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1. P2RX7 gene variants associate with altered inflammasome assembly and reduced pyroptosis in chronic nonbacterial osteomyelitis (CNO)

Author

Charras, Amandine, Hofmann, Sigrun R., Cox, Allison, Schulze, Felix, Russ, Susanne, Northey, Sarah, Liu, Xuan, Fang, Yongxiang, Haldenby, Sam, Hartmann, Hella, Bassuk, Alexander G., Carvalho, Ana, Sposito, Francesca, Grinstein, Lev, Rösen-Wolff, Angela, Meyer-Bahlburg, Almut, Beresford, Michael W., Lainka, Elke, Foell, Dirk, Wittkowski, Helmut, Girschick, Hermann J., Morbach, Henner, Uebe, Steffen, Hüffmeier, Ulrike, Ferguson, Polly J., and Hedrich, Christian M.

Published
2024
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2. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases

Author

de Jesus, Adriana A, Hou, Yangfeng, Brooks, Stephen, Malle, Louise, Biancotto, Angelique, Huang, Yan, Calvo, Katherine R, Marrero, Bernadette, Moir, Susan, Oler, Andrew J, Deng, Zuoming, Montealegre Sanchez, Gina A, Ahmed, Amina, Allenspach, Eric, Arabshahi, Bita, Behrens, Edward, Benseler, Susanne, Bezrodnik, Liliana, Bout-Tabaku, Sharon, Brescia, AnneMarie C, Brown, Diane, Burnham, Jon M, Caldirola, Maria Soledad, Carrasco, Ruy, Chan, Alice Y, Cimaz, Rolando, Dancey, Paul, Dare, Jason, DeGuzman, Marietta, Dimitriades, Victoria, Ferguson, Ian, Ferguson, Polly, Finn, Laura, Gattorno, Marco, Grom, Alexei A, Hanson, Eric P, Hashkes, Philip J, Hedrich, Christian M, Herzog, Ronit, Horneff, Gerd, Jerath, Rita, Kessler, Elizabeth, Kim, Hanna, Kingsbury, Daniel J, Laxer, Ronald M, Lee, Pui Y, Lee-Kirsch, Min Ae, Lewandowski, Laura, Li, Suzanne, Lilleby, Vibke, Mammadova, Vafa, Moorthy, Lakshmi N, Nasrullayeva, Gulnara, O'Neil, Kathleen M, Onel, Karen, Ozen, Seza, Pan, Nancy, Pillet, Pascal, Piotto, Daniela Gp, Punaro, Marilynn G, Reiff, Andreas, Reinhardt, Adam, Rider, Lisa G, Rivas-Chacon, Rafael, Ronis, Tova, Rösen-Wolff, Angela, Roth, Johannes, Ruth, Natasha Mckerran, Rygg, Marite, Schmeling, Heinrike, Schulert, Grant, Scott, Christiaan, Seminario, Gisella, Shulman, Andrew, Sivaraman, Vidya, Son, Mary Beth, Stepanovskiy, Yuriy, Stringer, Elizabeth, Taber, Sara, Terreri, Maria Teresa, Tifft, Cynthia, Torgerson, Troy, Tosi, Laura, Van Royen-Kerkhof, Annet, Wampler Muskardin, Theresa, Canna, Scott W, and Goldbach-Mansky, Raphaela

Subjects
Genetics, Clinical Research, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Autoimmune Diseases, Female, Humans, Interferon Type I, Interleukin-18, Macrophage Activation Syndrome, Male, Mutation, Panniculitis, Pulmonary Alveolar Proteinosis, Genetic diseases, Immunology, Inflammation, Innate immunity, Monogenic diseases, Medical and Health Sciences
Abstract

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Published
2020

6. Tissue inflammation induced by constitutively active STING is mediated by enhanced TNF signaling

Author

Luksch, Hella, primary, Schulze, Felix, additional, Geißler-Lösch, David, additional, Sprott, David, additional, Höfs, Lennart, additional, Szegö, Eva M, additional, Tonnus, Wulf, additional, Winkler, Stefan, additional, Günther, Claudia, additional, Linkermann, Andreas, additional, Behrendt, Rayk, additional, Teichmann, Lino L, additional, Falkenburger, Björn H, additional, and Rösen-Wolff, Angela, additional

Published
2024
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7. Episodische Fiebersyndrome – autoinflammatorische Syndrome

Author

Horneff, Gerd, Rösen-Wolff, Angela, Berner, Reinhard, Section editor, Hoffmann, Georg F., editor, Lentze, Michael J., editor, Spranger, Jürgen, editor, Zepp, Fred, editor, Berner, Reinhard, editor, Schaub, Jürgen, Founding Editor, and Schulte, Franz-Josef, Founding Editor

Published
2020
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8. Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Author

Eva M Szego, Laura Malz, Nadine Bernhardt, Angela Rösen-Wolff, Björn H Falkenburger, and Hella Luksch

Subjects
parkinson, synuclein, neurodegeneration, innate immunity, neuroinflammation, inflammasome, Medicine, Science, Biology (General), QH301-705.5
Abstract

Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral sclerosis, and the STING pathway has been implicated in the pathogenesis of further neurodegenerative diseases. To test whether STING activation is sufficient to induce neurodegeneration, we analysed a mouse model that expresses the constitutively active STING variant N153S. In this model, we focused on dopaminergic neurons, which are particularly sensitive to stress and represent a circumscribed population that can be precisely quantified. In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. These neuroinflammatory markers were already elevated in juvenile mice although at this age the number of dopaminergic neurons was still unaffected, thus preceding the degeneration of dopaminergic neurons. More neuroinflammatory markers were blunted in mice deficient for inflammasomes than in mice deficient for signalling by type I interferons. Neurodegeneration, however, was blunted in both mice. Collectively, these findings demonstrate that chronic activation of the STING pathway is sufficient to cause degeneration of dopaminergic neurons. Targeting the STING pathway could therefore be beneficial in Parkinson’s disease and further neurodegenerative diseases.

Published
2022
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9. Validation of reference genes for whole blood gene expression analysis in cord blood of preterm and full-term neonates and peripheral blood of healthy adults

Author

Kristin Hieronymus, Benjamin Dorschner, Felix Schulze, Neeta L. Vora, Joel S. Parker, Jennifer Lucia Winkler, Angela Rösen-Wolff, and Stefan Winkler

Subjects
Housekeeping genes, Comparative gene expression analysis, Validation, Whole blood, Neonates, Infants, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Preterm birth is the leading cause of neonatal morbidity and mortality, but research efforts in neonatology are complicated due to the unavailability of large volume blood samples. Whole blood assays can be used to overcome this problem by performing both functional and gene expression studies using small amounts of blood. Gene expression studies using RT-qPCR estimate mRNA-levels of target genes normalized to reference genes. The goal of this study was to identify and validate stable reference genes applicable to cord blood samples obtained from developing neonates of different gestational age groups as well as to adult peripheral blood samples. Eight reference gene candidates (ACTB, B2M, GAPDH, GUSB, HPRT, PPIB, RPLP0, RPL13) were analyzed using the three published software algorithms Bestkeeper, GeNorm and NormFinder. Results A normalization factor consisting of ACTB and PPIB allows for comparative expression analyses of neonatal samples from different gestational age groups. Normalization factors consisting of GAPDH and PPIB or ACTB and GAPDH are suitable when samples from preterm and full-term neonates and adults are compared. However, all candidate reference genes except RPLP0 exhibited significant intergroup gene expression variance and a higher gene expression towards an older age which resulted in a small but statistically significant systematic bias. Systematic analysis of RNA-seq data revealed new reference gene candidates with potentially superior stability. Conclusions The current study identified suitable normalization factors and proposed the use of the additional single gene RPLP0 to avoid systematic bias. This combination will enable comparative analyses not only between neonates of different gestational ages, but also between neonates and adults, as it facilitates more detailed investigations of developmental gene expression changes. The use of software algorithms did not prevent unintended systematic bias. This generally highlights the need for careful validation of such results to prevent false interpretation of potential age-dependent changes in gene expression. To identify the most stable reference genes in the future, RNA-seq based global approaches are recommended.

Published
2021
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10. Quantification of unperturbed phosphoprotein levels in immune cell subsets with phosphoflow to assess immune signaling in autoimmune disease

Author

Calvin Krollmann, Kevin Cieslak, Ruth-Miriam Koerber, Hella Luksch, Angela Rösen-Wolff, Peter Brossart, and Lino L. Teichmann

Subjects
Flow Cytometry/Mass Cytometry, Immunology, Science (General), Q1-390
Abstract

Summary: Activation of innate immune sensors by endogenous DNA and RNA can lead to autoimmune and autoinflammatory diseases. Quantification of the unperturbed phosphoprotein content in immune cells provides insight into the spontaneous activity of immune signaling pathways triggered by nucleic acid recognition. Here, we present a phosphoflow protocol for measuring phosphoproteins in mouse models of autoimmunity that incorporates strategies to preserve native phosphoprotein levels during sample collection and to reliably detect low signaling activity common in chronic disease states.For complete details on the use and execution of this protocol, please refer to Jütte et al. (2021).

