Fully Human Anti-CD19 CAR T Cells Derived from Systemic Lupus Erythematosus Patients Exhibit Cytotoxicity with Reduced Inflammatory Cytokine Production - Dingfelder, Janin; Aigner, Michael; Taubmann, Jule; Minopoulou, Ioanna; Park, Soo; Kaplan, Charles D.; Cheng, Joseph K.; Van Blarcom, Tom; Schett, Georg; Mackensen, Andreas; Lutzny-Geier, Gloria (Transplantation and Cellular Therapy, 2024)
KYV-101 is an autologous anti-CD19 chimeric antigen receptor (CAR)-T cell therapy under investigation for patients with B-cell driven autoimmune diseases. Hu19-CD828Z is a fully human anti-CD19 CAR designed and demonstrated to have a favorable clinical safety profile. Since anti-CD19 CAR T cells target and kill B cells in both circulation and tissues, the treatment with Hu19-CD828Z CAR T cells offers great potential in depleting autoreactive B cells. Demonstrate that Hu19-CD828Z CAR T cells manufactured from cryopreserved leukaphereses from patients with systemic lupus erythematosus (SLE) exhibit CAR-mediated and CD19-dependent cytokine release, proliferation and cytotoxicity when co-cultured with autologous primary B cells. T cells were enriched from cryopreserved leukaphereses from SLE patients or healthy donors (HD). CAR T cells were generated by transducing these cells with a lentiviral vector encoding Hu19-CD828Z. CAR-mediated and CD19-dependent activity was monitored in vitro in a set of cytotoxicity, cytokine release, and proliferation studies, in response to autologous primary CD19+ B cells, a CD19+ cell line (NALM-6), or a CD19− cell line (U937). Hu19-CD828Z CAR T cells produced from SLE patients or HD induced greater proliferation and dose-dependent cytotoxicity against both autologous primary B cells and the CD19+ NALM-6 cells than nontransduced control T cells or co-cultures with a CD19− cell line. Interestingly, there was lower inflammatory cytokine production from SLE patient-derived CAR T cells compared to HD donor-derived CAR T cells with either CD19+ cells or primary B cells. Hu19-CD828Z CAR T cells generated from SLE patient lymphocytes demonstrate CAR-mediated and CD19-dependent activity against autologous primary B cells with reduced inflammatory cytokine production supporting KYV-101 as a novel potential therapy for the depletion of pathogenic B cells in SLE patients.
CRIS-Team Scopus Importer:2024-04-19
Keywords: Chimeric antigen receptor; Cytokines; Systemic Lupus Erythematosus

Fulminant course of osteonecrosis of the jaw in a rheumatoid arthritis patient following oral bisphosphonate intake and biologic therapy - Ebker, Tobias; Rech, Jürgen; von Wilmowsky, Cornelius; Neukam, Friedrich Wilhelm; Stockmann, Philipp (Rheumatology, 2013)
CRIS-Team Scopus Importer:2021-02-03

Functional In Vivo Imaging of Macrophages - Wegner, Anja; Palmisano, Ralf; Uderhardt, Stefan (Methods in Molecular Biology, 2024)
Resident tissue macrophages (RTMs) are specialized phagocytes that are widely distributed throughout the body and are responsible for maintaining homeostasis. Recent advances in experimental techniques have enabled us to gain a greater insight into the actual in vivo biology of RTMs by observing their spatiotemporal dynamics directly in their native environment. Here, we detail a method for live tracking macrophages in a prototypical stromal tissue with high spatial and temporal resolution and great experimental versatility. Our approach builds on a custom intravital imaging platform and straightforward surgical preparation to gain access to an intact stromal compartment in order to analyze the morphological and behavioral dynamics of RTMs at single-cell resolution before and after experimental intervention. Furthermore, our versatile approach can also be utilized for live visualization of intracellular signaling and even for tracking cell organelles at subcellular resolution, and can be combined with downstream analyses such as multiplex confocal imaging, providing a unique insight into macrophage biology in vivo.
CRIS-Team Scopus Importer:2023-09-08
Keywords: In vivo imaging; Intravital imaging; Laser lesion; Peritoneum; Time-lapse microscopy; Tissue macrophages; Two-photon imaging

Ga-68-FAPI-04 PET/CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-related interstitial lung disease - Schmidkonz, Christian; Distler, Jörg; Treutlein, Christoph; Atzinger, Armin; Prante, Olaf; Ritt, Philipp; Goetz, T.; Bäuerle, Tobias; Cordes, Michael; Köhner, Markus; Kuwert, Torsten; Ramming, Andreas; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2021)
CRIS-Team WoS Importer:2022-01-07

gagCEST imaging at 3 T MRI in patients with articular cartilage lesions of the knee and intraoperative validation - Söllner, Stefan; Welsch, G. H.; Gelse, Kolja; Goldmann, A.; Kleyer, Arnd; Schett, Georg; Pachowsky, Milena (Osteoarthritis and Cartilage, 2021)
Objective: The aim of this study was to compare glycosaminoglycan chemical exchange saturation transfer (gagCEST) of knee cartilage with intraoperative results for the assessment of early osteoarthritis (OA) and to define gagCEST values for the differentiation between healthy and degenerated cartilage. Design: Twenty-one patients with cartilage lesions or moderate OA were examined using 3 T Magnetic Resonance Imaging (MRI). In this prospective study, regions of interest (ROIs) were examined by a sagittal gagCEST analysis and a morphological high-resolution three-dimensional, fat-saturated proton-density space sequence. Cartilage lesions were identified arthroscopically, graded by the International Cartilage Repair Society (ICRS) score in 42 defined ROIs per patient and consecutively compared with mean gagCEST values using analysis of variance and Spearman's rank correlation test. Receiver operating characteristics (ROC) curves were applied to identify gagCEST threshold values to differentiate between the ICRS grades. Results: A total of 882 ROIs were examined and graduated in ICRS score 0 (67.3%), 1 (25.2%), 2 (6.2%) and the merged ICRS 3 and 4 (1.0%). gagCEST values decreased with increasing grade of cartilage damage with a negative correlation between gagCEST values and ICRS scores. A gagCEST value threshold of 3.55% was identified to differentiate between ICRS score 0 (normal) and all other grades. Conclusions: gagCEST reflects the content of glycosaminoglycan and might provide a diagnostic tool for the detection of early knee-joint cartilage damage and for the non-invasive subtle differentiation between ICRS grades by MRI even at early stages in clinical practice.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Cartilage; Chemical exchange saturation transfer; MRI; Osteoarthritis

