and Melchers F
Subjects: Animals, Humans, Mice, Cell Differentiation, Granulocytes, Hematopoietic Stem Cells, Mice, Inbred C57BL, MicroRNAs genetics, MicroRNAs metabolism, Transcription Factor AP-1 metabolism
Abstract: Throughout life, hematopoietic stem cells (HSCs), residing in bone marrow (BM), continuously regenerate erythroid/megakaryocytic, myeloid, and lymphoid cell lineages. This steady-state hematopoiesis from HSC and multipotent progenitors (MPPs) in BM can be perturbed by stress. The molecular controls of how stress can impact hematopoietic output remain poorly understood. MicroRNAs (miRNAs) as posttranscriptional regulators of gene expression have been found to control various functions in hematopoiesis. We find that the miR-221/222 cluster, which is expressed in HSC and in MPPs differentiating from them, perturbs steady-state hematopoiesis in ways comparable to stress. We compare pool sizes and single-cell transcriptomes of HSC and MPPs in unperturbed or stress-perturbed, miR-221/222-proficient or miR-221/222-deficient states. MiR-221/222 deficiency in hematopoietic cells was induced in C57BL/6J mice by conditional vav-cre-mediated deletion of the floxed miR-221/222 gene cluster. Social stress as well as miR-221/222 deficiency, alone or in combination, reduced HSC pools 3-fold and increased MPPs 1.5-fold. It also enhanced granulopoisis in the spleen. Furthermore, combined stress and miR-221/222 deficiency increased the erythroid/myeloid/granulocytic precursor pools in BM. Differential expression analyses of single-cell RNAseq transcriptomes of unperturbed and stressed, proficient HSC and MPPs detected more than 80 genes, selectively up-regulated in stressed cells, among them immediate early genes (IEGs). The same differential single-cell transcriptome analyses of unperturbed, miR-221/222-proficient with deficient HSC and MPPs identified Fos, Jun, JunB, Klf6, Nr4a1, Ier2, Zfp36-all IEGs-as well as CD74 and Ly6a as potential miRNA targets. Three of them, Klf6, Nr4a1, and Zfp36, have previously been found to influence myelogranulopoiesis. Together with increased levels of Jun, Fos forms increased amounts of the heterodimeric activator protein-1 (AP-1), which is known to control the expression of the selectively up-regulated expression of the IEGs. The comparisons of single-cell mRNA-deep sequencing analyses of socially stressed with miR-221/222-deficient HSC identify 5 of the 7 Fos/AP-1-controlled IEGs, Ier2, Jun, Junb, Klf6, and Zfp36, as common activators of HSC from quiescence. Combined with stress, miR-221/222 deficiency enhanced the Fos/AP-1/IEG pathway, extended it to MPPs, and increased the number of granulocyte precursors in BM, inducing selective up-regulation of genes encoding heat shock proteins Hspa5 and Hspa8, tubulin-cytoskeleton-organizing proteins Tuba1b, Tubb 4b and 5, and chromatin remodeling proteins H3f3b, H2afx, H2afz, and Hmgb2. Up-regulated in HSC, MPP1, and/or MPP2, they appear as potential regulators of stress-induced, miR-221/222-dependent increased granulocyte differentiation. Finally, stress by serial transplantations of miR-221/222-deficient HSC selectively exhausted their lymphoid differentiation capacities, while retaining their ability to home to BM and to differentiate to granulocytes. Thus, miR-221/222 maintains HSC quiescence and multipotency by suppressing Fos/AP-1/IEG-mediated activation and by suppressing enhanced stress-like differentiation to granulocytes. Since miR-221/222 is also expressed in human HSC, controlled induction of miR-221/222 in HSC should improve BM transplantations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Published: 2023
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37. Cross-regulation of antibody responses against the SARS-CoV-2 Spike protein and commensal microbiota via molecular mimicry.