Published
2022
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14. Consensus protocols for the diagnosis and management of the hereditary autoinflammatory syndromes CAPS, TRAPS and MKD/HIDS: a German PRO-KIND initiative

Author

Sandra Hansmann, Elke Lainka, Gerd Horneff, Dirk Holzinger, Nikolaus Rieber, Annette F. Jansson, Angela Rösen-Wolff, Gabi Erbis, Martina Prelog, Juergen Brunner, Susanne M. Benseler, and Jasmin B. Kuemmerle-Deschner

Subjects
Autoinflammatory diseases, Treat-to-target, Consensus treatment plans, Management, Comparative effectiveness, Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestations. Early diagnosis and early start of effective therapies control the inflammation and prevent organ damage. The PRO-KIND initiative of the German Society of Pediatric Rheumatology (GKJR) aims to harmonize the diagnosis and management of children with rheumatic diseases nationally. The task of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group was to develop evidence-based, consensus diagnosis and management protocols including the first AID treat-to-target strategies. Methods The national CAPS/TRAPS/MKD/HIDS expert working group was established, defined its aims and conducted a comprehensive literature review synthesising the recent (2013 to 2018) published evidence including all available recommendations for diagnosis and management. General and disease-specific statements were anchored in the 2015 SHARE recommendations. An iterative expert review process discussed, adapted and refined these statements. Ultimately the GKJR membership vetted the proposed consensus statements, agreement of 80% was mandatory for inclusion. The approved statements were integrated into three disease specific consensus treatment plans (CTPs). These were developed to enable the implementation of evidence-based, standardized care into clinical practice. Results The CAPS/TRAPS/MKD/HIDS expert working group of 12 German and Austrian paediatric rheumatologists completed the evidence synthesis and modified a total of 38 statements based on the SHARE recommendation framework. In iterative reviews 36 reached the mandatory agreement threshold of 80% in the final GKJR member survey. These included 9 overarching principles and 27 disease-specific statements (7 for CAPS, 11 TRAPS, 9 MKD/HIDS). A diagnostic algorithm was established based on the synthesized evidence. Statements were integrated into diagnosis- and disease activity specific treat-to-target CTPs for CAPS, TRAPS and MKD/HIDS. Conclusions The PRO-KIND CAPS/TRAPS/MKD/HIDS working group established the first evidence-based, actionable treat-to-target consensus treatment plans for three rare hereditary autoinflammatory diseases. These provide a path to a rapid evaluation, effective control of disease activity and tailored adjustment of therapies. Their implementation will decrease variation in care and optimize health outcomes for children with AID.

Published
2020
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19. A Kinetic Response Model for Standardized Regression Analyses of Inflammation-Triggered Hypothermic Body Temperature-Time Courses in Mice

Author

Hans H. Diebner, Sören Reinke, Angela Rösen-Wolff, and Stefan Winkler

Subjects
kinetic response model, mathematical modeling, systems biology, caspase-1 signaling, inflammation, LPS shock, Physiology, QP1-981
Abstract

LPS is frequently used to induce experimental endotoxic shock, representing a standard model of acute inflammation in mice. The resulting inflammatory response leads to hypothermia of the experimental animals, which in turn can be used as surrogate for the severity of systemic inflammation. Although increasingly applied as a humane endpoint in murine studies, differences between obtained temperature-time curves are typically evaluated at a single time point with t-tests or ANOVA analyses. We hypothesized that analyses of the entire temperature-time curves using a kinetic response model could fit the data, which show a temperature decrease followed by a tendency to return to normal temperature, and could increase the statistical power. Using temperature-time curves obtained from LPS stimulated mice, we derived a biologically motivated kinetic response model based on a differential equation. The kinetic model includes four parameters: (i) normal body temperature (Tn), (ii) a coefficient related to the force of temperature autoregulation (r), (iii) damage strength (p0), and (iv) clearance rate (k). Kinetic modeling of temperature-time curves obtained from LPS stimulated mice is feasible and leads to a high goodness-of-fit. Here, modifying key enzymes of inflammatory cascades induced a dominant impact of genotypes on the damage strength and a weak impact on the clearance rate. Using a likelihood-ratio test to compare modeled curves of different experimental groups yields strongly enhanced statistical power compared to pairwise t-tests of single temperature time points. Taken together, the kinetic model presented in this study has several advantages compared to simple analysis of individual time points and therefore may be used as a standard method for assessing inflammation-triggered hypothermic response curves in mice.

Published
2021
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20. Supplementary Tables S3-5 from Activation of the cGAS/STING Axis in Genome-Damaged Hematopoietic Cells Does Not Impact Blood Cell Formation or Leukemogenesis

Author

Dressel, Nicole, primary, Natusch, Loreen, primary, Munz, Clara M., primary, Costas Ramon, Santiago, primary, Morcos, Mina N.F., primary, Loff, Anja, primary, Hiller, Björn, primary, Haase, Christa, primary, Schulze, Livia, primary, Müller, Patrick, primary, Lesche, Mathias, primary, Dahl, Andreas, primary, Luksch, Hella, primary, Rösen-Wolff, Angela, primary, Roers, Axel, primary, Behrendt, Rayk, primary, and Gerbaulet, Alexander, primary

Published
2023
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21. Table S1 from Activation of the cGAS/STING Axis in Genome-Damaged Hematopoietic Cells Does Not Impact Blood Cell Formation or Leukemogenesis

Author

Dressel, Nicole, primary, Natusch, Loreen, primary, Munz, Clara M., primary, Costas Ramon, Santiago, primary, Morcos, Mina N.F., primary, Loff, Anja, primary, Hiller, Björn, primary, Haase, Christa, primary, Schulze, Livia, primary, Müller, Patrick, primary, Lesche, Mathias, primary, Dahl, Andreas, primary, Luksch, Hella, primary, Rösen-Wolff, Angela, primary, Roers, Axel, primary, Behrendt, Rayk, primary, and Gerbaulet, Alexander, primary

Published
2023
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22. Supplementary Data from Activation of the cGAS/STING Axis in Genome-Damaged Hematopoietic Cells Does Not Impact Blood Cell Formation or Leukemogenesis

Author

Dressel, Nicole, primary, Natusch, Loreen, primary, Munz, Clara M., primary, Costas Ramon, Santiago, primary, Morcos, Mina N.F., primary, Loff, Anja, primary, Hiller, Björn, primary, Haase, Christa, primary, Schulze, Livia, primary, Müller, Patrick, primary, Lesche, Mathias, primary, Dahl, Andreas, primary, Luksch, Hella, primary, Rösen-Wolff, Angela, primary, Roers, Axel, primary, Behrendt, Rayk, primary, and Gerbaulet, Alexander, primary

Published
2023
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23. Data from Activation of the cGAS/STING Axis in Genome-Damaged Hematopoietic Cells Does Not Impact Blood Cell Formation or Leukemogenesis

Author

Dressel, Nicole, primary, Natusch, Loreen, primary, Munz, Clara M., primary, Costas Ramon, Santiago, primary, Morcos, Mina N.F., primary, Loff, Anja, primary, Hiller, Björn, primary, Haase, Christa, primary, Schulze, Livia, primary, Müller, Patrick, primary, Lesche, Mathias, primary, Dahl, Andreas, primary, Luksch, Hella, primary, Rösen-Wolff, Angela, primary, Roers, Axel, primary, Behrendt, Rayk, primary, and Gerbaulet, Alexander, primary

Published
2023
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26. STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice

Author

Brock G. Bennion, Carys A. Croft, Teresa L. Ai, Wei Qian, Amber M. Menos, Cathrine A. Miner, Marie-Louis Frémond, Jean-Marc Doisne, Prabhakar S. Andhey, Derek J. Platt, Jennifer K. Bando, Erin R. Wang, Hella Luksch, Thierry J. Molina, Elisha D.O. Roberson, Maxim N. Artyomov, Angela Rösen-Wolff, Marco Colonna, Frédéric Rieux-Laucat, James P. Di Santo, Bénédicte Neven, and Jonathan J. Miner

Subjects
STING, ILC, lymphoid tissue organogenesis, lymphopoiesis, SAVI, LTi cell, Biology (General), QH301-705.5
Abstract

Summary: STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer’s patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) α4β7+ progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORγT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORγT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORγT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.

Published
2020
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27. IL-11 and soluble VCAM-1 are important components of Hypoxia Conditioned Media and crucial for Mesenchymal Stromal Cells attraction

Author

Anastasia Gabrielyan, Mandy Quade, Michael Gelinsky, and Angela Rösen-Wolff

Subjects
Mesenchymal stromal cells, Hypoxia, Migration, IL-11, Svcam-1, SDF1-α, Biology (General), QH301-705.5
Abstract

Introduction: Bone marrow stromal cells (BMSC) are highly attractive for tissue engineering due to their ability to differentiate into different cell types, to expand extensively in vitro and to release paracrine soluble factors with a high regenerative potential. They were observed to migrate towards the sites of injury in response to chemotactic signals in vivo. During the last years hypoxia has become a proven method to control proliferation, differentiation and multipotency of BMSC. Conditioned medium from hypoxia-treated BMSC (Hypoxia-conditioned Medium; HCM) has been shown to have various favorable properties on tissue regeneration – such as on cell recruitment, wound healing, angiogenesis and revascularization. Due to this regenerative potential many studies attempt to further characterize HCM and its main functional components. In this study we used HCM generated from umbilical cord mesenchymal stem cells (UC-MSC) instead of BMSC, because GMP-verified methods were used to isolate and cultivate the cells and ensure their constant quality. UC-MSC have a high regenerative potential and are still immunologically naive and therefore highly unlikely to cause an immune reaction. In our article we took the first steps to closer investigate the role of umbilical cord MSC-derived HCM components, namely stromal cell-derived factor 1 (SDF-1α), interleukin 11 (IL-11) and soluble vascular cell adhesion molecule 1 (sVCAM-1). Results: Our results show previously unknown roles of IL-11 and sVCAM-1 in the attraction of BMSC. The synergistic effect of the investigated protein mixture consisting of IL-11, sVCAM-1 and SDF-1α as well as those recombinant proteins alone revealed a significantly higher chemoattractive capacity towards human BMSC compared to normoxic control medium. Both, the protein mixtures and proteins alone as well as UC-HCM showed an angiogenic effect by promoting the formation of significantly longer tubule structures and higher amounts of junctions and tubules compared to normoxic control medium. Conclusions: By showing the prominent upregulation of IL-11, sVCAM-1 and SDF-1α under hypoxic conditions compared to normoxic control and revealing their crucial role in migration of human BMSC we took a further step forward in characterization of the chemoattractive components of HCM.