Galectin-3 as a novel regulator of osteoblast-osteoclast interaction and bone homeostasis - Simon, Dominic; Derer, Anja; Andes, Fabian T.; Lezuo, Patrick; Bozec, Aline; Schett, Georg; Herrmann, Martin; Harre, Ulrike (Bone, 2017)
Bone tissue undergoes permanent and lifelong remodeling with a concerted action of bone-building osteoblasts and bone-resorbing osteoclasts. A precise cooperation between those two cell types is critical in the complex process of bone renewal. Galectin-3 is a member of the ?-galactoside-binding lectin family playing multiple roles in cell growth, differentiation and aggregation. As it has been described to be expressed in bone, galectin-3 might influence bone homeostasis by regulating the function and/or interplay of osteoblasts and osteoclasts. Here, we investigated the role of galectin-3 in osteoclastogenesis and osteoblast-osteoclast interactions. Bone histomorphometric analysis and ?CT measurements revealed a decreased trabecular bone volume and an increased osteoclast number in 12weeks old male galectin-3 knockout mice compared to wildtype littermates. Galectin-3 deficient bone marrow cells displayed a higher osteoclastogenic capacity in ex vivo differentiation assays, associated with elevated TRAF6 mRNA levels, suggesting an intrinsic inhibition of osteoclastogenesis by galectin-3 interfering with RANKL-mediated signaling. Furthermore, the addition of extracellular galectin-3 to murine or human osteoclastogenesis assays inhibited osteoclast formation and osteoclast numbers were higher in co-culture assays with galectin-3 deficient osteoblasts. In conclusion, our data suggest the secretion of galectin-3 as a novel mechanism for osteoblasts to control osteoclastogenesis and to maintain trabecular bone homeostasis independently of the RANKL/OPG-axis.
EVALuna2:13345

Gender- and site-specific differences of colorectal neoplasia relate to vitamin D - Aigner, E.; Stadlmayr, A.; Huber-Schoenauer, U.; Zwerina, J.; Husar-Memmer, E.; Niederseer, D.; Trauner, M.; Heuberger, A.; Hohla, F.; Schett, Georg; Patsch, W.; Datz, C. (Alimentary Pharmacology & Therapeutics, 2014)
The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion.To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors.One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded.Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016).A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.
EVALuna2:13058

GENDER DIFFERENCES IN PSA OUTCOME PARAMETERS AND THEIR CORRELATION WITH SKIN INVOLVEMENT: A CROSS-SECTIONAL ANALYSIS OF RABBIT-SPA PATIENTS - Regierer, A.; Weiss, A.; Behrens, F.; Feuchtenberger, M.; Schett, Georg; Baraliakos, X.; Zink, A.; Strangfeld, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Gender equity in academic rheumatology, current status and potential for improvement: a cross-sectional study to inform an EULAR task force - Ovseiko, Pavel; Gossec, Laure; Andreoli, Laura; Kiltz, Uta; Van Mens, Leonieke; Hassan, Neelam; Van Der Leeden, Marike; Siddle, Heidi J.; Alunno, Alessia; Mcinnes, Iain B.; Damjanov, Nemanja S.; Apparailly, Florence; et al. (RMD Open, 2022)
Objectives Evidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology. Methods This cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by chi(2) test and t-test. Results Data from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work-life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement. Conclusions There are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.
CRIS-Team WoS Importer:2022-08-26

Generation and Analysis of Human and Murine Osteoclasts - Steffen, Ulrike; Andes, Fabian T.; Schett, Georg (Current Protocols in Immunology, 2019)
Osteoclasts are the only bone-resorbing cells in the body. Together with bone-forming osteoblasts, they are responsible for bone homeostasis and constant bone remodeling. Aberrant activation of osteoclasts leads to bone loss, as seen in postmenopausal osteoporosis or in autoimmune diseases like rheumatoid arthritis. Although much research has been performed to understand and prevent osteoclast-mediated bone loss, the mechanisms of osteoclast hyperactivation are not completely understood. This unit describes several protocols for ex vivo generation of murine and human osteoclasts, allowing study of the effects of specific cells, cytokines, or chemical substances on osteoclast formation and activity without the need for expensive and time-consuming animal experiments. In addition, we provide protocols for specific staining of osteoclasts and for analysis of resorption activity using calcium phosphate–coated surfaces or bone slices. © 2019 by John Wiley & Sons, Inc.
CRIS-Team Scopus Importer:2019-06-21
Keywords: bone marrow; osteoclast generation; PBMC; resorption; TRAP staining