Author: Bondareva M, Budzinski L, Durek P, Witkowski M, Angermair S, Ninnemann J, Kreye J, Letz P, Ferreira-Gomes M, Semin I, Guerra GM, Momsen Reincke S, Sánchez-Sendin E, Yilmaz S, Sempert T, Heinz GA, Tizian C, Raftery M, Schönrich G, Matyushkina D, Smirnov IV, Govorun VM, Schrezenmeier E, Stefanski AL, Dörner T, Zocche S, Viviano E, Klement N, Sehmsdorf KJ, Lunin A, Chang HD, Drutskaya M, Kozlovskaya L, Treskatsch S, Radbruch A, Diefenbach A, Prüss H, Enghard P, Mashreghi MF, and Kruglov AA
Subjects: Humans, Animals, Mice, Spike Glycoprotein, Coronavirus, Antibody Formation, Molecular Mimicry, SARS-CoV-2, Antibodies, Monoclonal, Antibodies, Viral, Immunoglobulin A, Secretory, Immunoglobulin G, Antibodies, Neutralizing, COVID-19, Microbiota
Abstract: The commensal microflora provides a repertoire of antigens that illicit mucosal antibodies. In some cases, these antibodies can cross-react with host proteins, inducing autoimmunity, or with other microbial antigens. We demonstrate that the oral microbiota can induce salivary anti-SARS-CoV-2 Spike IgG antibodies via molecular mimicry. Anti-Spike IgG antibodies in the saliva correlated with enhanced abundance of Streptococcus salivarius 1 month after anti-SARS-CoV-2 vaccination. Several human commensal bacteria, including S. salivarius, were recognized by SARS-CoV-2-neutralizing monoclonal antibodies and induced cross-reactive anti-Spike antibodies in mice, facilitating SARS-CoV-2 clearance. A specific S. salivarius protein, RSSL-01370, contains regions with homology to the Spike receptor-binding domain, and immunization of mice with RSSL-01370 elicited anti-Spike IgG antibodies in the serum. Additionally, oral S. salivarius supplementation enhanced salivary anti-Spike antibodies in vaccinated individuals. Altogether, these data show that distinct species of the human microbiota can express molecular mimics of SARS-CoV-2 Spike protein, potentially enhancing protective immunity., Competing Interests: Declaration of interests Related to this work, Deutsches Rheuma-Forschungszentrum (DRFZ) has filed a patent application., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2023
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38. New dawn of cellular therapies in autoimmune diseases.

Author: Wagner DL and Ostendorf L
Abstract: Competing Interests: D.L.W. is named as an inventor on multiple patent applications on cell and gene therapies and is a scientific co-founder of TCBalance Biopharmaceuticals GmbH, focused on regulatory T cell therapy.
Published: 2023
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39. Sustained responses after anti-CD38 treatment with daratumumab in two patients with refractory systemic lupus erythematosus.

Author: Alexander T, Ostendorf L, Biesen R, Schneider U, Burmester GR, and Hiepe F
Abstract: Competing Interests: Competing interests: TA received study support from Janssen.
Published: 2023
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40. Severe chronic non-bacterial osteomyelitis in combination with total MPO deficiency and responsiveness to TNFα inhibition.

Author: Sundqvist M, Christenson K, Wekell P, Björnsdottir H, Dahlstrand Rudin A, Sanchez Klose FP, Kallinich T, Welin A, Björkman L, Bylund J, Karlsson-Bengtsson A, and Berg S
Subjects: Female, Humans, Adalimumab therapeutic use, Inflammation, Reactive Oxygen Species, Tumor Necrosis Factor-alpha, Child, Adolescent, Malnutrition, Osteomyelitis diagnosis, Osteomyelitis drug therapy
Abstract: We describe a female patient suffering from severe chronic non-bacterial osteomyelitis (CNO) with systemic inflammation and advanced malnutrition and complete deficiency of myeloperoxidase (MPO). CNO is a rare autoinflammatory bone disorder associated with dysregulation of the innate immune system. MPO deficiency is a genetic disorder with partial or complete absence of the phagocyte peroxidase MPO. MPO deficiency has no established clinical phenotype but reports indicate increased susceptibility to infection and chronic inflammation. The patient's symptoms began at 10 years of age with pain in the thighs, systemic inflammation and malnutrition. She was diagnosed with CNO at 14 years of age. Treatment with nonsteroidal anti-inflammatory drugs, corticosteroids, bisphosphonates or IL1-receptor antagonists (anakinra) did not relieve the symptoms. However, the patient responded instantly and recovered from her clinical symptoms when treated with TNFα blockade (adalimumab). Three years after treatment initiation adalimumab was withdrawn, resulting in rapid symptom recurrence. When reintroducing adalimumab, the patient promptly responded and went into remission. In addition to clinical and laboratory profiles, neutrophil functions (reactive oxygen species, ROS; neutrophil extracellular traps, NETs; degranulation; apoptosis; elastase activity) were investigated both in a highly inflammatory state (without treatment) and in remission (on treatment). At diagnosis, neither IL1β, IL6, nor TNFα was significantly elevated in serum, but since TNFα blockade terminated the inflammatory symptoms, the disease was likely TNFα-driven. All neutrophil parameters were normal both during treatment and treatment withdrawal, except for MPO-dependent intracellular ROS- and NET formation. The role of total MPO deficiency for disease etiology and severity is discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sundqvist, Christenson, Wekell, Björnsdottir, Dahlstrand Rudin, Sanchez Klose, Kallinich, Welin, Björkman, Bylund, Karlsson-Bengtsson and Berg.)
Published: 2023
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41. Serum TGF-β as a predictive biomarker for severe disease and fatality of COVID-19.