Published
2020
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28. Non-canonical Caspase-1 Signaling Drives RIP2-Dependent and TNF-α-Mediated Inflammation In Vivo

Author

Sören Reinke, Mary Linge, Hans H. Diebner, Hella Luksch, Silke Glage, Anne Gocht, Avril A.B. Robertson, Matthew A. Cooper, Sigrun R. Hofmann, Ronald Naumann, Mihail Sarov, Rayk Behrendt, Axel Roers, Frank Pessler, Joachim Roesler, Angela Rösen-Wolff, and Stefan Winkler

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1β and IL-18 to their mature forms and triggers pyroptosis. These caspase-1 functions are linked to its enzymatic activity. However, loss-of-function missense mutations in CASP1 do not prevent autoinflammation in patients, despite decreased IL-1β production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor κB (NF-κB) activation, independent of IL-1β processing. Here, we report two mouse models of enzymatically inactive caspase-1-C284A, demonstrating the relevance of this pathway in vivo. In contrast to Casp1−/− mice, caspase-1-C284A mice show pronounced hypothermia and increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-α but independent of the NLRP3 inflammasome. LPS-stimulated whole blood from patients carrying loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-α. Taken together, these results reveal non-canonical caspase-1 signaling in vivo. : Reinke et al. show that enzymatically inactive caspase-1-C284A mediates non-canonical caspase-1 signaling. This pathway is RIP2 dependent and mediated by TNF-α but independent from IL-1 cytokines. Keywords: caspase-1, Rip2, NF-κB, TNF-α, non-canonical caspase-1 signaling, enzymatic activity

Published
2020
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29. A tissue-based approach to selection of reference genes for quantitative real-time PCR in a sheep osteoporosis model

Author

Felix Schulze, Deeksha Malhan, Thaqif El Khassawna, Christian Heiss, Anja Seckinger, Dirk Hose, and Angela Rösen-Wolff

Subjects
Reference gene, Sheep, MSC, geNorm, NormFinder, BestKeeper, Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background In order to better understand the multifactorial nature of osteoporosis, animal models are utilized and compared to healthy controls. Female sheep are well established as a model for osteoporosis induced by ovariectomy, calcium and vitamin D low diet, application of steroids, or a combination of these treatments. Transcriptional studies can be performed by applying quantitative real time PCR (RT-qPCR). RT-qPCR estimates mRNA-levels of target genes in relation to reference genes. A chosen set of reference genes should not show variation under experimental conditions. Currently, no standard reference genes are accepted for all tissue types and experimental conditions. Studies examining reference genes for sheep are rare and only one study described stable reference in mandibular bone. However, this type of bone differs from trabecular bone where most osteoporotic fractures occur. The present study aimed at identifying a set of reference genes for relative quantification of transcriptional activity of ovine spine bone and ovine in vitro differentiated mesenchymal stromal cells (MSC) for reliable comparability. Methods Twelve candidate reference genes belonging to different functional classes were selected and their expression was measured from cultured ovMSCs (n = 18) and ovine bone samples (n = 16), respectively. RefFinder was used to rank the candidate genes. Results We identified B2M, GAPDH, RPL19 and YWHAZ as the best combination of reference genes for normalization of RT-qPCR results for transcriptional analyses of these ovine samples. Conclusion This study demonstrates the importance of applying a set of reference genes for RT-qPCR analysis in sheep. Based on our data we recommend using four identified reference genes for relative quantification of gene expression studies in ovine bone or for in vitro experiments with osteogenically differentiated ovine MSCs.

Published
2017
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30. Activation of the cGAS/STING Axis in Genome-Damaged Hematopoietic Cells Does Not Impact Blood Cell Formation or Leukemogenesis

Author

Dressel, Nicole, primary, Natusch, Loreen, additional, Munz, Clara M., additional, Costas Ramon, Santiago, additional, Morcos, Mina N.F., additional, Loff, Anja, additional, Hiller, Björn, additional, Haase, Christa, additional, Schulze, Livia, additional, Müller, Patrick, additional, Lesche, Mathias, additional, Dahl, Andreas, additional, Luksch, Hella, additional, Rösen-Wolff, Angela, additional, Roers, Axel, additional, Behrendt, Rayk, additional, and Gerbaulet, Alexander, additional

Published
2023
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34. Metabolically conditioned media derived from bone marrow stromal cells or human skin fibroblasts act as effective chemoattractants for mesenchymal stem cells

Author

Anastasia Gabrielyan, Elena Neumann, Michael Gelinsky, and Angela Rösen-Wolff

Subjects
Mesenchymal stromal cells, Fibroblasts, Hypoxia, Migration, Tissue repair, Medicine (General), R5-920, Biochemistry, QD415-436
Abstract

Abstract Background The main goal of bone tissue engineering has been the generation of healthy bone in order to replace affected tissue. Therefore, optimized biomaterials are needed which allow the survival and growth of mesenchymal stem cells. Until now the key challenge in the clinical application of cell-based tissue engineering bone implants was poor diffusion of oxygen into the tissue, making functional blood vessel networks a necessity. With their ability to evolve into different cell types, to expand extensively in vitro, and to release paracrine soluble factors, bone marrow stromal cells (BMSC) are highly attractive for tissue engineering. During the last years hypoxia became a proven method to control proliferation, differentiation, and pluripotency of BMSC. Here we applied different methods to characterize metabolically conditioned media (MCM) in comparison to hypoxia conditioned media (HCM) and evaluated their ability to attract BMSC in 2-D migration assays. Methods BMSC and fibroblasts of human origin were isolated and cultivated to obtain HCM and MCM. Both media were characterized by angiogenesis arrays, cytokine arrays, and ELISA for selected factors. 2-D migration tests were performed with Corning Transwell®-96 permeable support chambers with porous polyester membranes with a pore size of 8.0 μm. Results Characterization of HCM and MCM revealed that the concentration of angiogenic factors was higher in MCM than in HCM. However, the chemoattractive capacity of MCM for BMSC was equivalent to that of HCM. HCM and MCM produced by human skin fibroblasts attracted human BMSC as efficiently as HCM and MCM produced by human BMSC. Conclusions HCM and MCM have a high chemoattractive capacity for BMSC. Both conditioned media harbor high concentrations of angiogenic factors which are important for angiogenesis and cell migration. Both chemoattracting conditioned media can also be derived from skin fibroblasts which can easily be obtained from patients in individualized therapy approaches.

Published
2017
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35. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one