Generation of a Core Set of Items to Develop Classification Criteria for Scleroderma Renal Crisis Using Consensus Methodology - Butler, Emily-Ann; Baron, Murray; Fogo, Agnes B.; Frech, Tracy; Ghossein, Cybele; Hachulla, Eric; Hoa, Sabrina; Johnson, Sindhu R.; Khanna, Dinesh; Mouthon, Luc; Nikpour, Mandana; Proudman, Susanna; et al. (Arthritis and Rheumatology, 2019)
ObjectiveTo generate a core set of items to develop classification criteria for scleroderma renal crisis (SRC) using consensus methodology. MethodsAn international, multidisciplinary panel of experts was invited to participate in a 3-round Delphi exercise developed using a survey based on items identified by a scoping review. In round 1, participants were asked to identify omissions and clarify ambiguities regarding the items in the survey. In round 2, participants were asked to rate the validity and feasibility of the items using Likert-type scales ranging from 1 to 9 (where 1 = very invalid/unfeasible, 5 = uncertain, and 9 = very valid/feasible). In round 3, participants reviewed the results and comments from round 2 and were asked to provide final ratings. Items rated as highly valid and feasible (median scores 7 for each) in round 3 were selected as the provisional core set of items. A consensus meeting using a nominal group technique was conducted to further reduce the core set of items. ResultsNinety-nine experts from 16 countries participated in the Delphi exercise. Of the 31 items in the survey, consensus was achieved on 13, in the categories hypertension, renal insufficiency, proteinuria, and hemolysis. Eleven experts took part in the nominal group technique discussion, where consensus was achieved in 5 domains: blood pressure, acute kidney injury, microangiopathic hemolytic anemia, target organ dysfunction, and renal histopathology. ConclusionA core set of items that characterize SRC was identified using consensus methodology. This core set will be used in future data-driven phases of this project to develop classification criteria for SRC.
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Generation of an oncolytic herpes simplex virus 1 expressing human MelanA - Boscheinen, Jan; Thomann, Sabrina; Knipe, David M.; Deluca, Neal; Schuler-Thurner, Beatrice; Gross, Stefanie; Dörrie, Jan; Schaft, Niels; Bach, Christian; Rohrhofer, Anette; Werner-Klein, Melanie; Schmidt, Barbara; et al. (Frontiers in Immunology, 2019)
Robust anti-tumor immunity requires innate as well as adaptive immune responses. We have shown that plasmacytoid dendritic cells develop killer cell-like activity in melanoma cell cocultures after exposure to the infectious but replication-deficient herpes simplex virus 1 (HSV-1) d106S. To combine this innate effect with an enhanced adaptive immune response, the gene encoding human MelanA/MART-1 was inserted into HSV-1 d106S via homologous recombination to increase direct expression of this tumor antigen. Infection of Vero cells using this recombinant virus confirmed MelanA expression by Western blotting, flow cytometry, and immunofluorescence. HSV-1 d106S-MelanA induced expression of the transgene in fibroblast and melanoma cell lines not naturally expressing MelanA. Infection of a melanoma cell line with CRISPR-Cas9-mediated knockout of MelanA confirmed de novo expression of the transgene in the viral context. Dependent on MelanA expression, infected fibroblast and melanoma cell lines induced degranulation of HLA-matched MelanA-specific CD8+ T cells, followed by killing of infected cells. To study infection of immune cells, we exposed peripheral blood mononuclear cells and in vitro-differentiated macrophages to the parental HSV-1 d106S, resulting in expression of the transgene GFP in CD11c+ cells and macrophages. These data provide evidence that the application of MelanA-encoding HSV-1 d106S could enhance adaptive immune responses and re-direct MelanA-specific CD8+ T cells to tumor lesions, which have escaped adaptive immune responses via downregulation of their tumor antigen. Hence, HSV-1 d106S-MelanA harbors the potential to induce innate immune responses in conjunction with adaptive antitumor responses by CD8+ T cells, which should be evaluated in further studies.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Cytotoxic T cell response; Herpes virus; Malignant melanoma; Oncolytic viruses; Vaccine

Genetic Analysis of MPO Variants in Four Psoriasis Subtypes in Patients from Germany - Haskamp, Stefan; Horowitz, Joseph; Oji, Vinzenz; Philipp, Sandra; Sticherling, Michael; Schäkel, Knut; Schuhmann, Sarah; Prinz, Jörg C.; Burkhardt, Harald; Behrens, Frank; Böhm, Beate; Köhm, Michaela; et al. (Journal of Investigative Dermatology, 2021)
CRIS-Team Scopus Importer:2021-03-26

Genetic Associations of Non–Major Histocompatibility Complex Susceptibility Loci with Systemic Sclerosis in a Han Chinese Population - Pu, Weilin; Zhang, Rui; Ma, Yanyun; Liu, Qingmei; Jiang, Shuai; Liu, Jing; Zhao, Yinhuan; Tu, Wenzhen; Guo, Gang; Zuo, Xiaoxia; Wang, Qingwen; Chen, Yuanyuan; et al. (Journal of Investigative Dermatology, 2022)
CRIS-Team Scopus Importer:2022-01-28

Genetic barrier to resistance: a critical parameter for efficacy of neutralizing monoclonal antibodies against SARS-CoV-2 in a nonhuman primate model - Stahl-Hennig, Christiane; Peter, Antonia Sophia; Cordsmeier, Arne; Stolte-Leeb, Nicole; Vestweber, Ramona; Socher, Eileen; Merida, Samuel Alberto; Sauermann, Ulrike; Bleyer, Martina; Fraedrich, Kirsten; Grunwald, Thomas; Winkler, Thomas; et al. (Journal of Virology, 2024)
The potency of antibody neutralization in cell culture has been used as the key criterion for selection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for clinical development. As other aspects may also influence the degree of protection in vivo, we compared the efficacy of two neutralizing monoclonal antibodies (TRES6 and 4C12) targeting different epitopes of the receptor binding domain (RBD) of SARS-CoV-2 in a prophylactic setting in rhesus monkeys. All four animals treated with TRES6 had reduced viral loads in the upper respiratory tract 2 days after naso-oropharyngeal challenge with the Alpha SARS-CoV-2 variant. Starting 2 days after challenge, mutations conferring resistance to TRES6 were dominant in two of the rhesus monkeys, with both animals failing to maintain reduced viral loads. Consistent with its lower serum neutralization titer at the day of challenge, prophylaxis with 4C12 tended to suppress viral load at day 2 less efficiently than TRES6. However, a week after challenge, mean viral loads in the lower respiratory tract in 4C12-treated animals were lower than in the TRES6 group and no mutations conferring resistance to 4C12 could be detected in viral isolates from nasal or throat swabs. Thus, genetic barrier to resistance seems to be a critical parameter for the efficacy of prophylaxis with monoclonal antibodies against SARS-CoV-2. Furthermore, comparison of antibody concentrations in respiratory secretions to those in serum shows reduced distribution of the 4C12 antibody into respiratory secretions and a delay in the appearance of antibodies in bronchoalveolar lavage fluid compared to their appearance in secretions of the upper respiratory tract.<br

Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus - Morris, David L.; Sheng, Yujun; Zhang, Yan; Wang, Yong-Fei; Zhu, Zhengwei; Tombleson, Philip; Chen, Lingyan; Graham, Deborah S. Cunninghame; Bentham, James; Roberts, Amy L.; Chen, Ruoyan; Zuo, Xianbo; et al. (Nature Genetics, 2016)
Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.
EVALuna2:13300

Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status - Lyons, Paul A.; Peters, James E.; Alberici, Federico; Liley, James; Coulson, Richard M.R.; Astle, William; Baldini, Chiara; Bonatti, Francesco; Cid, Maria C.; Elding, Heather; Emmi, Giacomo; Epplen, Jörg; et al. (Nature Communications, 2019)
Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
CRIS-Team Scopus Importer:2019-11-22

Genotypes, clinical presentation, treatment and outcome of Cryptococcosis in Germany: Pilot study for a retrospective cohort study 2004-2017 - Kuepper-Tetzel, C. P.; Becker, S.; Wolf, T.; Dziobaka, J.; Harrer, Thomas; Koppe, U.; Stephan, C.; Rickerts, V. (MYCOSES, 2019)
CRIS-Team WoS Importer:2019-09-24

Geometric Constraints Enable Self-Supervised Sinogram Inpainting in Sparse-View Tomography - Wagner, Fabian; Thies, Mareike; Maul, Noah; Pfaff, Laura; Aust, Oliver; Pechmann, Sabrina; Syben, Christopher; Maier, Andreas (17th International Meeting on Fully Three-Dimensional Image Reconstruction in Radiology and Nuclear Medicine (Fully3D), 2023)
The diagnostic quality of computed tomography (CT) scans is usually restricted by the induced patient dose, scan speed, and image quality. Sparse-angle tomographic scans reduce radiation exposure and accelerate data acquisition, but suffer from image artifacts and noise. Existing image processing algorithms can restore CT reconstruction quality but often require large training data sets or can not be used for truncated objects. This work presents a self-supervised projection inpainting method that allows optimizing missing projective views via gradient-based optimization. By reconstructing independent stacks of projection data, a self-supervised loss is calculated in the CT image domain and used to directly optimize projection image intensities to match the missing tomographic views constrained by the projection geometry. Our experiments on real X-ray microscope (XRM) tomographic mouse tibia bone scans show that our method improves reconstructions by 3.1-7.4%/7.7-17.6% in terms of PSNR/SSIM with respect to the interpolation baseline. Our approach is applicable as a flexible self-supervised projection inpainting tool for tomographic applications.<br

German guidelines for the sequential medical treatment of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs - Albrecht, Katinka T; Krueger, Klaus; Wollenhaupt, Juergen; Alten, Rieke; Backhaus, Marina; Baerwald, Christoph; Bolten, Wolfgang; Braun, Juergen; Burkhardt, Harald; Burmester, Gerd R.; Gaubitz, Markus; Gause, Angela; et al. (Rheumatology International, 2014)
The German Society of Rheumatology approved new German guidelines for the sequential medical treatment of rheumatoid arthritis (RA) based on the European League Against Rheumatism (EULAR) recommendations for the management of RA published in 2010. An update of the EULAR systematic literature research was performed in Medline, Embase, and Cochrane databases. Meta-analyses, controlled trials, cohort studies, and registry data addressing traditional and biologic disease-modifying antirheumatic drugs, glucocorticoids, and treatment strategies published between January 2009 and August 2011 were included. Two reviewers independently evaluated and compared the additional data that had been published after the time limit set by the EULAR recommendations. A national guideline working group developed an adapted set of recommendations. The new German guidelines were accepted by vote using an informal Delphi approach. Twelve recommendations and the resulting updated treatment algorithm were developed and approved as a practical orientation for rheumatologists. These recommendations are based on a successive treatment with traditional and biologic disease-modifying drugs depending on the individual progress of the disease and distinct patient characteristics. The German guidelines have been developed on the basis of the internationally well-recognized EULAR recommendations. In addition, more recent evidence from a systematic literature research was considered. They have been developed and approved by a group of national experts aiming at guidance for rheumatologists to reach best medical practice.
EVALuna2:12908

German Mobile Apps for Patients With Psoriasis: Systematic Search and Evaluation - Lull, Christian; von Ahnen, Jan Alwin; Gross, Georg; Olsavszky, Victor; Knitza, Johannes; Leipe, Jan; Schmieder, Astrid (JMIR mHealth and uHealth, 2022)
BACKGROUND: Psoriasis is a chronic inflammatory skin disease. The visibility of erythematous plaques on the skin as well as the pain and itchiness caused by the skin lesions frequently leads to psychological distress in patients. Smartphone apps are widespread and easily accessible. Earlier studies have shown that apps can effectively complement current management strategies for patients with psoriasis. However, no analysis of such apps has been published to date. OBJECTIVE: The aim of this study is to systematically identify and objectively assess the quality of current publicly available German apps for patients with psoriasis using the Mobile Application Rating Scale (MARS) and compile brief ready-to-use app descriptions. METHODS: We conducted a systematic search and assessment of German apps for patients with psoriasis available in the Google Play Store and Apple App Store. The identified apps were randomly assigned to 1 of 3 reviewers, who independently rated them using the German MARS (MARS-G). The MARS-G includes 15 items from 4 different sections (engagement, functionality, aesthetics, and information) to create an overall mean score for every app. Scores can range from 1 for the lowest-quality apps to 5 for the highest-quality apps. Apps were ranked according to their mean MARS-G rating, and the highest-ranked app was evaluated independently by 2 patients with psoriasis using the user version of the MARS-G (uMARS-G). Furthermore, app information, including origin, main function, and technical aspects, was compiled into a brief overview. RESULTS: In total, we were able to identify 95 unique apps for psoriasis, of which 15 were available in both app stores. Of these apps, 5 were not specifically intended for patients with psoriasis, 1 was designed for clinical trials only, and 1 was no longer available at the time the evaluation process began. Consequently, the remaining 8 apps were included in the final evaluation. The mean MARS-G scores ranged from 3.51 to 4.18. The app with the highest mean MARS-G score was Psoriasis Helferin (4.18/5.00). When rated by patients, however, the app was rated lower in all subcategories, resulting in a mean uMARS-G score of 3.48. Most apps had a commercial background and a focus on symptom tracking. However, only a fraction of the apps assessed used validated instruments to measure the user's disease activity. CONCLUSIONS: App quality was heterogeneous, and only a minority of the identified apps were available in both app stores. When evaluated by patients, app ratings were lower than when evaluated by health care professionals. This discrepancy highlights the importance of involving patients when developing and evaluating health-related apps as the factors that make an app appealing to users may differ between these 2 groups. TRIAL REGISTRATION: Deutsches Register Klinischer Studien DRKS00020963; https://tinyurl.com/ye98an5b.
CRIS-Team Scopus Importer:2022-06-03
Keywords: dermatology; disease management; eHealth; health app; mental health; mHealth; mobile health; psoriasis; skin; smartphone application; teledermatology; telemedicine