Author: Frischbutter S, Durek P, Witkowski M, Angermair S, Treskatsch S, Maurer M, Radbruch A, and Mashreghi MF
Subjects: Humans, Biomarkers, Dexamethasone therapeutic use, Disease Progression, Transforming Growth Factor beta, COVID-19
Abstract: For targeted intervention in coronavirus disease 2019 (COVID-19), there is a high medical need for biomarkers that predict disease progression and severity in the first days after symptom onset. This study assessed the utility of early transforming growth factor β (TGF-β) serum levels in COVID-19 patients to predict disease severity, fatality, and response to dexamethasone therapy. Patients with severe COVID-19 had significantly higher TGF-β levels (416 pg/mL) as compared to patients with mild (165 pg/mL, p < 0.0001) or moderate COVID-19 (241 pg/mL; p < 0.0001). Receiver operating characteristics area under the curve values were 0.92 (95% confidence interval [CI] 0.85-0.99, cut-off: 255 pg/mL) for mild versus severe COVID-19, and 0.83 (95% CI 0.65-1.0, cut-off: 202 pg/mL) for moderate versus severe COVID-19. Patients who died of severe COVID-19 had significantly higher TGF-β levels (453 pg/mL) as compared to convalescent patients (344 pg/mL), and TGF-β levels predicted fatality (area under the curve: 0.75, 95% CI 0.53-0.96). TGF-β was significantly reduced in severely ill patients treated with dexamethasone (301 pg/mL) as compared to untreated patients (416 pg/mL; p < 0.05). Early TGF-β serum levels in COVID-19 patients predict, with high accuracy, disease severity, and fatality. In addition, TGF-β serves as a specific biomarker to assess response to dexamethasone treatment., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
Published: 2023
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42. Detecting and exploiting the circadian clock in rheumatoid arthritis.

Author: Wilantri S, Grasshoff H, Lange T, Gaber T, Besedovsky L, and Buttgereit F
Abstract: Over the past four decades, research on 24-h rhythms has yielded numerous remarkable findings, revealing their genetic, molecular, and physiological significance for immunity and various diseases. Thus, circadian rhythms are of fundamental importance to mammals, as their disruption and misalignment have been associated with many diseases and the abnormal functioning of many physiological processes. In this article, we provide a brief overview of the molecular regulation of 24-h rhythms, their importance for immunity, the deleterious effects of misalignment, the link between such pathological rhythms and rheumatoid arthritis (RA), and the potential exploitation of chronobiological rhythms for the chronotherapy of inflammatory autoimmune diseases, using RA as an example., (© 2023 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)
Published: 2023
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43. Treat-to-target strategies for the management of familial Mediterranean Fever in children.