Author

F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H. M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido, Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Maria Alessio, Giovanni Conti, Federico Marchetti, Alberto Tommasini, Silvana Martino, Romina Gallizzi, Annalisa Salis, Francesca Schena, Francesco Caroli, Alberto Martini, Gianluca Damonte, Isabella Ceccherini, Marco Gattorno, Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Darragh Duffy, Vincent Bondet, Yoann Rose, Bénédicte Neven, Yanick Crow, Mathieu P. Rodero, Yvonne Kusche, Johannes Roth, Katarzyna Barczyk-Kahlert, Giovanna Ferrara, Annalisa Chiocchetti, Silvio Polizzi, Josef Vuch, Diego Vozzi, Anna Mondino, Erica Valencic, Serena Pastore, Andrea Taddio, Flavio Faletra, Umberto Dianzani, Ugo Ramenghi, Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, Deborah Stone, Wanxia Tsai, Amanda Ombrello, Tina Romeo, Elaine F. Remmers, JaeJin Chae, Massimo Gadina, Steven Welch, Seza Ozen, Rezan Topaloglu, Mario Abinun, Daniel L. Kastner, Ivona Aksentijevich, Donatella Vairo, Rosalba Monica Ferraro, Giulia Zani, Jessica Galli, Micaela De Simone, Marco Cattalini, Elisa Fazzi, Silvia Giliani, Ebun Omoyinmi, Ariane Standing, Dorota Rowczenio, Annette Keylock, Sonia Melo Gomes, Fiona Price-Kuehne, Sira Nanthapisal, Claire Murphy, Thomas Cullup, Lucy Jenkins, Kimberly Gilmour, Despina Eleftheriou, Helen Lachmann, Philip Hawkins, Nigel Klein, Paul Brogan, Anita Dhanrajani, Mercedes Chan, Stephanie Pau, Janet Ellsworth, Jaime Guzman, Florence A. Aeschlimann, Marinka Twilt, Simon W. Eng, Shehla Sheikh, Ronald M. Laxer, Diane Hebert, Damien Noone, Christian Pagnoux, Susanne M. Benseler, Rae S. Yeung, Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Niklas Grün, Dirk Föll, Pieter Van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni-Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Fabrizio De Benedetti, Lorenza Putignani, Berna Eren Fidanci, Kenan Barut, Serap Arıcı, Dogan Simsek, Mustafa Cakan, Ezgi D. Batu, Sezgin Şahin, Ayşenur Kısaarslan, Ebru Yilmaz, Özge Basaran, Ferhat Demir, Kubra Ozturk, Zübeyde Gunduz, Betül Sozeri, Balahan Makay, Nuray Ayaz, Onder Yavascan, Ozlem Aydog, Yelda Bilginer, Zelal Ekinci, Dilek Yıldız, Faysal Gök, Muferret Erguven, Erbil Unsal, Ozgur Kasapcopur, For the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR), Hafize E. Sönmez, Betül Sözeri, Yonatan Butbul, Seza Özen, Claudia Bracaglia, Giusi Prencipe, Manuela Pardeo, Geneviève Lapeyre, Emiliano Marasco, Walter Ferlin, Robert Nelson, Cristina de Min, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, K. Marzan, N. Wulffraat, R. Schneider, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Stefano Volpi, Claudia Pastorino, Francesca Kalli, Alessia Omenetti, Sabrina Chiesa, Arinna Bertoni, Paolo Picco, Gilberto Filaci, Elisabetta Traggiai, Marie-Louise Fremond, Naoki Kitabayashi, Olivero Sacco, Isabelle Meyts, Marie-Anne Morren, Carine Wouters, Eric Legius, Isabelle Callebaut, Christine Bodemer, Frederic Rieux-Laucat, Mathieu Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat, K. Annink, N. ter Haar, S. Al-Mayouf, G. Amaryan, K. Barron, S. Benseler, P. Brogan, L. Cantarini, M. Cattalini, A. Cochino, F. Dedeoglu, A. De Jesus, O. Dellacasa, E. Demirkaya, P. Dolezalova, K. Durrant, G. Fabio, R. Gallizzi, R. Goldbach-Mansky, E. Hachulla, V. Hentgen, T. Herlin, M. Hofer, H. Hoffman, A. Insalaco, A. Jansson, I. Koné-Paut, A. Kozlova, J. Kuemmerle-Deschner, R. Laxer, S. Nielsen, I. Nikishina, A. Ombrello, E. Papadopoulou-Alataki, A. Ravelli, D. Rigante, R. Russo, Y. Uziel, Nienke ter Haar, Jerold Jeyaratnam, Anna Simon, Matteo Doglio, Jordi Anton, Consuelo Modesto, Pierre Quartier, Esther Hoppenreijs, Luca Cantarini, Loredana Lepore, Inmaculada Calvo Penades, Christina Boros, Rita Consolini, Donato Rigante, Ricardo Russo, Jana Pachlopnik Schmid, Thirusha Lane, Nicolino Ruperto, Joost Frenkel, Chiara Passarelli, Elisa Pisaneschi, Virginia Messia, Antonio Novelli, Fabrizio Debenedetti, P. A. Brogan, X. Wei, Martina Finetti, Francesca Orlando, Elisabetta Cortis, Angela Miniaci, Nicola Ruperto, Charlotte Eijkelboom, Pavla Dolezalova, Isabelle Koné-Paut, Marija Jelusic-Drazic, Liliana Bezrodnik, Mari Carmen Pinedo, Valda Stanevicha, Marielle van Gijn, Silvia Federici, Hermann Girschick, Gerd Ganser, Susan Nielsen, Troels Herlin, Sulaiman Mohammed Al-Mayouf, Michael Hofer, Jasmin Kuemmerle-Deschner, Susanne Schalm, Annette Jansson, on behalf of PRINTO and Eurofever registry, Marta Marchi, Chiara Marini, Angelo Ravelli, Alberto Garaventa, Sonia Carta, Enrica Balza, Patrizia Castellani, Caterina Pellecchia, Silvia Borghini, Maria Libera Trotta, Anna Rubartelli, Andrew Henrey, Thomas Loughin, Roberta Berard, Natalie Shiff, Roman Jurencak, Susanne Benseler, Lori Tucker, on behalf of ReACCh-Out Investigators, Charalampia Papadopoulou, Ying Hong, Petra Krol, Yiannis Ioannou, Clarissa Pilkington, Hema Chaplin, Stephania Simou, Marietta Charakida, Lucy Wedderburn, Lynn R. Spiegel, Sara Ahola Kohut, Jennifer Stinson, Paula Forgeron, Miriam Kaufman, Nadia Luca, Khush Amaria, Mary Bell, J Swart, F. Boris, E. Castagnola, A. Groll, G. Giancane, G. Horneff, H. I. Huppertz, T. Wolfs, E. Alekseeva, V. Panaviene, F. Uettwiller, V. Stanevicha, L. M. Ailioaie, E. Tsitami, S. Kamphuis, G. Susic, F. Sztajnbok, B. Flato, A. Pistorio, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Janet E. McDonagh, Wendy Thomson, Kimme L. Hyrich, CAPS, Maarit Tarkiainen, Pirjo Tynjala, Pekka Lahdenne, Janne Martikainen, Acute-JIA Study Group, Meredyth Wilkinson, Christopher Piper, Georg Otto, Claire T. Deakin, Stefanie Dowle, Stefania Simou, Daniel Kelberman, Claudia Mauri, Elizabeth Jury, David Isenberg, Lucy R. Wedderburn, Kiran Nistala, I. Foeldvari, D. J. Lovell, G. Simonini, M. Bereswill, J. Kalabic, Kiem Oen, Brian M. Feldman, Brenden Dufault, Jennifer Lee, Karen Watanabe Duffy, Ciaran Duffy, ReACCh-Out Investigators, N. Tzaribachev, G. Vega-Cornejo, I. Louw, A. Berman, I. Calvo, R. Cuttica, F. Avila-Zapata, R. Cimaz, E. Solau-Gervais, R. Joos, G. Espada, X. Li, M. Nys, R. Wong, S. Banerjee, For Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology Collaborative Study Group (PRCSG), Rebecca Nicolai, Margherita Verardo, Adele D’Amico, Luisa Bracci-Laudiero, Gian Marco Moneta, Gillian Rice, Anne-Laure Mathieu, Sulliman O. Omarjee, Tracy A. Briggs, James O’Sullivan, Simon Williams, Rolando Cimaz, Eve Smith, Michael W. Beresford, Yanick J. Crow, GENIAL Investigators, UK JSLE Study Group, Madeleine Rooney, Nick Bishop, joyce davidson, Clarissa pilkington, Michael Beresford, Jacqui Clinch, Rangaraj Satyapal, Helen Foster, Janet Gardner Medwin, Janet McDonagh, Sue Wyatt, On Behalf of the British Society for Paediatric and Adolescent Rheumatology, Valentina Litta Modignani, Francesco Baldo, Stefano Lanni, Alessandro Consolaro, Giovanni Filocamo, Helen J. Lachmann, on behalf of Eurofever Registry, Gianmarco Moneta, Camilla Celani, Bilade Cherqaoui, Linda Rossi-Semerano, Perrine Dusser, Véronique Hentgen, Claire Grimwood, Linda Rossi, Isabelle Kone Paut, Veronique Hentgen, Denise Lasigliè, Denise Ferrera, Giulia Amico, Marco Di Duca, Laura Obici, Roberto Ravazzolo, Ryuta Nishikomori, Juan Arostegui, Andrea Petretto, Chiara Lavarello, Elvira Inglese, Federica Vanoni, Michaël Hofer, on behalf of EUROFEVER PROJECT, P. N. Hawkins, T. van der Poll, U. A. Walker, H. H. Tilson, Pascal N. Tyrrell, Raphaela Goldbach-Mansky, Norbert