German Mobile Apps for Patients with Psoriatic Arthritis: Systematic App Search and Content Analysis - Gross, Georg; Lull, Christian; von Ahnen, Jan; Olsavszky, Victor; Knitza, Johannes; Schmieder, Astrid; Leipe, Jan (Health Policy and Technology, 2022)
Background: Psoriatic arthritis (PsA) is a chronic musculoskeletal disease. Functional limitations result in significant patient burden. The use of smartphone apps to complement medical treatments could increase patients’ adherence resulting in better clinical outcome and consequently increased quality of life. Objective: This study aimed to assess and compare currently available smartphone apps for PsA patients using a standardized rating scale. Methods: We conducted a systematic screening of apps for PsA patients in German App Stores and selected apps meeting inclusion criteria: availability in both app stores, German or English language, relevant for patients with psoriatic arthritis, not developed for congress use or clinical studies, no fee-based apps. Three reviewers evaluated apps using the Mobile Application Rating Scale (MARS). Analysis included technical features and mean scores as well as interrater agreement and linear regression. The best-rated app was then rated by PsA patients. Results: Among 232 screened apps, 8 met all inclusion criteria. The app “Rheuma-Auszeit” scored highest with a healthcare provider MARS rating of 4.4 and a patient userMARS rating of 3.7. Subjective quality was lower for all apps. App store star ratings and MARS ratings were not significantly correlated (P=0.34). No app was Conformité Européenne (CE) certified and no underlying clinical studies were found. Conclusions: App quality was heterogenous and generally low. Star ratings – the only accessible tool for patients – does not suffice to identify high-quality apps. We suggest involving patients in development of apps. Since patients and physicians have different perceptions of app quality, we recommend a joint development and evaluation process.
CRIS-Team Scopus Importer:2022-12-09
Keywords: Disease management; eHealth; Mental health; mHealth; Psoriatic arthritis; Smartphone application; telemedicine; Telerheumatology

German Mobile Apps in Rheumatology: Review and Analysis Using the Mobile Application Rating Scale (MARS) - Knitza, Johannes; Tascilar, Koray; Messner, Eva-Maria; Meyer, Marco; Vossen, Diana; Pulla, Almut; Bosch, Philipp; Kittler, Julia; Kleyer, Arnd; Sewerin, Philipp; Mucke, Johanna; Haase, Isabell; et al. (JMIR mHealth and uHealth, 2019)
Background: Chronic rheumatic diseases need long-term treatment and professional supervision. Mobile apps promise to improve the lives of patients and physicians. In routine practice, however, rheumatology apps are largely unknown and little is known about their quality and safety.
CRIS-Team WoS Importer:2019-08-27

Global disparities in the treatment of idiopathic inflammatory myopathies: results from an international online survey study. - Ziade, Nelly; Aoude, Marc; Hmamouchi, Ihsane; Naveen, R.; Lilleker, James B.; Sen, Parikshit; Joshi, Mrudula; Agarwal, Vishwesh; Kardes, Sinan; Day, Jessica; Makol, Ashima; Milchert, Marcin; et al. (Rheumatology, 2024)
OBJECTIVES: We aimed to explore current practice and interregional differences in the treatment of idiopathic inflammatory myopathies (IIMs). We triangulated these observations considering countries' gross national income (GNI), disease subtypes, and symptoms using patient-reported information. METHODS: A cross-sectional ancillary analysis of the 'COVID-19 vaccination in auto-immune disease' (COVAD) e-survey containing demographic characteristics, IIM subtypes (DM, PM, IBM, anti-synthetase syndrome [ASSD], immune-mediated necrotizing myopathy [IMNM], overlap myopathies [OM]), current symptoms (surrogate for organ involvement) and treatments (corticosteroids [CS], immunomodulators [IM], i.e. antimalarials, immunosuppressants [IS], IVIG, biologic treatments and targeted-synthetic small molecules). Treatments were presented descriptively according to continents, GNI, IIM and organ involvement, and associated factors were analysed using multivariable binary logistic regressions. RESULTS: Of 18 851 respondents from 94 countries, 1418 with IIM were analysed (age 61 years, 62.5% females). DM (32.4%), IBM (24.5%) and OM (15.8%) were the most common subtypes. Treatment categories included IS (49.4%), CS (38.5%), IM (13.8%) and IVIG (9.4%). Notably, treatments varied across regions, GNI categories (IS mostly used in higher-middle income, IM in lower-middle income, IVIG and biologics largely limited to high-income countries), IIM subtypes (IS and CS associated with ASSD, IM with OM and DM, IVIG with IMNM, and biologic treatments with OM and ASSD) and disease manifestations (IS and CS with dyspnoea). Most inter-regional treatment disparities persisted after multivariable analysis. CONCLUSION: We identified marked regional treatment disparities in a global cohort of IIM. These observations highlight the need for international consensus-driven management guidelines considering patient-centred care and available resources.
EVALuna2:544059