Author: Ehlers L, Rolfes E, Lieber M, Müller D, Lainka E, Gohar F, Klaus G, Girschick H, Hörstermann J, Kümmerle-Deschner J, Brunner J, Palm-Beden K, Tenbrock K, von Wrangel L, Faßhauer M, Blank N, Trauzeddel R, von Stuckrad ASL, Higgins S, Welzel T, Lutz T, Hentgen V, Foell D, Wittkowski H, and Kallinich T
Subjects: Child, Humans, Colchicine therapeutic use, Consensus, Pyrin, Practice Guidelines as Topic, Arthritis, Biological Products, Familial Mediterranean Fever diagnosis, Familial Mediterranean Fever drug therapy
Abstract: Background: The objective of this initiative was to develop a treat-to-target (T2T) approach for the management of patients with Familial Mediterranean Fever (FMF), including the definition of a complex treatment target, and establish strategies that improve patient care and long-term outcome., Methods: An initial set of statements as well as a flow chart visualising the proposed concept was developed. To adapt the preliminary statements to the current state of knowledge, a systematic literature search was performed and the modified statements were subject to a Delphi approach. To ensure the applicability of the statements in daily practice, an online survey was conducted among paediatric rheumatologists in Germany. In addition, data from the national AID-NET registry were analysed with respect to therapeutic response., Results: This T2T initiative yielded a total of 26 statements guiding FMF management with respect to diagnosis, treatment targets, treatment strategies and monitoring. The online survey identified cut-off values for inflammatory markers indicating treatment intensification and appropriate measures in case of colchicine intolerance or non-adherence. The analysis of data derived from the national AID-NET showed that colchicine therapy was successfully terminated in 61% of patients (27 out of 44) with heterozygous MEFV mutations. Multidimensional treatment targets incorporating objective and subjective reported outcome measures were developed. These provide the basis for stratifying patients into the following treatment paths: continue colchicine, persisting attacks / inflammation, colchicine intolerance, persisting arthritis, colchicine reduction and adjustment/reduction of biologics., Conclusions: The proposed consensus treatment plan for the management of FMF incorporates multidimensional targets allowing transparent treatment decisions, which will promote personalised disease management and increase adherence to therapy., (© 2023. BioMed Central Ltd., part of Springer Nature.)
Published: 2023
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44. Distinct molecular profiles of skull bone marrow in health and neurological disorders.

Author: Kolabas ZI, Kuemmerle LB, Perneczky R, Förstera B, Ulukaya S, Ali M, Kapoor S, Bartos LM, Büttner M, Caliskan OS, Rong Z, Mai H, Höher L, Jeridi D, Molbay M, Khalin I, Deligiannis IK, Negwer M, Roberts K, Simats A, Carofiglio O, Todorov MI, Horvath I, Ozturk F, Hummel S, Biechele G, Zatcepin A, Unterrainer M, Gnörich J, Roodselaar J, Shrouder J, Khosravani P, Tast B, Richter L, Díaz-Marugán L, Kaltenecker D, Lux L, Chen Y, Zhao S, Rauchmann BS, Sterr M, Kunze I, Stanic K, Kan VWY, Besson-Girard S, Katzdobler S, Palleis C, Schädler J, Paetzold JC, Liebscher S, Hauser AE, Gokce O, Lickert H, Steinke H, Benakis C, Braun C, Martinez-Jimenez CP, Buerger K, Albert NL, Höglinger G, Levin J, Haass C, Kopczak A, Dichgans M, Havla J, Kümpfel T, Kerschensteiner M, Schifferer M, Simons M, Liesz A, Krahmer N, Bayraktar OA, Franzmeier N, Plesnila N, Erener S, Puelles VG, Delbridge C, Bhatia HS, Hellal F, Elsner M, Bechmann I, Ondruschka B, Brendel M, Theis FJ, and Erturk A
Subjects: Animals, Humans, Mice, Brain diagnostic imaging, Brain metabolism, Carrier Proteins metabolism, Positron-Emission Tomography methods, Receptors, GABA metabolism, Bone Marrow metabolism, Nervous System Diseases metabolism, Nervous System Diseases pathology, Skull cytology, Skull diagnostic imaging
Abstract: The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases., Competing Interests: Declaration of interests M. Brendel received speaker honoraria from GE healthcare, Roche, and Life Molecular Imaging and is an advisor of Life Molecular Imaging. J.H. reports personal fees, research grants, and non-financial support from Merck, Bayer, Novartis, Roche, Biogen, and Celgene and non-financial support of the Guthy-Jackson Charitable Foundation—none in relation to this study. C.P. is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. T.K. has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Teva Pharma, Merck, Novartis, Sanofi/Genzyme, Roche, and Biogen as well as grant support from Novartis and Chugai Pharma—none in relation to this study. M.K. has been on advisory boards for Biogen, medDay Pharmaceuticals, Novartis, and Sanofi; has received grant support from Sanofi and Biogen; and has received speaker fees from Abbvie, Almirall, Biogen, medDay Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi, and Teva—none in relation to this study. R.P. has received speaker honoraria, research support, and consultancy fees from Janssen, Eli Lilly, Biogen, Wilmar Schwabe, Takeda, Novo Nordisk, and Bayer Healthcare. N.K. has received speaker honoraria from Novartis and Regeneron and research grants from Regeneron—none in relationship to this study. M.I.T., H.S.B., M.N., and A.E. received speaker honoraria from Miltenyi Biotec—none in relation to this study. A.E. is co-founder of Deep Piction and 1X1 Biotech., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Published: 2023
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45. Reduced Humoral and Cellular Immune Response to Primary COVID-19 mRNA Vaccination in Kidney Transplanted Children Aged 5-11 Years.