Blank, Hal M. Hoffman, Elisabeth Weissbarth-Riedel, Boris Huegle, Tilmann Kallinich, Ahmet Gul, Marlen Oswald, Fatma Dedeoglu, Aki Hanaya, Takako Miyamae, Manabu Kawamoto, Yumi Tani, Takuma Hara, Yasushi Kawaguchi, Satoru Nagata, Hisashi Yamanaka, Almira Ćosićkić, Fahrija Skokić, Belkisa Čolić, Sanimir Suljendić, Anna Kozlova, Irina Mersiyanova, Mariya Panina, Lily Hachtryan, Vasiliy Burlakov, Elena Raikina, Alexey Maschan, Anna Shcherbina, Banu Acar, Meryem Albayrak, Betul Sozeri, Sezgin Sahin, Amra Adrovic, Nese Inan, Serhan Sevgi, Caroline M. Andreasen, Anne Grethe Jurik, Mia B. Glerup, Christian Høst, Birgitte T. Mahler, Ellen-Margrethe Hauge, Cecilia Lazea, Laura Damian, Calin Lazar, Rodica Manasia, Chloe M. Stephenson, Vimal Prajapati, Paivi M. Miettunen, Dilek Yılmaz, Yavuz Tokgöz, Yasin Bulut, Harun Çakmak, Ferah Sönmez, Elif Comak, Gülşah Kaya Aksoy, Mustafa Koyun, Sema Akman, Yunus Arıkan, Ender Terzioğlu, Osman Nidai Özdeş, İbrahim Keser, Hüseyin Koçak, Ayşen Bingöl, Aygen Yılmaz, Reha Artan, X. Xu, Fatemeh F. Mehregan, Vahid Ziaee, Mohammad H. Moradinejad, Francesco La Torre, Clotilde Alizzi, Pio D’Adamo, G. Junge, J. Gregson, Hasmik Sargsyan, Hulya Zengin, Berna E. Fidanci, Cagla Kaymakamgil, Dilek Konukbay, Dilek Yildiz, Faysal Gok, Iris Stoler, Judith Freytag, Banu Orak, Christine Seib, Lars Esmann, Eva Seipelt, Faekah Gohar, Dirk Foell, Ismail Dursun, Sebahat Tulpar, Sibel Yel, Demet Kartal, Murat Borlu, Funda Bastug, Hakan Poyrazoglu, Zubeyde Gunduz, Kader Kose, Mehmet E. Yuksel, Abdullah Calıskan, Ahmet B. Cekgeloglu, Ruhan Dusunsel, Katerina Bouchalova, Jana Franova, Marcel Schuller, Marie Macku, Katerina Theodoropoulou, Raffaella Carlomagno, Annette von Scheven-Gête, Claudia Poloni, Laura O. Damian, Dan Cosma, Amanda Radulescu, Dan Vasilescu, Liliana Rogojan, Simona Rednic, Mihaela Lupse, Lien De Somer, Pierre Moens, Rocio Galindo Zavala, Laura Martín Pedraz, Esmeralda Núñez Cuadros, Gisela Díaz-Cordovés Rego, Antonio L. Urda Cardona, Ilaria Dal Forno, Sara Pieropan, Ombretta Viapiana, Davide Gatti, Gloria Dallagiacoma, Paola Caramaschi, Domenico Biasi, Daniel Windschall, Ralf Trauzeddel, Hartwig Lehmann, Rainer Berendes, Maria Haller, Manuela Krumrey-Langkammerer, Antje Nimtz-Talaska, Philipp Schoof, Ralf Felix Trauzeddel, Christine Nirschl, Estefania Quesada-Masachs, Carla Aguilar Blancafort, Sara Marsal Barril, Francisca Aguiar, Rita Fonseca, Duarte Alves, Ana Vieira, Alberto Vieira, Jorge A. Dias, Iva Brito, Gordana Susic, Vera Milic, Goran Radunovic, Ivan Boricic, Pauline Marteau, Catherine Adamsbaum, Michel De Bandt, Irène Lemelle, Chantal Deslandre, Tu Anh Tran, Anne Lohse, Elisabeth Solau-Gervais, Pascal Pillet, Julien Wipff, Cécile Gaujoux-Viala, Sylvain Breton, Valérie Devauchelle-Pensec, Sandra Gran, Olesja Fehler, Stefanie Zenker, Michael Schäfers, Thomas Vogl, Severine Guillaume Czitrom, EH Pieter Van Dijkhuizen, Silvia Magni Manzoni, Francesca Magnaguagno, Laura Tanturri de Horatio, Nienke M. Ter Haar, Annemieke S. Littooij, Vitor A. Teixeira, Raquel Campanilho-Marques, Ana F. Mourão, Filipa O. Ramos, Manuela Costa, Wafa A. Madan, Orla G. Killeen, Adriana Rodriguez Vidal, Diana Sueiro Delgado, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Aleksey Kozhevnikov, Nina Pozdeeva, Mikhail Konev, Evgeniy Melchenko, Vladimir Kenis, Gennadiy Novik, Aysenur Pac Kısaarslan, Butsabong Lerkvaleekul, Suphaneewan Jaovisidha, Witaya Sungkarat, Niyata Chitrapazt, Praman Fuangfa, Thumanoon Ruangchaijatuporn, Soamarat Vilaiyuk, Dan Ø. Pradsgaard, Arne Hørlyck, Anne H. Spannow, Carsten W. Heuck, Talia Diaz, Fernando Garcia, Lorenia De La Cruz, Nadina Rubio, Joanna Świdrowska-Jaros, Elzbieta Smolewska, Mirta Lamot, Lovro Lamot, Mandica Vidovic, Edi Paleka Bosak, Ivana Rados, Miroslav Harjacek, Nikolay Tzaribachev, Polymnia Louka, Romiesa Hagoug, Chiara Trentin, Olga Kubassova, Mark Hinton, Mikael Boesen, Olena A. Oshlianska, Illya A. Chaikovsky, G. Mjasnikov, A. Kazmirchyk, Umberto Garagiola, Irene Borzani, Paolo Cressoni, Fabrizia Corona, Eszter Dzsida, Giampietro Farronato, Antonella Petaccia, Alenka Gagro, Agneza Marija Pasini, Goran Roic, Ozren Vrdoljak, Lucija Lujic, Matija Zutelija-Fattorini, Monika M. Esser, Deepthi R. Abraham, Craig Kinnear, Glenda Durrheim, Mike Urban, Eileen Hoal, Victoria B. Nikolayenko, Kubilay Şahin, Yasar Karaaslan, Adele Civino, Giovanni Alighieri, Sergio Davì, Roberto Rondelli, Andrea Magnolato, Francesca Ricci, Alma Olivieri, Valeria Gerloni, Bianca Lattanzi, Francesca Soscia, Alessandro De Fanti, Stefania Citiso, Lorenzo Quartulli, Maria Cristina Maggio, Manuela Marsili, Maria Antonietta Pelagatti, Valentino Conter, Franca Fagioli, Andrea Pession, Marco Garrone, Mariangela Rinaldi, Jaime De Inocencio, Stella Garay, Daniel J. Lovell, Berit Flato, EPOCA Study Group, Angela Aquilani, Simona Cascioli, Ivan Caiello, Denise Pires-Marafón, Rita Carsetti, Emily Robinson, Salvatore Albani, Wilco de Jager, Sytze de Roock, Trang Duong, Justine Ellis, Kimme Hyrich, Laetitia Jervis, Daniel Lovell, Lucy Marshall, Elizabeth D. Mellins, Kirsten Minden, Jane Munro, Peter A. Nigrovic, Jason Palman, Sunil Sampath, Laura E. Schanberg, Susan D. Thompson, Richard Vesely, Chris Wallace, Chris Williams, Qiong Wu, Nico Wulffraat, Rae S. M. Yeung, M. B. Seyger, D. Arikan, J. K. Anderson, A. Lazar, D. A. Williams, C. Wang, R. Tarzynski-Potempa, J. S. Hymans, Gabriele Simonini, Erika Scoccimarro, Irene Pontikaki, Teresa Giani, Alessandro Ventura, Pier Luigi Meroni, Gaetana Minnone, Marzia Soligo, Luigi Manni, Luisa Bracci Laudiero, Noortje Groot, I. Grein, N. M. Wulffraat, R. Schepp, G. Berbers, C. C. Barbosa Sandoval de Souza, V. Paes Leme Ferriani, G. Pileggi, S. de Roock, Ingrid H. R. Grein, Silvia Scala, Elisa Patrone, Casper Schoemaker, on behalf of Dutch JIA patient organization, Wendy Costello, on behalf of ENCA, Suzanne Parsons, Jean-David Cohen, Damien Bentayou, Marc-Antoine Bernard Brunel, Sonia Trope, Jens Klotsche, Miriam Listing, Martina Niewerth, Gerd Horneff, Angelika Thon, Hans-Iko Huppertz, Kirsten Mönkemöller, Ivan Foeldvari, ICON study group, Achille Marino, Stefano Stagi, Niccolò Carli, Federico Bertini, Adriana S. Díaz-Maldonado, Sally Pino, Pilar Guarnizo, Alfonso Ragnar Torres-Jimenez, Berenice Sanchez-Jara, Eunice Solis-Vallejo, Adriana Ivonne Cespedes-Cruz, Maritza Zeferino-Cruz, Julia Veronica Ramirez-Miramontes, Ankur Kumar, Anju Gupta, Deepti Suri, Amit Rawat, Nandita Kakkar, Surjit Singh, Özge A. Gücenmez, Erbil Ünsal, Bo Magnusson, Karina Mördrup, Anna Vermé, Christina Peterson, Board of the Swedish Pediatric Rheumatology Registry, Caroline Freychet, Jean Louis Stephan, Cathryn E. Harkness, Leanne Foster, Emma Henry, Pauline Taggart, Coskun F. Ozkececi, Esra Kurt, Gokalp Basbozkurt, Daiva Gorczyca, Jacek Postępski, Aleksandra Czajkowska, Bogumiła Szponar, Mariola Paściak, Anna Gruenpeter, Iwona Lachór-Motyka, Daria Augustyniak, Edyta Olesińska, Emediong S. Asuka, Tatyana Golovko, Samuel U. Aliejim, Emilio Inarejos Clemente, Estibaliz Iglesias Jimenez, Joan Calzada Hernandez, Sergi Borlan Fernandez, Clara Gimenez Roca, David Moreno Romo, Natalia Rodriguez Nieva, Juan Manuel Mosquera Angarita, Jordi Anton Lopez, Esmeralda Nuñez-Cuadros, Gisela Diaz-Cordovés, Rocío Galindo-Zavala, Antonio Urda-Cardona, Antonio Fernández-Nebro, Daniel Álvarez de la Sierra, Marina Garcia Prat, Mónica Martínez Gallo, Ricardo Pujol Borrell, Ana M. Marín Sánchez, Etienne Merlin, Sylvie Fraitag, Jean-Louis