Glucocorticoid Doses and Acute-Phase Reactants at Giant Cell Arteritis Flare in a Randomized Trial of Tocilizumab - Stone, John H.; Tuckwell, Katie; Dimonaco, Sophie; Klearman, Micki; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Schulze-Koops, Hendrik; et al. (Arthritis and Rheumatology, 2019)
OBJECTIVE: To evaluate glucocorticoid doses and serological findings in patients with giant cell arteritis (GCA) flares. METHODS: Patients with GCA were randomly assigned to receive double-blind dosing with subcutaneous tocilizumab (TCZ) 162 mg weekly plus 26-week prednisone (TCZ-QW+Pred-26), every-other-week TCZ plus 26-week prednisone (TCZ-Q2W+Pred-26), placebo plus 26-week prednisone (PBO+Pred-26), or placebo plus 52-week prednisone (PBO+Pred-52). Outcomes were prednisone dose, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) at the time of flare and remission during 52 weeks. RESULTS: One hundred patients received TCZ-QW+Pred-26, 49 received TCZ-Q2W+Pred-26, 50 received PBO+Pred-26, and 51 received PBO+Pred-52. Among 149 TCZ-treated patients, 36 (24%) experienced flare, 23 (64%) of whom were still receiving prednisone (median dose, 2.0 mg/day). Among 101 PBO+Pred-treated patients, 59 (58%) experienced flare, 45 (76%) of whom were receiving prednisone (median dose, 5.0 mg/day). Many flares occurred while patients were taking more than 10 mg/day prednisone: 9 (25%) in the TCZ groups and 13 (22.0%) in the placebo groups. Thirty-three flares (92%) in TCZ-treated groups and 20 (34%) in PBO+Pred-treated groups occurred with normal CRP. More than half the PBO+Pred-treated patients had elevated CRP without flare. Benefits of the combination of TCZ plus prednisone over prednisone alone for remission induction were apparent by 8 weeks. CONCLUSION: Most GCA flares occurred while patients were still receiving prednisone. Acute-phase reactants were not reliable indicators of flare in patients treated with TCZ plus prednisone or with prednisone alone. The addition of TCZ to prednisone facilitates earlier GCA control. This article is protected by copyright. All rights reserved.
EVALuna2:69393

Glucocorticoid-induced relapse of COVID-19 in a patient with sarcoidosis - Györfi, Andrea-Hermina; Kopp, Markus; May, Matthias; Vetter, Marcel; Uder, Michael; Kremer, Andreas; Schett, Georg; Harrer, Thomas; Distler, Jörg (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2020-11-20

Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis - Koenen, Mascha; Culemann, Stephan; Vettorazzi, Sabine; Caratti, Giorgio; Frappart, Lucien; Baum, Wolfgang; Krönke, Gerhard; Baschant, Ulrike; Tuckermann, Jan P. (Annals of the Rheumatic Diseases, 2018)
BACKGROUND: Glucocorticoid (GC) therapy is frequently used to treat rheumatoid arthritis due to potent anti-inflammatory actions of GCs. Direct actions of GCs on immune cells were suggested to suppress inflammation. OBJECTIVES: Define the role of the glucocorticoid receptor (GR) in stromal cells for suppression of inflammatory arthritis. METHODS: Bone marrow chimeric mice lacking the GR in the hematopoietic or stromal compartment, respectively, and mice with impaired GR dimerisation (GRdim) were analysed for their response to dexamethasone (DEX, 1 mg/kg) treatment in serum transfer-induced arthritis (STIA). Joint swelling, cell infiltration (histology), cytokines, cell composition (flow cytometry) and gene expression were analysed and RNASeq of wild type and GRdim primary murine fibroblast-like synoviocytes (FLS) was performed. RESULTS: GR deficiency in immune cells did not impair GC-mediated suppression of STIA. In contrast, mice with GR-deficient or GR dimerisation-impaired stromal cells were resistant to GC treatment, despite efficient suppression of cytokines. Intriguingly, in mice with impaired GR function in the stromal compartment, GCs failed to stimulate non-classical, non-activated macrophages (Ly6Cneg, MHCIIneg) and associated anti-inflammatory markers CD163, CD36, AnxA1, MerTK and Axl. Mice with GR deficiency in FLS were partially resistant to GC-induced suppression of STIA. Accordingly, RNASeq analysis of DEX-treated GRdim FLS revealed a distinct gene signature indicating enhanced activity and a failure to reduce macrophage inflammatory protein (Mip)-1α and Mip-1β. CONCLUSION: We report a novel anti-inflammatory mechanism of GC action that involves GR dimerisation-dependent gene regulation in non-immune stromal cells, presumably FLS. FLS control non-classical, anti-inflammatory polarisation of macrophages that contributes to suppression of inflammation in arthritis.
EVALuna2:34952

GLUCOCORTICOIDS PRESCRIBING PRACTICES IN SYSTEMIC SCLEROSIS: AN ANALYSIS OF THE EUSTAR DATABASE. - Iudici, Michele; Mongin, D.; Siegert, E.; Carreira, P.; Distler, Jörg; Henes, J.; Zanatta, E.; Hachulla, E.; De Luca, G.; Souza Muller, C.; Salvador, M. J.; Tandaipan, J. L.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Glucocorticoids prescribing practices in systemic sclerosis: an analysis of the EUSTAR database - Iudici, Michele; Mongin, Denis; Siegert, Elise; Carreira, Patricia E.; Distler, Jörg; Henes, Joerg; Zanatta, Elisabetta; Hachulla, Eric; De Luca, Giacomo; Mueller, Carolina De Souza; Santiago, Tania; Tandaipan, Jose-Luis; et al. (Rheumatology, 2022)
Objectives To estimate the prevalence of long-term exposure to glucocorticoids (GCs) and to identify factors associated with, and variations in prescribing practices over time and across recruiting countries. Methods We included patients with SSc having a visit recorded in the EUSTAR database from January 2013 onward. We analysed the prevalence and the main features of GCs users, their exposure to GCs over time, and their GCs dosages. Multivariable linear regression was used to analyse the factors identified as associated with GCs intake duration. Time trends, and variations in GCs utilization across recruiting countries were explored. Missing data were imputed using multiple imputation with chained equations. Results The 9819 patients included were mostly females (85%), the majority had lcSSc (73%), and the median age was 58 years. At baseline, 34% of patients (n = 2769/8109) (48% dcSSc vs 29% lcSSc) were on GCs, and the median dose was 7.5 mg/day. GCs users were more frequently males and anti-Scl70 positive, and more commonly had dcSSc and more severe disease. On average, GCs users spent 25% of their follow-up time (median 33.2 months) on GCs, with no significant between-subsets difference. Notably, 33% (n = 971/2959) and 22% (n = 647/2959) of patients followed up for >1 year had received GCs for >6 and >12 months, respectively. Multivariable analysis showed that patient and disease characteristics poorly explained the variability in GCs exposure (adjusted-R-2 = 0.06, P < 0.001). GCs utilization varied within and across countries, and gradually decreased over time (36% in 2013 vs 23% in 2018). Conclusions GCs are widely and long-term prescribed in SSc, with significant between-countries and within-country differences. A gradual decrease in their utilization has been observed.
CRIS-Team WoS Importer:2022-10-28