Author: Lalia JK, Schild R, Lütgehetmann M, Dunay GA, Kallinich T, Kobbe R, Massoud M, Oh J, Pietzsch L, Schulze-Sturm U, Schuetz C, Sibbertsen F, Speth F, Thieme S, Witkowski M, Berner R, Muntau AC, Gersting SW, Toepfner N, Pagel J, and Paul K
Subjects: Humans, Child, BNT162 Vaccine, COVID-19 Vaccines, SARS-CoV-2, Immunity, Cellular, Kidney, RNA, Messenger genetics, Antibodies, Viral, Vaccination, Immunity, Humoral, Kidney Transplantation, COVID-19 prevention & control
Abstract: The situation of limited data concerning the response to COVID-19 mRNA vaccinations in immunocom-promised children hinders evidence-based recommendations. This prospective observational study investigated humoral and T cell responses after primary BNT162b2 vaccination in secondary immunocompromised and healthy children aged 5-11 years. Participants were categorized as: children after kidney transplantation (KTx, n = 9), proteinuric glomerulonephritis (GN, n = 4) and healthy children (controls, n = 8). Expression of activation-induced markers and cytokine secretion were determined to quantify the T cell response from PBMCs stimulated with peptide pools covering the spike glycoprotein of SARS-CoV-2 Wuhan Hu-1 and Omicron BA.5. Antibodies against SARS-CoV-2 spike receptor-binding domain were quantified in serum. Seroconversion was detected in 56% of KTx patients and in 100% of the GN patients and controls. Titer levels were significantly higher in GN patients and controls than in KTx patients. In Ktx patients, the humoral response increased after a third immunization. No differences in the frequency of antigen-specific CD4+ and CD8+ T cells between all groups were observed. T cells showed a predominant anti-viral capacity in their secreted cytokines; however, this capacity was reduced in KTx patients. This study provides missing evidence concerning the humoral and T cell response in immunocompromised children after COVID-19 vaccination.
Published: 2023
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46. Rescue combination treatment of anti-MDA5-associated ARDS with daratumumab.

Author: Ostendorf L, Muench F, Thormählen L, Galbavý Z, Körner R, Nee J, and Schneider U
Subjects: Humans, Antibodies, Monoclonal therapeutic use, Respiratory Distress Syndrome drug therapy, Respiratory Distress Syndrome etiology
Abstract: Competing Interests: Competing interests: None declared.
Published: 2023
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47. Enhanced Mott cell formation linked with IgM Fc receptor (FcμR) deficiency.