Stephan, Federico Annoni, Giancarla Di Landro, Sofia Torreggiani, Marta Torcoletti, Georgina Tiller, Jo Buckle, Angela Cox, Peter Gowdie, Roger C. Allen, Jonathan D. Akikusa, Hayde G. Hernández-Huirache, Edel R. Rodea-Montero, William Fahy, Christelle Sordet, Karin B. Berggren, Johanna T. Kembe, Joyce Bos, Wineke Armbrust, Marco van Brussel, Jeanette Cappon, Pieter Dijkstra, Jan Geertzen, Elizabeth Legger, Marion van Rossum, Pieter Sauer, Otto Lelieveld, Levent Buluc, Gur Akansel, Bahar Muezzinoglu, Ljubov Rychkova, Tatyana Knyazeva, Anna Pogodina, Tatyana Belova, Tamara Mandzyak, Ekaterina Kulesh, Alessandro Cafarotti, Cosimo Giannini, Roberta Salvatore, Giuseppe Lapergola, Caterina Di Battista, Maria Loredana Marcovecchio, Raffaella Basilico, Piernicola Pelliccia, Francesco Chiarelli, Luciana Breda, Beverley Almeida, Sarah Tansley, Harsha Gunawardena, Neil McHugh, Juvenile Dermatomyositis Research Group (JDRG), Jessie Aouizerate, Marie De Antonio, Christine Barnerias, Guillaume Bassez, Isabelle Desguerre, Romain Gherardi, Jean-Luc Charuel, François-Jérôme Authier, Cyril Gitiaux, C. H. Spencer, Rabheh Abdul Aziz, Chack-Yung Yu, Brent Adler, Sharon Bout-Tabaku, Katherine Lintner, Melissa Moore-Clingenpeel, Liza McCann, Nicola Ambrose, Mario Cortina-Borja, Juvenile Dermatomyositis Cohort and Biomarker Study (JCDBS), Prasad T. Oommen, Fabian Speth, Johannes-Peter Haas, Working Group “Juvenile Dermatomyositis” of the German Society for Paediatric and Adolescent Rheumatology (GKJR), Claudio Lavarello, Gabriella Giancane, Angela Pistorio, Lisa Rider, Rohit Aggarwal, Sheila K. Oliveira, Ruben Cuttica, Michel Fischbach, Gary Sterba, Karine Brochard, Frank Dressler, Patrizia Barone, Ruben Burgos-Vargas, Elizabeth Candell Chalom, Marine Desjonqueres, Graciela Espada, Anders Fasth, Stella Maris Garay, Rose-Marie Herbigneaux, Claire Hoyoux, Chantal Job Deslandre, Frederick W. Miller, Jiri Vencovsky, Erdal Sag, Gulsev Kale, Haluk Topaloglu, Beril Talim, Francesco Zulian, Tadej Avcin, Roberto Marini, Anne Pagnier, Michel Rodiere, Christine Soler, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Ana V. Villarreal, Nydia Acevedo, Yuridiana Ramirez, Enrique Faugier, Rocio Maldonado, Bita Arabshahi, John H. Lee, Ian Leibowitz, Lawrence O. Okong’o, Jo Wilmshurst, Monika Esser, Christiaan Scott, Ezgi Deniz Batu, Nagehan Emiroglu, Hafize Emine Sonmez, Gokcen Dilsa Tugcu, Zehra Serap Arici, Ebru Yalcin, Deniz Dogru, Ugur Ozcelik, Mithat Haliloglu, Nural Kiper, Masato Yashiro, Mutsuko Yamada, Toshihiko Yabuuchi, Tomonobu Kikkawa, Nobuyuki Nosaka, Yosuke Fujii, Yukie Saito, Hirokazu Tsukahara, Sulaiman M. Al-Mayouf, Nora AlMutiari, Mohammed Muzaffer, Rawiah shehata, Adel Al-Wahadneh, Reem Abdwani, Safia Al-Abrawi, Mohammed Abu-shukair, Zeyad El-Habahbeh, Abdullah Alsonbul, Aleksandra Szabat, Monika Chęć, Violetta Opoka-Winiarska, Biman Saikia, Ranjana W. Minz, Christine Arango, Clara Malagon, Maria D. P. Gomez, Angela C. Mosquera, Ricardo Yepez, Tatiana Gonzalez, Camilo Vargas, GRIP study group, Marta Balzarin, Biagio Castaldi, Elena Reffo, Francesca Sperotto, Giorgia Martini, Alessandra Meneghel, Ornella Milanesi, Ozgur Kasapçopur, Maria Teresa Terreri, Ekaterina Alexeeva, Maria Katsicas, Mikhail Kostik, Thomas Lehman, W.-Alberto Sifuentes-Giraldo, Vanessa Smith, Flavio Sztajnbok, Tadey Avcin, Maria Jose Santos, Dana Nemcova, Cristina Battagliotti, Liora Harel, Mahesh Janarthanan, Kathryn Torok, Nicola Helmus, Eileen Baildem, Michael Blakley, Kim Fligelstone, Antonia Kienast, Clare Pain, Amanda Saracino, Gabriele Simoni, Lisa Weibel, Maria K. Osminina, Nathalia A. Geppe, Olga V. Niconorova, Olesya V. Karashtina, Oksana V. Abbyasova, Olga V. Shpitonkova, Sinem Durmus, Hafize Uzun, Angela Mauro, Eleonora Fanti, Fabio Voller, Franca Rusconi, Fernando Garcia-Rodriguez, Ana V. Villarreal-Treviño, Angel J. Flores-Pineda, Paola B. Lara-Herrea, Diego R. Salinas-Encinas, Talia Diaz-Prieto, Maria R. Maldonado-Velazquez, Sarbelio Moreno-Espinosa, Enrique Faugier-Fuentes, Mirella Crapanzano, Ilaria Parissenti, Man S. Parihar, Pandiarajan Vignesh, ManojKumar Rohit, Kavitha Gopalan, Savita V. Attri, Alan Salama, David Jayne, Mark Little, Yulia Kostina, Galina Lyskina, Olga Shpitonkova, Alena Torbyak, Olga Shirinsky, Maria Francesca Gicchino, Maria Cristina Smaldone, Mario Diplomatico, Alma Nunzia Olivieri, C H. Spencer, Richard McClead, Hiren Patel, Chung-Yung Yu, Dita Cebecauerová, Tomáš Dallos, Edita Kabíčková, Martin Kynčl, Daniela Chroustová, Jozef Hoza, Dana Němcová, Vladimír Tesař, Pavla Doležalová, Tuncay Hazirolan, Fatih Ozaltin, Fabiola Almeida, Isabela H. Faria de Paula, Maíra M. Sampaio, Fernando N. Arita, Andressa G. Alves, Maria Carolina Santos, Eunice M. Okuda, Silvana B. Sacchetti, Fernanda Falcini, Marini Francesca, Gemma Lepri, Marco Matucci-Cerinic, Maria Luisa Brandi, Hakan Kisaoglu, Sema Misir, Selim Demir, Yuksel Aliyazicioglu, Mukaddes Kalyoncu, Carlos Eduardo Ramalho, Fabiola D. Almeida, Joan Calzada-Hernández, Rosa Bou, Estíbaliz Iglesias, Judith Sánchez-Manubens, Fredy Hermógenes Prada Martínez, Clara Giménez Roca, Sergi Borlan Fernández, Marek Bohm, Kamran Mahmood, Valentina Leone, Mark Wood, Ken-Ichi Yamaguchi, Satoshi Fujikawa, Working Group of Behçet’s Disease, Pediatric Rheumatology Association of Japan (PRAJ), Kyu Yeun Kim, Do Young Kim, Dong Soo Kim, Maka Ioseliani, Ivane Chkhaidze, Maia Lekishvili, Nana Tskhakaia, Shorena Tvalabeishvili, Aleksandre Kajrishvili, Maiko Takakura, Masaki Shimizu, Natsumi Inoue, Mao Mizuta, Akihiro Yachie, Giovanni Corsello, Maryam Piram, Carla Maldini, Sandra Biscardi, Nathalie Desuremain, Catherine Orzechowski, Emilie Georget, Delphine Regnard, Isabelle Kone-Paut, Alfred Mahr, Mihaela Sparchez, Zeno Sparchez, Nydia Acevedo Silva, Ana V. Villarreal Treviño, Yuridiana Ramirez Loyola, Talia Diaz Prieto, Enrique Faugier Fuentes, Maria D. R. Maldonado Velazquez, Pilar Perez, Sagar Bhattad, Ranjana Minz, Jitendra Shandilya, Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, Ana Villarreal, Yuridiana Ramírez, Zeynep Birsin Özçakar, Suat Fitoz, Fatos Yalcinkaya, Annacarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Priyankar Pal, Kimo Stein, Sandra Enciso, Michael Jeng, Despoina Maritsi, Randy C. Cron, Anne Thorwarth, Sae Lim von Stuckrad, Angela Rösen-Wolff, Hella Luksch, Patrick Hundsdoerfer, Peter Krawitz, Nuray Aktay Ayaz, Doğan Simsek, Şebnem Sara Kılıc, Emine Sonmez, Aysenur Pac Kisaarslan, Ozge Altug Gucenmez, Z. Serap Arıcı, Fatih Kelesoglu, Zelal Ekinci Ekinci, Maria Miranda-Garcia, Carolin Pretzer, Michael Frosch, F. Gohar, Angela McArdle, Niamh Callan, Belinda Hernandez, Miha Lavric, Oliver FitzGerald, Stephen R. Pennington, Joachim Peitz, Joern Kekow, Ariane Klein, Anna C. Schulz, Frank Weller-Heinemann, Anton Hospach, J-Peter Haas, BIKER collaborative group, Karen Put, Jessica Vandenhaute, Anneleen Avau, Annemarie van Nieuwenhuijze, Ellen Brisse, Tim Dierckx, Omer Rutgeerts, Josselyn E. Garcia-Perez, Jaan Toelen, Mark Waer, Georges Leclercq, An Goris, Johan Van Weyenbergh, Adrian Liston, Patrick Matthys, Carine H. Wouters, Yasuo Nakagishi, Michael J. Ombrello, Victoria Arthur, Anne Hinks, Patricia Woo, International Childhood Arthritis Genetics (INCHARGE) Consortium, Barbara Stanimirovic, Biljana Djurdjevic-Banjac, Olivera Ljuboja, Boris Hugle, MArgarita Onoufriou, Olga Vougiouka, Kenza Bouayed, Sanae El Hani, Imane Hafid, Nabiha Mikou, Nunu Shelia, Mari Laan, Jaanika Ilisson, and Chris Pruunsild