Glucose transporter type 1: metabolic player in antibody-secreting plasma cells - Bierling, Theresa; Gumann, A.; Van Schie, K.; Wittner, Jens; Wichert, M.; Hauke, Manuela; Toes, R. E.; Mielenz, Dirk; Jäck, Hans-Martin; Pracht, Katharina (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

GLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity - Bierling, Theresa; Gumann, Amelie; Ottmann, Shannon; Schulz, Sebastian; Weckwerth, Leonie; Thomas, Jana; Geßner, Arne; Wichert, Magdalena; Kuwert, Frederic; Rost, Franziska; Hauke, Manuela; Freudenreich, Tatjana; et al. (Cell Reports, 2024)
Glucose uptake increases during B cell activation and antibody-secreting cell (ASC) differentiation, but conflicting findings prevent a clear metabolic profile at different stages of B cell activation. Deletion of the glucose transporter type 1 (GLUT1) gene in mature B cells (GLUT1-cKO) results in normal B cell development, but it reduces germinal center B cells and ASCs. GLUT1-cKO mice show decreased antigen-specific antibody titers after vaccination. In vitro, GLUT1-deficient B cells show impaired activation, whereas established plasmablasts abolish glycolysis, relying on mitochondrial activity and fatty acids. Transcriptomics and metabolomics reveal an altered anaplerotic balance in GLUT1-deficient ASCs. Despite attempts to compensate for glucose deprivation by increasing mitochondrial mass and gene expression associated with glycolysis, the tricarboxylic acid cycle, and hexosamine synthesis, GLUT1-deficient ASCs lack the metabolites for energy production and mitochondrial respiration, limiting protein synthesis. We identify GLUT1 as a critical metabolic player defining the germinal center response and humoral immunity.
CRIS-Team Scopus Importer:2024-02-23
Keywords: adaptive immune response; antibody-secreting cell; CP: Immunology; CP: Metabolism; glucose transporter type 1; GLUT1; glycolysis; metabolism; mitochondrial respiration; plasma cell; plasmablast

Glutathione peroxidase 3 is a novel clinical diagnostic biomarker and potential therapeutic target for neutrophils in rheumatoid arthritis - Chen, Tao; Zhou, Zhen; Peng, Minge; Hu, Huifang; Sun, Rui; Xu, Jiayi; Zhu, Chenxi; Li, Yanhong; Zhang, Qiuping; Luo, Yubin; Yang, Bin; Dai, Lunzhi; et al. (Arthritis Research & Therapy, 2023)
Background: Neutrophils have a critical role in the pathogenesis of rheumatoid arthritis (RA) with immune system dysfunction. However, the molecular mechanisms of this process mediated by neutrophils still remain elusive. The purpose of the present study is to identify hub genes in neutrophils for diagnosis and treatment of RA utilizing publicly available datasets. Methods: Gene expression profiles were downloaded from the Gene Expression Omnibus, and batch-corrected and normalized expression data were obtained using the ComBat package. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were used to conduct significantly functional analysis and crucial pathways. The resulting co-expression genes modules and hub genes were generated based on the weighted gene co-expression network analysis and visualization by Cytoscape. Flow cytometry was conducted to detect reactive oxygen species (ROS) levels in neutrophils. Results: Neutrophils underwent transcriptional changes in synovial fluid (SF) of RA patients, different from peripheral blood of healthy controls or patients with RA. Especially, glycolysis, HIF-1 signaling, NADH metabolism, and oxidative stress were affected. These hub genes were strongly linked with classical glycolysis-related genes (ENO1, GAPDH, and PKM) responsible for ROS production. The antioxidant enzyme glutathione peroxidase 3 (GPX3), a ROS scavenger, was first identified as a hub gene in RA neutrophils. Neutrophils from patients with autoinflammatory and autoimmune diseases had markedly enhanced ROS levels, most notably in RA SF. Conclusion: This research recognized hub genes and explored the characteristics of neutrophils in RA. Our findings suggest that the novel hub gene GPX3 is involved in the neutrophil-driven oxidative stress-mediated pathogenesis of RA. It has the potency to be a target for neutrophil-directed RA therapy.
CRIS-Team Scopus Importer:2023-05-05
Keywords: Hub genes; Neutrophils; Reactive oxygen species; Rheumatoid arthritis

Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. - Harre, Ulrike; Lang, Stefanie; Pfeifle, René; Rombouts, Yoann; Frühbeißer, Sabine; Amara, Khaled; Bang, Holger; Lux, Anja; Koeleman, Carolien A.; Baum, Wolfgang; Dietel, Katharina; Gröhn, Franziska; et al. (Nature Communications, 2015)
Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone los

