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1. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization

Author

Fuchs, Anke, Gliwiński, Mateusz, Grageda, Nathali, Spiering, Rachel, Abbas, Abul K, Appel, Silke, Bacchetta, Rosa, Battaglia, Manuela, Berglund, David, Blazar, Bruce, Bluestone, Jeffrey A, Bornhäuser, Martin, Brinke, Anja ten, Brusko, Todd M, Cools, Nathalie, Cuturi, Maria Cristina, Geissler, Edward, Giannoukakis, Nick, Gołab, Karolina, Hafler, David A, van Ham, S Marieke, Hester, Joanna, Hippen, Keli, Di Ianni, Mauro, Ilic, Natasa, Isaacs, John, Issa, Fadi, Iwaszkiewicz-Grześ, Dorota, Jaeckel, Elmar, Joosten, Irma, Klatzmann, David, Koenen, Hans, van Kooten, Cees, Korsgren, Olle, Kretschmer, Karsten, Levings, Megan, Marek-Trzonkowska, Natalia Maria, Martinez-Llordella, Marc, Miljkovic, Djordje, Mills, Kingston HG, Miranda, Joana P, Piccirillo, Ciriaco A, Putnam, Amy L, Ritter, Thomas, Roncarolo, Maria Grazia, Sakaguchi, Shimon, Sánchez-Ramón, Silvia, Sawitzki, Birgit, Sofronic-Milosavljevic, Ljiljana, Sykes, Megan, Tang, Qizhi, Vives-Pi, Marta, Waldmann, Herman, Witkowski, Piotr, Wood, Kathryn J, Gregori, Silvia, Hilkens, Catharien MU, Lombardi, Giovanna, Lord, Phillip, Martinez-Caceres, Eva M, and Trzonkowski, Piotr

Subjects
Vaccine Related, Autoimmune Disease, Inflammatory and immune system, minimum information model, T regulatory cells, immunotherapy, good manufacturing practice, cell therapy, immune tolerance, Immunology, Medical Microbiology
Abstract

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

Published
2018

3. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.

Author

Fuchs, Anke, Gliwiński, Mateusz, Grageda, Nathali, Spiering, Rachel, Abbas, Abul K, Appel, Silke, Bacchetta, Rosa, Battaglia, Manuela, Berglund, David, Blazar, Bruce, Bluestone, Jeffrey A, Bornhäuser, Martin, Ten Brinke, Anja, Brusko, Todd M, Cools, Nathalie, Cuturi, Maria Cristina, Geissler, Edward, Giannoukakis, Nick, Gołab, Karolina, Hafler, David A, van Ham, S Marieke, Hester, Joanna, Hippen, Keli, Di Ianni, Mauro, Ilic, Natasa, Isaacs, John, Issa, Fadi, Iwaszkiewicz-Grześ, Dorota, Jaeckel, Elmar, Joosten, Irma, Klatzmann, David, Koenen, Hans, van Kooten, Cees, Korsgren, Olle, Kretschmer, Karsten, Levings, Megan, Marek-Trzonkowska, Natalia Maria, Martinez-Llordella, Marc, Miljkovic, Djordje, Mills, Kingston HG, Miranda, Joana P, Piccirillo, Ciriaco A, Putnam, Amy L, Ritter, Thomas, Roncarolo, Maria Grazia, Sakaguchi, Shimon, Sánchez-Ramón, Silvia, Sawitzki, Birgit, Sofronic-Milosavljevic, Ljiljana, Sykes, Megan, Tang, Qizhi, Vives-Pi, Marta, Waldmann, Herman, Witkowski, Piotr, Wood, Kathryn J, Gregori, Silvia, Hilkens, Catharien MU, Lombardi, Giovanna, Lord, Phillip, Martinez-Caceres, Eva M, and Trzonkowski, Piotr

Subjects
T regulatory cells, cell therapy, good manufacturing practice, immune tolerance, immunotherapy, minimum information model, Autoimmune Disease, Vaccine Related, Inflammatory and Immune System, Immunology, Medical Microbiology
Abstract

Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.