Author: Mahmoudi Aliabadi P, Al-Qaisi K, Jani PK, Honjo K, Klemm U, Lee KH, Baumgarth N, Radbruch A, Melchers F, and Kubagawa H
Subjects: Animals, Mice, Plasma Cells metabolism, Immunoglobulin M genetics, Immunoglobulin M metabolism, Receptors, Fc genetics, B-Lymphocytes metabolism
Abstract: In previous studies, Mott cells, an unusual form of plasma cells containing Ig-inclusion bodies, were frequently observed in peripheral lymphoid tissues in our IgM Fc receptor (FcμR)-deficient (KO) mouse strain. Because of discrepancies in the reported phenotypes of different Fcmr KO mouse strains, we here examined two additional available mutant strains and confirmed that such enhanced Mott-cell formation was a general phenomenon associated with FcμR deficiency. Splenic B cells from Fcmr KO mice clearly generated more Mott cells than those from WT mice when stimulated in vitro with LPS alone or a B-1, but not B-2, activation cocktail. Nucleotide sequence analysis of the Ig variable regions of a single IgMλ + Mott-hybridoma clone developed from splenic B-1 B cells of Fcmr KO mice revealed the near (VH) or complete (Vλ) identity with the corresponding germline gene segments and the addition of six or five nucleotides at the VH/DH and DH/JH junctions, respectively. Transduction of an FcμR cDNA into the Mott hybridoma significantly reduced cells containing IgM-inclusion bodies with a concomitant increase in IgM secretion, leading to secreted IgM binding to FcμR expressed on Mott transductants. These findings suggest a regulatory role of FcμR in the formation of Mott cells and IgM-inclusion bodies., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
Published: 2023
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48. Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients.

Author: Vanni A, Mazzoni A, Semeraro R, Capone M, Maschmeyer P, Lamacchia G, Salvati L, Carnasciali A, Farahvachi P, Giani T, Simonini G, Filocamo G, Romano M, Liotta F, Mashreghi MF, Cosmi L, Cimaz R, Magi A, Maggi L, and Annunziato F
Subjects: Humans, Synovial Fluid, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, CD4-Positive T-Lymphocytes, Inflammation, Arthritis, Juvenile
Abstract: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T-lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single-cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single-cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4 + and CD8 + T cells, those characterized by PD-1 expression were clonally expanded tissue-resident memory (Trm)-like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD-1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)
Published: 2023
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49. Regulation of tumor angiogenesis by the crosstalk between innate immunity and endothelial cells.

Author: Ebeling S, Kowalczyk A, Perez-Vazquez D, and Mattiola I
Abstract: Endothelial cells and immune cells are major regulators of cancer progression and prognosis. Endothelial cell proliferation and angiogenesis are required for providing nutrients and oxygen to the nascent tumor and infiltration of immune cells to the tumor is dependent on endothelial cell activation. Myeloid cells and innate lymphocytes have an important role in shaping the tumor microenvironment by crosstalking with cancer cells and structural cells, including endothelial cells. Innate immune cells can modulate the activation and functions of tumor endothelial cells, and, in turn, endothelial cell expression of adhesion molecules can affect immune cell extravasation. However, the mechanisms underlying this bidirectional crosstalk are not fully understood. In this review, we will provide an overview of the current knowledge on the pathways regulating the crosstalk between innate immune cells and endothelial cells during tumor progression and discuss their potential contribution to the development of novel anti-tumor therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ebeling, Kowalczyk, Perez-Vazquez and Mattiola.)
Published: 2023
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50. Hemolytic anemia following intravenous immunoglobulins in children with PIMS-TS: Two case reports.

Author: Sedlin E, Lau S, von Bernuth H, Kallinich T, and Mayer B
Abstract: This is the first case report on two children presenting with immediate and severe hemolytic anemia following the administration of high-dose intravenous immunoglobulins (IVIGs) in the context of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Hemolytic anemia was described as a significant decrease in hemoglobin and an increase in lactate dehydrogenase after the second administration of high-dose IVIGs was performed. Both patients were found to have AB blood group. One of our patients showed massive pallor, weakness, and inability to walk in association with hemolysis. However, in both cases, the anemia was self-limiting and transfusion of red blood cells was not required: both patients recovered without persistent impact. Nonetheless, we aim to draw attention to this widely unknown adverse effect of IVIG, especially in the context of PIMS-TS. We suggest determining the patient's blood group prior to high-dose IVIG infusion and replacing the second IVIG through high-dose steroids or anticytokine therapy. Using IVIGs containing lower titers of specifically anti-A or anti-B antibodies to avoid isoagglutinin-caused hemolytic anemia is desirable; however, the information is not routinely available., Competing Interests: HvB was employed by Labor Berlin GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Sedlin, Lau, von Bernuth, Kallinich and Mayer.)
Published: 2023
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