Subjects
Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published
2017
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36. Heparin modification of a biomimetic bone matrix modulates osteogenic and angiogenic cell response in vitro

Author

M Quade, S Knaack, D Weber, U König, B Paul, P Simon, A Rösen-Wolff, R Schwartz-Albiez, M Gelinsky, and A Lode

Subjects
collagen, heparin, hydroxyapatite, endothelial cells, mesenchymal stem cells, osteogenic differentiation, angiogenesis, co-culture, Diseases of the musculoskeletal system, RC925-935, Orthopedic surgery, RD701-811
Abstract

In this study, the effect of heparin-modified collagen type I/hydroxyapatite (HA) nanocomposites on key processes of bone regeneration – osteogenesis and angiogenesis – was characterised in vitro. Two approaches were applied for heparin modification: it was either integrated during material synthesis (in situ) or added to the porous scaffolds after their fabrication (post). Cultivation of human bone marrow-derived stromal cells (hBMSC), in heparin-modified versus heparin-free scaffolds, revealed a positive effect of the heparin modification on their proliferation and osteogenic differentiation. The amount of heparin rather than the method used for modification influenced the cell response favouring proliferation at smaller amount (30 mg/g collagen) and differentiation at larger amount (150 mg/g collagen). A co-culture of human umbilical vein endothelial cells (HUVEC) and osteogenically induced hBMSC was applied for in vitro angiogenesis studies. Pre-vascular networks have formed in the porous structure of scaffolds which were not modified with heparin or modified with a low amount of heparin (30 mg/g collagen). The modification with higher heparin quantities seemed to inhibit tubule formation. Pre-loading of the scaffolds with VEGF influenced formation and stability of the pre-vascular structures depending on the presence of heparin: In heparin-free scaffolds, induction of tubule formation and sprouting was more pronounced whereas heparin-modified scaffolds seemed to promote stabilisation of the pre-vascular structures. In conclusion, the modification of mineralised collagen with heparin by using both approaches was found to modulate cellular processes essential for bone regeneration; the amount of heparin has been identified to be crucial to direct cell responses.

Published
2017
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37. Validation and standardization of a FRET-based whole-cell lysate RNase H2 activity assay

Author

Roers, Axel, Rösen-Wolff, Angela, Technische Universität Dresden, Schulz, Marian Simon, Roers, Axel, Rösen-Wolff, Angela, Technische Universität Dresden, and Schulz, Marian Simon

Abstract

Ribonucleotide excision repair (RER) is an RNase H2-dependent DNA-repair mechanism removing mis-incorporated ribonucleotides to maintain DNA stability. Decreased RNase H2 activity leads to an accumulation of ribonucleotides in the DNA, destabilizing and eventually damaging the DNA. This results in double-strand breaks, chromosome abberations, impaired segregation of defective chromosomes, and the formation of micronuclei with unstable nuclear membranes. Upon breakdown of the mironuclear envelope, the released chromatin triggers a cGAS-STING-dependent immune cascade that stimulates the production of type I interferons and cytokines. RNase H2 deficiency directly contributes to autoinflammation and autoimmunity and might further play a role in several types of cancer, aging and neurodegeneration. Therefore, RNase H2 activity is a promising diagnostic and prognostic marker. However, until today, no method for quantification of RNase H2 activity has been validated for a clinical use. Herein, a standard operating procedure for a high-throughput FRET-based whole cell lysate RNase H2 assay is implemented and validated delivering standard curves, statistical benchmarks and standardization to an externally validated control. Providing high sensitivity and strict linearity over a wide working range, the assay is applicable to various human cell or tissue samples with overall methodological assay variability from 8.6% to 16%. Human T cells were identified as a suitable cell type for the implementation of a clinical screening method, showing relatively small inter-individual variability when activity is normalized to cell number. Indeed, decreased RNase H2 activity was detected in T cells from one patient with systemic sclerosis and two patients with systemic lupus erythematosus who carried RNASEH2 mutations known to disrupt enzyme function in vitro compared with a control group of 24 healthy donors. With these findings, this dissertation provides fundamentals for the implementa, Ribonukleotid-Exzisionsreparatur ist ein RNase-H2-abhängiger DNA-Reparaturmechanismus, der durch die Entfernung fälschlich eingebauter Ribonukleotide die Integrität und Stabilität der DNA erhält. Eine verminderte RNase-H2-Aktivität führt zu einer Anhäufung von Ribonukleotiden in der DNA, wodurch die DNA destabilisiert wird und schließlich Schaden nimmt. Das Resultat sind Doppelstrangbrüche, Chromosomenabberationen, eine gestörte Segregation der defekten Chromosomen und die Bildung von „Mikrokernen“ mit instabilen Kernmembranen. Bei Zerfall dieser Mikrokern-Hüllen löst das freiwerdende Chromatin eine cGAS-STING-abhängige Immunkaskade aus, welche die Bildung von Typ-I-Interferonen und Zytokinen stimuliert. Verminderte RNase-H2-Aktivität trägt dadurch direkt zur Entstehung von Autoinflammation und Autoimmunität bei und spielt wahrscheinlich auch als Malignitätsfaktor einiger Karzinome, sowie bei Alterungsprozessen und Neurodegeneration eine Rolle. Daher kann RNase-H2-Aktivität als ein vielversprechender diagnostischer und prognostischer Marker angesehen werden. Bisher etablierte Methoden zur Messung der RNase-H2-Enzymaktivität verfügen jedoch nicht über die Standardisierung und Validierung, welche für den klinischen Einsatz notwendig sind. Diese Dissertation implementiert eine Standardvorgehensweise, Standardkurven und statistische Kenngrößen für einen FRET-basierten RNase-H2-Assay. Der Assay ist für die Anwendung mit Zelllysaten validiert, und liefert standardisierte Ergebnisse. Durch eine hohe Sensitivität und eine strikte Linearität über einen großen Arbeitsbereich kann der Assay in vielen verschiedenen Zell- oder Gewebetypen angewendet werden. Die Gesamt-Variabilität beträgt dabei zwischen 8,6 % bis 16 %. Aufgrund einer relativ niedrigen inter-individuellen Schwankung der zellulären RNase-H2-Aktivität sind menschliche T-Zellen ein geeigneter Zelltyp für klinische Vergleichsstudien. So konnte in T-Zellen einer Patientin mit Systemischer Sklerose und zweier Patientin

Published
2023

38. The German National Registry of Primary Immunodeficiencies (2012–2017)

Author

Sabine M. El-Helou, Anika-Kerstin Biegner, Sebastian Bode, Stephan R. Ehl, Maximilian Heeg, Maria E. Maccari, Henrike Ritterbusch, Carsten Speckmann, Stephan Rusch, Raphael Scheible, Klaus Warnatz, Faranaz Atschekzei, Renata Beider, Diana Ernst, Stev Gerschmann, Alexandra Jablonka, Gudrun Mielke, Reinhold E. Schmidt, Gesine Schürmann, Georgios Sogkas, Ulrich H. Baumann, Christian Klemann, Dorothee Viemann, Horst von Bernuth, Renate Krüger, Leif G. Hanitsch, Carmen M. Scheibenbogen, Kirsten Wittke, Michael H. Albert, Anna Eichinger, Fabian Hauck, Christoph Klein, Anita Rack-Hoch, Franz M. Sollinger, Anne Avila, Michael Borte, Stephan Borte, Maria Fasshauer, Anja Hauenherm, Nils Kellner, Anna H. Müller, Anett Ülzen, Peter Bader, Shahrzad Bakhtiar, Jae-Yun Lee, Ursula Heß, Ralf Schubert, Sandra Wölke, Stefan Zielen, Sujal Ghosh, Hans-Juergen Laws, Jennifer Neubert, Prasad T. Oommen, Manfred Hönig, Ansgar Schulz, Sandra Steinmann, Klaus Schwarz, Gregor Dückers, Beate Lamers, Vanessa Langemeyer, Tim Niehues, Sonu Shai, Dagmar Graf, Carmen Müglich, Marc T. Schmalzing, Eva C. Schwaneck, Hans-Peter Tony, Johannes Dirks, Gabriele Haase, Johannes G. Liese, Henner Morbach, Dirk Foell, Antje Hellige, Helmut Wittkowski, Katja Masjosthusmann, Michael Mohr, Linda Geberzahn, Christian M. Hedrich, Christiane Müller, Angela Rösen-Wolff, Joachim Roesler, Antje Zimmermann, Uta Behrends, Nikolaus Rieber, Uwe Schauer, Rupert Handgretinger, Ursula Holzer, Jörg Henes, Lothar Kanz, Christoph Boesecke, Jürgen K. Rockstroh, Carolynne Schwarze-Zander, Jan-Christian Wasmuth, Dagmar Dilloo, Brigitte Hülsmann, Stefan Schönberger, Stefan Schreiber, Rainald Zeuner, Tobias Ankermann, Philipp von Bismarck, Hans-Iko Huppertz, Petra Kaiser-Labusch, Johann Greil, Donate Jakoby, Andreas E. Kulozik, Markus Metzler, Nora Naumann-Bartsch, Bettina Sobik, Norbert Graf, Sabine Heine, Robin Kobbe, Kai Lehmberg, Ingo Müller, Friedrich Herrmann, Gerd Horneff, Ariane Klein, Joachim Peitz, Nadine Schmidt, Stefan Bielack, Ute Groß-Wieltsch, Carl F. Classen, Jessica Klasen, Peter Deutz, Dirk Kamitz, Lisa Lassay, Klaus Tenbrock, Norbert Wagner, Benedikt Bernbeck, Bastian Brummel, Eusebia Lara-Villacanas, Esther Münstermann, Dominik T. Schneider, Nadine Tietsch, Marco Westkemper, Michael Weiß, Christof Kramm, Ingrid Kühnle, Silke Kullmann, Hermann Girschick, Christof Specker, Elisabeth Vinnemeier-Laubenthal, Henriette Haenicke, Claudia Schulz, Lothar Schweigerer, Thomas G. Müller, Martina Stiefel, Bernd H. Belohradsky, Veronika Soetedjo, Gerhard Kindle, and Bodo Grimbacher