Published
2017

4. Beiträge zum 29. Darmstädter Geotechnik-Kolloquium am 7. März 2024

Author

Zachert, Hauke, Kochnev, Alexander, Siegel, Simon, Black, Christoph, Wall, Johannes, Dallinger, Christina, Rebhan, Matthias J., Daxer, Hans-Peter, Tschuchnigg, Franz, Marte, Roman, Schuch, Markus, Klass, Clemens, Breit, Klaus, Beckhaus, Karsten, Ibuk, Hursit, Jäger, Stefan, Labenski, Johannes, Poenaru, Alexandru, Treffeisen, Torben, Schnell, Sebastian, Sklorz, Michael, Schöppner, Clemens, Jaramillo Castro, July Ellen, Henke, Sascha, Detert, Oliver, Daubner, Marcus, Schneider, Marc, Hell, Marylin, Wittekoek, Britt, Eekelen, Suzanne J. M. van, Schauber, Pascal, Pandrea, Paul, Topolnicki, Michał, Makowska, Karolina, Baumgartner, Lorenz, Kasper, Tobias, Cagimda, Inan, Karpa, Gudrun, Fontara, Ioanna-Kleonik, Appel, Silke, Wegerl, Markus, Baur, Raphael, Voigt, Jens, Koch, Lothar, Maier-Rotter, Mona, Gündling, Norbert, Gutwald, Jörg, Niemetz, Gunther, Wehr, Christoph, Böhm, Sebastian, Zachert, Hauke, Kochnev, Alexander, Siegel, Simon, Black, Christoph, Wall, Johannes, Dallinger, Christina, Rebhan, Matthias J., Daxer, Hans-Peter, Tschuchnigg, Franz, Marte, Roman, Schuch, Markus, Klass, Clemens, Breit, Klaus, Beckhaus, Karsten, Ibuk, Hursit, Jäger, Stefan, Labenski, Johannes, Poenaru, Alexandru, Treffeisen, Torben, Schnell, Sebastian, Sklorz, Michael, Schöppner, Clemens, Jaramillo Castro, July Ellen, Henke, Sascha, Detert, Oliver, Daubner, Marcus, Schneider, Marc, Hell, Marylin, Wittekoek, Britt, Eekelen, Suzanne J. M. van, Schauber, Pascal, Pandrea, Paul, Topolnicki, Michał, Makowska, Karolina, Baumgartner, Lorenz, Kasper, Tobias, Cagimda, Inan, Karpa, Gudrun, Fontara, Ioanna-Kleonik, Appel, Silke, Wegerl, Markus, Baur, Raphael, Voigt, Jens, Koch, Lothar, Maier-Rotter, Mona, Gündling, Norbert, Gutwald, Jörg, Niemetz, Gunther, Wehr, Christoph, and Böhm, Sebastian

Abstract

Themenschwerpunkte: 1. Klimawandelfolgen und Nachhaltigkeit 2. Digitalisierung und künstliche Intelligenz 3. Planung und Bemessung von Infrastrukturprojekten 4. Großprojekte

Published
2024

6. Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland

Author

Wiley, Mandi M, primary, Khatri, Bhuwan, additional, Joachims, Michelle L, additional, Tessneer, Kandice L, additional, Stolarczyk, Anna M, additional, Rasmussen, Astrid, additional, Anaya, Juan-Manuel, additional, Aqrawi, Lara A, additional, Bae, Sang-Cheol, additional, Baecklund, Eva, additional, Bjork, Albin, additional, Brun, Johan G, additional, Bucher, Sara Magnusson, additional, Dand, Nick, additional, Eloranta, Maija-Leena, additional, Engelke, Fiona, additional, Forsblad-d'Elia, Helena, additional, Fugmann, Cecilia, additional, Glenn, Stuart B, additional, Gong, Chen, additional, Gottenberg, Jacques-Eric, additional, Hammenfors, Daniel, additional, Imgenberg-Kreuz, Juliana, additional, Jensen, Janicke Liaaen, additional, Johnsen, Svein Joar Auglaend, additional, Jonsson, Malin V, additional, Kelly, Jennifer A, additional, Khanam, Sharmily, additional, Kim, Kwangwoo, additional, Kvarnstrom, Marika, additional, Mandl, Thomas, additional, Martin, Javier, additional, Morris, David L, additional, Nocturne, Gaetane, additional, Norheim, Katrine Braekke, additional, Olsson, Peter, additional, Palm, Oyvind, additional, Pers, Jacques-Olivier, additional, Rhodus, Nelson L, additional, Sjowall, Christopher, additional, Skarstein, Kathrine, additional, Taylor, Kimberly E, additional, Tombleson, Phil, additional, Thorlacius, Gudny Ella, additional, Venuturupalli, Swamy, additional, Vital, Edward M, additional, Wallace, Daniel J., additional, Grundahl, Kiely M, additional, Radfar, Lida, additional, Brennan, Michael T, additional, James, Judith A, additional, Scofield, R. Hal, additional, Gaffney, Patrick M, additional, Criswell, Lindsey A, additional, Jonsson, Roland, additional, Appel, Silke, additional, Eriksson, Per, additional, Bowman, Simon J, additional, Omdal, Roald, additional, Ronnblom, Lars, additional, Warner, Blake M., additional, Rischmueller, Maureen, additional, Witte, Torsten, additional, Farris, A. Darise, additional, Mariette, Xavier, additional, Shiboski, Caroline H, additional, Wahren-Herlenius, Marie, additional, Alarcon-Riquelme, Marta E, additional, Ng, Wan-Fai, additional, Sivils, Kathy L., additional, Guthridge, Joel M, additional, Adrianto, Indra, additional, Vyse, Timothy J, additional, Tsao, Betty P, additional, Nordmark, Gunnel, additional, and Lessard, Christopher J, additional

Published
2023
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11. Variability of Primary Sjögren's Syndrome Is Driven by Interferon α and Interferon α Blood Levels Are Associated With the Class II HLA–DQ Locus

Author

Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Hélène, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana‐Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, Gottenberg, Jacques Eric, Dernis, Emmanuelle, Devauchelle‐Pensec, Valerie, Dieude, Philippe, Dubost, Jean‐Jacques, Fauchais, Anne‐Laure, Goeb, Vincent, Hachulla, Eric, Hatron, Pierre Yves, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Salliot, Carinne, Rist, Stephanie, Saraux, Alain, Vittecoq, Olivier, Nocturne, Gaétane, Ravaud, Philippe, Seror, Raphaèle, Abel, Laurent, Alcover, Andres, Aschard, Hugues, Astrom, Kalla, Bousso, Philippe, Bruhns, Pierre, Cumano, Ana, Demangel, Caroline, Deriano, Ludovic, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gelpi, Odile, GompertsBoneca, Ivo, Hasan, Milena, Hercberg, Serge, Lantz, Olivier, Leclerc, Claude, Mouquet, Hugo, Pellegrini, Sandra, Pol, Stanislas, Rausell, Antonio, Rogge, Lars, Sakuntabhai, Anavaj, Schwartz, Olivier, Shorte, Spencer, Soumelis, Vassili, Tangy, Frédéric, Tartour, Eric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie‐Noëlle, Albert, Matthew L., Biomédecine computationelle des systèmes / Computational systems biomedicine, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie Translationnelle - Translational Immunology lab, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Lausanne University Hospital, University of Bergen (UiB), Oklahoma Medical Research Foundation (OMRF), University of Oklahoma Health Sciences Center (OUHSC), Université de Strasbourg (UNISTRA), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biogen Inc. [Cambridge, MA, USA], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (grant 806975). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Unionand the European Federation of Pharmaceutical Industries and Associations. This work was also supported by the National Institutes of Health (National Institute of Arthritis and Musculoskeletal Skin Disease grant R01-AR-065953). The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome(ASSESS) national multicenter prospective cohort was formed in 2006 with aFrench Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology. Dr. Gottenberg’s work was supported by Bristol Myers Squibbfor transcriptomic analysis of the ASSESS and Norwegian cohorts and by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögrenet des syndromes secs). Drs. Trutschel’s and Schwikowski’s work was supported by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs)., Milieu Intérieur Consortium, ASSESS study investigators, and NECESSITY Consortium: Emmanuelle Dernis, Valerie Devauchelle-Pensec, Philippe Dieude, Jean-Jacques Dubost, Anne-Laure Fauchais, Vincent Goeb, Eric Hachulla, Pierre Yves Hatron, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Carinne Salliot, Stephanie Rist, Alain Saraux, Jean Sibilia, Olivier Vittecoq, Gaétane Nocturne, Philippe Ravaud, Raphaèle Seror, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Odile Gelpi, Ivo GompertsBoneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci., European Project: 806975,NECESSITY, Clauss, Isabelle, and NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID

Subjects
Proteomics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sjogren's Syndrome, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, HLA-DQ Antigens, Immunology, Humans, Interferon-alpha, Immunology and Allergy, Prospective Studies
Abstract

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa). Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA–DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., Arthritis & Rheumatology, 74 (12), ISSN:2326-5191, ISSN:2326-5205

Published
2022
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12. Additional file 1 of Impaired activation of STAT5 upon IL-2 stimulation in Tregs and elevated sIL-2R in Sjögren’s syndrome

Author

Keindl, Magdalena, Davies, Richard, Bergum, Brith, Brun, Johan G., Hammenfors, Daniel, Jonsson, Roland, Lyssenko, Valeriya, and Appel, Silke

Abstract

Additional file 1: Table S1. Fluorescently labelled antibodies and amine dyes used for phospho-flow cytometry. Figure S1. Representative gating strategy used in the analysis of phosphorylation of STAT5 in PBMCs. Lymphocytes were gated based on their forward scatter area (FSC-A) and side scatter area (SSC-A) properties, followed by singlet gating based on SSC-A and side scatter height (SSC-H). Subsequently, CD3+ CD4+ T cells were gated. The different samples were then identified through the intensities of their Alexa Fluor 488, Pacific Blue and Pacific Orange staining (barcoding). One representative sample is shown to display further gating steps. Tregs and Tconv were identified based on their surface antigen presentation (Tregs: CD25+ CD127- , Tconv: CD25- ). Finally, cells with phosphorylated STAT5 at position Y964 were gated in Tregs and Tconv. Figure S2. (A) In the non-severe Sjögren’s syndrome (SS) group seropositive patients had significantly higher sIL-2R compared with seronegative patients. (B) A histogram of the saliva weight (ml/5 min) produced by patients with Sjögren’s syndrome after paraffin stimulation. The vertical dashed line shows the cut-off at 3.5 ml/5 min which we used to split between patients with severe and non-severe phenotype. (Mann-Whitney U test was used in the comparison between the different groups. *p≤0.05, **p≤0.01, ***p≤0.001, and ***p≤ 0.0001.). Figure S3. The selected 51 individuals for the phospho-flow cytometry analysis are representative of the whole cohort and display significantly higher sIL-2R in patients with Sjögren’s syndrome (SS) (A), particularly those with low saliva production (B). (Mann-Whitney U test was used in the comparison between the different groups. *p ≤0.05, **p≤0.01, ***p≤0.001, and ***p≤0.0001). Figure S4. Percentage of pSTAT5+ Tregs and their association with serology. (A) Seropositive patients with Sjögren’s syndrome had a significantly higher frequency of pSTAT5+ Tregs at baseline compared with seronegative patients (right panel), whereas no difference was observed in IL-2 stimulated Tregs (left panel). (B) The difference in pSTAT5+ Tregs between baseline and IL-2 stimulation was slightly lower in seropositive patients with Sjögren’s syndrome. (Mann-Whitney U test was used in the comparison between the different groups. *p≤ 0.05, **p≤0.01, ***p≤0.001, and ***p≤0.0001.). Figure S5. Frequency of pSTAT5+ Tregs and their association with plasma sIL-2R. (A) Higher plasma sIL-2R levels significantly associated with higher frequency of pSTAT5+ Tregs at baseline (right panel), whereas no correlation was observed in IL-2 stimulated Tregs (left panel). (B) The difference in pSTAT5+ Tregs between baseline and IL-2 stimulation did not correlate with sIL-2R (To evaluate the association between two variables we applied the Pearson correlation formula.).