Subjects
registry for primary immunodeficiency, primary immunodeficiency (PID), German PID-NET registry, PID prevalence, European Society for Immunodeficiencies (ESID), IgG substitution therapy, Immunologic diseases. Allergy, RC581-607
Abstract

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

Published
2019
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39. Autoinflammation – Eine klinische und genetische Herausforderung

Author

Gerd Horneff, Angela Rösen-Wolff, and Catharina Schütz

Subjects
Whole genome sequencing, Gynecology, medicine.medical_specialty, Rheumatology, business.industry, medicine, Dermatology, business, Exome sequencing
Abstract

Die klinisch-rheumatologische Praxis ist in den letzten 2 Jahrzehnten mit einer stets steigenden Anzahl autoinflammatorischer Erkrankungen konfrontiert, deren immunologische Pathomechanismen aufgeklart wurden und die sich teilweise klinisch gut einordnen lassen. Diente die gezielte genetische Diagnostik bislang der Bestatigung der klinischen Diagnose, so hat sich heute die genetische Sequenzierungstechnik verbessert. Die Hochdurchsatzsequenzierung z. B. durch Panelsequenzierung, Whole-Exom- und Whole-Genom-Sequenzierung ermoglicht einen vollig neuen diagnostischen Ansatz. Die Entscheidung zur klinischen und/oder genetischen Diagnosestellung ist damit zur taglichen Herausforderung geworden. In dieser Arbeit werden die klinischen, immunologischen und genetischen Aspekte der autoinflammatorischen Erkrankungen gegenubergestellt.

Published
2022
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43. Systematic analysis of candidate reference genes for gene expression analysis in hyperoxia-based mouse models of bronchopulmonary dysplasia

Author

Marius A Möbius, Stefan Winkler, Mary Linge, and Angela Rösen-Wolff

Subjects
Male, Ribosomal Proteins, Pulmonary and Respiratory Medicine, Hypoxanthine Phosphoribosyltransferase, Physiology, Gene Expression, Hyperoxia, Lung injury, Real-Time Polymerase Chain Reaction, Pathogenesis, Mice, Physiology (medical), Reference genes, Gene expression, medicine, Animals, Lung, Bronchopulmonary Dysplasia, business.industry, Electron Transport Complex II, Gene Expression Profiling, Lung Injury, Cell Biology, respiratory system, TATA-Box Binding Protein, medicine.disease, Housekeeping gene, Mice, Inbred C57BL, Oxygen, Disease Models, Animal, Animals, Newborn, Bronchopulmonary dysplasia, Lung disease, Cancer research, Cytokines, Female, medicine.symptom, business, Signal Transduction
Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of preterm infants. Mouse models of hyperoxia-induced lung injury are often used to study pathogenesis and potential therapeutic approaches of BPD. Beside histological studies, gene expression analysis of lung tissue is typically used as experimental readout. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is the standard method for gene expression analysis; however, the accuracy of the quantitative data depends on the appropriate selection of reference genes. No data on validated reference genes for hyperoxia-induced neonatal lung injury in mice are available. In this study, 12 potential reference genes were systematically analyzed for their expression stability in lung tissue of neonatal mice exposed to room air or hyperoxia and healthy adult controls using published software algorithms. Analysis of gene expression data identified Hprt, Tbp, and Hmbs as the most stable reference genes and proposed combinations of Hprt/Sdha or Hprt/Rpl13a as potential normalization factors. These reference genes and normalization factors were validated by comparing Il6 gene and protein expression and may facilitate accurate gene expression analysis in lung tissues of similar designed studies.

Published
2021
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45. Correction: Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Author

Nina Kessler, Susanne F. Viehmann, Calvin Krollmann, Karola Mai, Katharina M. Kirschner, Hella Luksch, Prasanti Kotagiri, Alexander M.C. Böhner, Dennis Huugen, Carina C. de Oliveira Mann, Simon Otten, Stefanie A.I. Weiss, Thomas Zillinger, Kristiyana Dobrikova, Dieter E. Jenne, Rayk Behrendt, Andrea Ablasser, Eva Bartok, Gunther Hartmann, Karl-Peter Hopfner, Paul A. Lyons, Peter Boor, Angela Rösen-Wolff, Lino L. Teichmann, Peter Heeringa, Christian Kurts, and Natalio Garbi

Subjects
Immunology, Immunology and Allergy
Published
2022
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46. Correction: Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Author

Kessler, Nina, primary, Viehmann, Susanne F., additional, Krollmann, Calvin, additional, Mai, Karola, additional, Kirschner, Katharina M., additional, Luksch, Hella, additional, Kotagiri, Prasanti, additional, Böhner, Alexander M.C., additional, Huugen, Dennis, additional, de Oliveira Mann, Carina C., additional, Otten, Simon, additional, Weiss, Stefanie A.I., additional, Zillinger, Thomas, additional, Dobrikova, Kristiyana, additional, Jenne, Dieter E., additional, Behrendt, Rayk, additional, Ablasser, Andrea, additional, Bartok, Eva, additional, Hartmann, Gunther, additional, Hopfner, Karl-Peter, additional, Lyons, Paul A., additional, Boor, Peter, additional, Rösen-Wolff, Angela, additional, Teichmann, Lino L., additional, Heeringa, Peter, additional, Kurts, Christian, additional, and Garbi, Natalio, additional

Published
2022
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49. Epstein-Barr-Virus

Author

Rösen-Wolff, Angela, Darai, Gholamreza, editor, Handermann, Michaela, editor, Sonntag, Hans-Günther, editor, Tidona, Christian A., editor, and Zöller, Lothar, editor

Published
2009
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50. Constitutively active STING causes neuroinflammation and degeneration of dopaminergic neurons in mice

Author

Laura Malz, Eva M Szego, Nadine Bernhardt, Angela Rösen-Wolff, Björn H Falkenburger, and Hella Luksch

Subjects
General Immunology and Microbiology, genetics [Neuroinflammatory Diseases], General Neuroscience, pathology [Dopaminergic Neurons], metabolism [Dopaminergic Neurons], pathology [Neurodegenerative Diseases], neurodegeneration, General Medicine, metabolism [Microglia], General Biochemistry, Genetics and Molecular Biology, neuroinflammation, neuroscience, Mice, metabolism [Neuroinflammatory Diseases], synuclein, nervous system, genetics [Parkinson Disease], inflammasome, parkinson, Neuroinflammatory Diseases, Animals, ddc:600, innate immunity, mouse
Abstract

Stimulator of interferon genes (STING) is activated after detection of cytoplasmic dsDNA by cGAS (cyclic GMP-AMP synthase) as part of the innate immunity defence against viral pathogens. STING binds TANK-binding kinase 1 (TBK1). TBK1 mutations are associated with familial amyotrophic lateral sclerosis, and the STING pathway has been implicated in the pathogenesis of further neurodegenerative diseases. To test whether STING activation is sufficient to induce neurodegeneration, we analysed a mouse model that expresses the constitutively active STING variant N153S. In this model, we focused on dopaminergic neurons, which are particularly sensitive to stress and represent a circumscribed population that can be precisely quantified. In adult mice expressing N153S STING, the number of dopaminergic neurons was smaller than in controls, as was the density of dopaminergic axon terminals and the concentration of dopamine in the striatum. We also observed alpha-synuclein pathology and a lower density of synaptic puncta. Neuroinflammation was quantified by staining astroglia and microglia, by measuring mRNAs, proteins and nuclear translocation of transcription factors. These neuroinflammatory markers were already elevated in juvenile mice although at this age the number of dopaminergic neurons was still unaffected, thus preceding the degeneration of dopaminergic neurons. More neuroinflammatory markers were blunted in mice deficient for inflammasomes than in mice deficient for signalling by type I interferons. Neurodegeneration, however, was blunted in both mice. Collectively, these findings demonstrate that chronic activation of the STING pathway is sufficient to cause degeneration of dopaminergic neurons. Targeting the STING pathway could therefore be beneficial in Parkinson's disease and further neurodegenerative diseases.Neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases are characterised by neurons getting damaged and dying. Many factors contribute to this process, but few can be effectively controlled by therapies. Interestingly, previous studies have highlighted that inflammation, a process normally triggered by foreign agents or biological damage, is often associated with neurons degenerating. However, it is unclear whether these responses are the cause or the consequence of brain cell damage. In injured neurons, the genetic information normally contained inside a dedicated cellular compartment can start to leak into the surrounding parts of the cell. This damage triggers an inflammatory response through the STING pathway, a mechanism previously implicated in the onset of Parkinson’s disease. In these patients, the neurons that produce the signalling molecule dopamine start to die, leading to difficulty with movement. Whether STING can directly cause this neuronal loss remains unknown. To answer this question, Szegö, Malz et al. genetically engineered mice in which the STING pathway is permanently activated. The animals had fewer dopamine-producing neurons and accumulated harmful clumps of proteins; both these biological features are characteristic signs of Parkinson’s disease. Crucially, signs of inflammation were present before neurons started to show damage, suggesting that inflammatory responses could cause neurodegeneration. Further experiments revealed that STING triggers several molecular cascades; blocking one only of these pathways did not keep the neurons healthy. Neurodegenerative diseases are a growing concern around the world. The results from Szegö, Malz et al. suggest that preventing prolonged inflammatory may reduce the risk of neurodegeneration. If further research confirms these findings, in particular in humans, well-known treatments against inflammation could potentially become relevant to fight these conditions.

Published
2022
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