Published
2022
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16. Genetic and clinical basis for two distinct subtypes of primary Sjögren's syndrome

Author

Thorlacius, Guðný Ella, Hultin-Rosenberg, Lina, Sandling, Johanna K., Bianchi, Matteo, Imgenberg-Kreuz, Juliana, Pucholt, Pascal, Theander, Elke, Kvarnström, Marika, Forsblad-D'elia, Helena, Bucher, Sara Magnusson, Norheim, Katrine B., Johnsen, Svein Joar Auglænd, Hammenfors, Daniel, Skarstein, Kathrine, Jonsson, Malin V., Baecklund, Eva, Aqrawi, Lara A., Jensen, Janicke Liaaen, Palm, Øyvind, Morris, Andrew P., Alexsson, Andrei, Backlin, Carin, Rönnblom, Lars, Vasaitis, Lilian, Eloranta, Maija Leena, Syvänen, Ann Christine, Mathioudaki, Argyri, Farias, Fabiana H.G., Meadows, Jennifer, Nordin, Jessika, Lindblad-Toh, Kerstin, Björk, Albin, Lundberg, Ingrid E., Sepúlveda, Jorge I.Ramírez, Wahren-Herlenius, Marie, Eriksson, Daniel, Eriksson, Per, Sjöwall, Christopher, Mandl, Thomas, Rantapaä¨-Dahlqvist, Solbritt, Brokstad, Karl A., Jonsson, Roland, Appel, Silke, Brun, Johan G., Norheim, Katrine Brække, Omdal, Roald, Aqrawi, Lara Adnan, Pielberg, Gerli Rosengren, Murén, Eva, Karlsson, Åsa, Andersson, Göran, Ahlgren, Kerstin M., Lobell, Anna, Söderkvist, Peter, Kämpe, Olle, Landegren, Nils, Meadows, Jennifer R.S., Lind, Lars, and Nordmark, Gunnel

Subjects
musculoskeletal diseases, stomatognathic diseases, stomatognathic system, gene polymorphism, autoantibodies, autoimmunity, Sjögren's syndrome, eye diseases
Abstract

Objectives: Clinical presentation of primary Sjögren's syndrome (pSS) varies considerably. A shortage of evidence-based objective markers hinders efficient drug development and most clinical trials have failed to reach primary endpoints. Methods: We performed a multicentre study to identify patient subgroups based on clinical, immunological and genetic features. Targeted DNA sequencing of 1853 autoimmune-related loci was performed. After quality control, 918 patients with pSS, 1264 controls and 107 045 single nucleotide variants remained for analysis. Replication was performed in 177 patients with pSS and 7672 controls. Results: We found strong signals of association with pSS in the HLA region. Principal component analysis of clinical data distinguished two patient subgroups defined by the presence of SSA/SSB antibodies. We observed an unprecedented high risk of pSS for an association in the HLA-DQA1 locus of odds ratio 6.10 (95% CI: 4.93, 7.54, P=2.2×10-62) in the SSA/SSB-positive subgroup, while absent in the antibody negative group. Three independent signals within the MHC were observed. The two most significant variants in MHC class I and II respectively, identified patients with a higher risk of hypergammaglobulinaemia, leukopenia, anaemia, purpura, major salivary gland swelling and lymphadenopathy. Replication confirmed the association with both MHC class I and II signals confined to SSA/SSB antibody positive pSS. Conclusion: Two subgroups of patients with pSS with distinct clinical manifestations can be defined by the presence or absence of SSA/SSB antibodies and genetic markers in the HLA locus. These subgroups should be considered in clinical follow-up, drug development and trial outcomes, for the benefit of both subgroups.

Published
2021
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17. Identification of a lysosomal peptide transport system induced during dendritic cell development

Author

Demirel, Özlem, Waibler, Zoe, Kalinke, Ulrich, Grünebach, Frank, Appel, Silke, Brossart, Peter, Hasilik, Andrej, Tampé, Robert, Abele, Rupert, Demirel, Özlem, Waibler, Zoe, Kalinke, Ulrich, Grünebach, Frank, Appel, Silke, Brossart, Peter, Hasilik, Andrej, Tampé, Robert, and Abele, Rupert

Abstract

The delivery of protein fragments to major histocompatibility complex (MHC)-loading compartments of professional antigen-presenting cells is essential in the adaptive immune response against pathogens. Apart from the crucial role of the transporter associated with antigen processing (TAP) for peptide loading of MHC class I molecules in the endoplasmic reticulum, TAP-independent translocation pathways have been proposed but not identified so far. Based on its overlapping substrate specificity with TAP, we herein investigated the ABC transporter ABCB9, also named TAP-like (TAPL). Remarkably, TAPL expression is strongly induced during differentiation of monocytes to dendritic cells and to macrophages. TAPL does not, however, restore MHC class I surface expression in TAP-deficient cells, demonstrating that TAPL alone or in combination with single TAP subunits does not form a functional transport complex required for peptide loading of MHC I in the endoplasmic reticulum. In fact, by using quantitative immunofluorescence and subcellular fractionation, TAPL was detected in the lysosomal compartment co-localizing with the lysosome-associated membrane protein LAMP-2. By in vitro assays, we demonstrate a TAPL-specific translocation of peptides into isolated lysosomes, which strictly requires ATP hydrolysis. These results suggest a mechanism by which antigenic peptides have access to the lysosomal compartment in professional antigen-presenting cells.

Published
2021

22. Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With IL2RA and PTPN2 Gene Polymorphisms

Author

Keindl, Magdalena, Fedotkina, Olena, du Plessis, Elsa, Jain, Ruchi, Bergum, Brith, Mygind Jensen, Troels, Laustrup Moller, Cathrine, Falhammar, Henrik, Nyström, Thomas, Catrina, Sergiu-Bogdan, Jörneskog, Gun, Groop, Leif, Eliasson, Mats, Eliasson, Björn, Brismar, Kerstin, Nilsson, Peter M., Berg, Tore Julsrud, Appel, Silke, Lyssenko, Valeriya, Keindl, Magdalena, Fedotkina, Olena, du Plessis, Elsa, Jain, Ruchi, Bergum, Brith, Mygind Jensen, Troels, Laustrup Moller, Cathrine, Falhammar, Henrik, Nyström, Thomas, Catrina, Sergiu-Bogdan, Jörneskog, Gun, Groop, Leif, Eliasson, Mats, Eliasson, Björn, Brismar, Kerstin, Nilsson, Peter M., Berg, Tore Julsrud, Appel, Silke, and Lyssenko, Valeriya

Abstract

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic beta cells. Further, patients with T1D have 3-4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the IL2RA and PTPN2 gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naive to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that IL2RA and PTPN2 gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monit

Published
2020
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28. Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With IL2RA and PTPN2 Gene Polymorphisms

Author

Keindl, Magdalena, primary, Fedotkina, Olena, additional, du Plessis, Elsa, additional, Jain, Ruchi, additional, Bergum, Brith, additional, Mygind Jensen, Troels, additional, Laustrup Møller, Cathrine, additional, Falhammar, Henrik, additional, Nyström, Thomas, additional, Catrina, Sergiu-Bogdan, additional, Jörneskog, Gun, additional, Groop, Leif, additional, Eliasson, Mats, additional, Eliasson, Björn, additional, Brismar, Kerstin, additional, Nilsson, Peter M., additional, Berg, Tore Julsrud, additional, Appel, Silke, additional, and Lyssenko, Valeriya, additional

Published
2020
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44. Maturation of monocyte derived dendritic cells with OK432 boosts IL-12p70 secretion and conveys strong T-cell responses

Author

Aarstad Hans, Jonsson Roland, Karlsen Marie, Hovden Arnt-Ove, and Appel Silke

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Design of tumour specific immunotherapies using the patients' own dendritic cells (DC) is a fast advancing scientific field. The functional qualities of the DC generated in vitro are critical, and today's gold standard for maturation is a cytokine cocktail consisting of IL-1β, IL-6, TNF-α and PGE2 generating cells lacking IL-12p70 production. OK432 is an immunotherapeutic agent derived from killed Streptococcus pyogenes that has been used clinically to treat malignant and benign neoplasms for decades. Methods In this study, we analysed the effects of OK432 on DC maturation, DC migration, cytokine and chemokine secretion as well as T-cell stimulatory capacity, and compared it to the cytokine cocktail alone and combinations of OK432 with the cytokine cocktail. Results OK432 induced a marked up-regulation of CD40 on the cell surface as well as a strong inflammatory response from the DC with significantly more secretion of 19 different cytokines and chemokines compared to the cytokine cocktail. Interestingly, secretion of IL-15 and IL-12p70 was detected at high concentrations after maturation of DC with OK432. However, the OK432 treated DC did not migrate as well as DC treated with cytokine cocktail in a transwell migration assay. During allogeneic T-cell stimulation OK432 treated DC induced proliferation of over 50 percent of CD4 and 30 percent of CD8 T-cells for more than two cell divisions, whereas cytokine cocktail treated DC induced proliferation of 12 and 11 percent of CD4 and CD8 T-cells, respectively. Conclusions The clinically approved compound OK432 has interesting properties that warrants its use in DC immunotherapy and should be considered as a potential immunomodulating agent in cancer immunotherapy.

Published
2011
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47. Intelligent Quarters Hamburg: Zur Tragwerksplanung schwingungsentkoppelter Hochhäuser.

Author

Hensel, Thomas, Wiechert, Michael, Appel, Silke, and Lochte‐Holtgreven, Stephan

Subjects
SUBWAY design & construction, STRUCTURAL dynamics, JOINT ventures, STRUCTURAL mechanics
Abstract

Copyright of Bautechnik is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2020
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50. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization

Author

Fuchs, Anke, primary, Gliwiński, Mateusz, additional, Grageda, Nathali, additional, Spiering, Rachel, additional, Abbas, Abul K., additional, Appel, Silke, additional, Bacchetta, Rosa, additional, Battaglia, Manuela, additional, Berglund, David, additional, Blazar, Bruce, additional, Bluestone, Jeffrey A., additional, Bornhäuser, Martin, additional, ten Brinke, Anja, additional, Brusko, Todd M., additional, Cools, Nathalie, additional, Cuturi, Maria Cristina, additional, Geissler, Edward, additional, Giannoukakis, Nick, additional, Gołab, Karolina, additional, Hafler, David A., additional, van Ham, S. Marieke, additional, Hester, Joanna, additional, Hippen, Keli, additional, Di Ianni, Mauro, additional, Ilic, Natasa, additional, Isaacs, John, additional, Issa, Fadi, additional, Iwaszkiewicz-Grześ, Dorota, additional, Jaeckel, Elmar, additional, Joosten, Irma, additional, Klatzmann, David, additional, Koenen, Hans, additional, van Kooten, Cees, additional, Korsgren, Olle, additional, Kretschmer, Karsten, additional, Levings, Megan, additional, Marek-Trzonkowska, Natalia Maria, additional, Martinez-Llordella, Marc, additional, Miljkovic, Djordje, additional, Mills, Kingston H.G., additional, Miranda, Joana P., additional, Piccirillo, Ciriaco A., additional, Putnam, Amy L., additional, Ritter, Thomas, additional, Roncarolo, Maria Grazia, additional, Sakaguchi, Shimon, additional, Sánchez-Ramón, Silvia, additional, Sawitzki, Birgit, additional, Sofronic-Milosavljevic, Ljiljana, additional, Sykes, Megan, additional, Tang, Qizhi, additional, Vives-Pi, Marta, additional, Waldmann, Herman, additional, Witkowski, Piotr, additional, Wood, Kathryn J., additional, Gregori, Silvia, additional, Hilkens, Catharien M. U., additional, Lombardi, Giovanna, additional, Lord, Phillip, additional, Martinez-Caceres, Eva M., additional, and Trzonkowski, Piotr, additional

Published
2018
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