Glycosylation of random IgG distinguishes seropositive and seronegative rheumatoid arthritis - Magorivska, I.; Donczo, B.; Dumych, Tetiana; Karmash, A.; Boichuk, Maryana; Hychka, Kateryna; Mihalj, Martina; Szabo, M.; Csanky, E.; Rech, Jürgen; Guttman, A.; Vari, S. G.; et al. (Autoimmunity, 2018)
The N-glycosylation of human immunoglobulins, especially IgGs, plays a critical role in determining affinity of IgGs towards their effector (pro- and anti-inflammatory) receptors. However, it is still not clear whether altered glycosylation is involved in only antibody-dependent disorders like seropositive rheumatoid arthritis (RA) or also in pathologies with similar clinical manifestations, but no specific autoantibodies like seronegative RA. The clarification of that uncertainty was the aim of the current study. Another study aim was the detection of specific glycan forms responsible for altered exposure of native glycoepitopes. We studied sera from seropositive RA (n = 15) and seronegative RA (n = 12) patients for exposure of glycans in native IgG molecules, followed by determination of specific glycans by capillary electrophoresis with laser-induced fluorescent detection (CE-LIF). Aged-matched groups of normal healthy donors (NHD) and samples of intravenous immunoglobulin IgG preparations (IVIG) served as controls. There was significantly stronger binding of Lens culinaris agglutinin (LCA) and Aleuria aurantia lectin (AAL) lectins towards IgG from seropositive RA compared to seronegative RA or NHD. CE-LIF analysis revealed statistically significant increases in bisecting glycans FA2BG2 (p = .006) and FABG2S1 (p = .005) seropositive RA, accompanied by decrease of bisecting monogalactosylated glycan FA2(6)G1 (p = .074) and non-bisecting monosialylated glycan FA2(3)G1S1 (p = .055). The results suggest that seropositive RA is distinct from seronegative RA in terms of IgG glycan moieties, attributable to specific immunoglobulin molecules present in seropositive disease. These glycans were determined to be bisecting GlcNAc-bearing forms FA2BG2 and FABG2S1, and their appearance increased the availability of LCA and AAL lectin-binding sites in native IgG glycoepitopes.
EVALuna2:35016

Gout, hyperuricaemia and crystal-associated disease network (G-CAN) consensus statement regarding labels and definitions of disease states of gout - Bursill, David; Taylor, William J.; Terkeltaub, Robert; Abhishek, Abhishek; So, Alexander K.; Vargas-Santos, Ana Beatriz; Gaffo, Angelo Lino; Rosenthal, Ann; Tausche, Anne Kathrin; Reginato, Anthony; Manger, Bernhard; Sciré, Carlo; et al. (Annals of the Rheumatic Diseases, 2019)
Objective: There is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout. Methods: A content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions. Results: The content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', ' asymptomatic monosodium urate crystal deposition', ' asymptomatic hyperuricaemia with monosodium urate crystal deposition', ' gout', ' tophaceous gout', ' erosive gout', ' first gout flare' and ' recurrent gout flares'. There was consensus agreement that the label ' gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus). Conclusion: Consensus agreement has been established for the labels and definitions of eight gout disease states, including ' gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.
CRIS-Team Scopus Importer:2019-09-24
Keywords: gout; hyperuricemia; language; monosodium urate crystals; nomenclature; terminology; urate

Gout mimicking rheumatoid arthritis - Petsch, Christina; Guilhon de Araujo, Elizabeth; Hueber, Axel; Schett, Georg; Manger, Bernhard; Rech, Jürgen (Seminars in Arthritis and Rheumatism, 2017)
EVALuna2:13107

Graphene-Induced Hyperthermia (GIHT) Combined With Radiotherapy Fosters Immunogenic Cell Death - Podolska, Malgorzata; Shan, Xiaomei; Janko, Christina; Boukherroub, Rabah; Gaipl, Udo; Szunerits, Sabine; Frey, Benjamin; Munoz, Luis Enrique (Frontiers in Oncology, 2021)
Radiotherapy and chemotherapy are the standard interventions for cancer patients, although cancer cells often develop radio- and/or chemoresistance. Hyperthermia reduces tumor resistance and induces immune responses resulting in a better prognosis. We have previously described a method to induce tumor cell death by local hyperthermia employing pegylated reduced graphene oxide nanosheets and near infrared light (graphene-induced hyperthermia, GIHT). The spatiotemporal exposure/release of heat shock proteins (HSP), high group mobility box 1 protein (HMGB1), and adenosine triphosphate (ATP) are reported key inducers of immunogenic cell death (ICD). We hypothesize that GIHT decisively contributes to induce ICD in irradiated melanoma B16F10 cells, especially in combination with radiotherapy. Therefore, we investigated the immunogenicity of GIHT alone or in combination with radiotherapy in melanoma B16F10 cells. Tumor cell death in vitro revealed features of apoptosis that is progressing fast into secondary necrosis. Both HSP70 and HMGB1/DNA complexes were detected 18 hours post GIHT treatment, whereas the simultaneous release of ATP and HMGB1/DNA was observed only 24 hours post combined treatment. We further confirmed the adjuvant potential of these released DAMPs by immunization/challenge experiments. The inoculation of supernatants of cells exposed to sole GIHT resulted in tumor growth at the site of inoculation. The immunization with cells exposed to sole radiotherapy rather fostered the growth of secondary tumors in vivo. Contrarily, a discreet reduction of secondary tumor volumes was observed in mice immunized with a single dose of cells and supernatants treated with the combination of GIHT and irradiation. We propose the simultaneous release of several DAMPs as a potential mechanism fostering anti-tumor immunity against previously irradiated cancer cells.
CRIS-Team Scopus Importer:2021-09-17
Keywords: hyperthermia; immunogenic cell death; melanoma; multimodal; radiotherapy; reduced graphene oxide

Graphene Oxide Nanosheets for Localized Hyperthermia-Physicochemical Characterization, Biocompatibility, and Induction of Tumor Cell Death - Podolska, Malgorzata; Barras, Alexandre; Alexiou, Christoph; Frey, Benjamin; Gaipl, Udo; Boukherroub, Rabah; Szunerits, Sabine; Janko, Christina; Munoz, Luis Enrique (Cells, 2020)
Background: The main goals of cancer treatment are not only to eradicate the tumor itself but also to elicit a specific immune response that overcomes the resistance of tumor cells against chemo- and radiotherapies. Hyperthermia was demonstrated to chemo- and radio-sensitize cancerous cells. Many reports have confirmed the immunostimulatory effect of such multi-modal routines. Methods: We evaluated the interaction of graphene oxide (GO) nanosheets; its derivatives reduced GO and PEGylated rGO, with components of peripheral blood and evaluated its thermal conductivity to induce cell death by localized hyperthermia. Results: We confirmed the sterility and biocompatibility of the graphene nanomaterials and demonstrated that hyperthermia applied alone or in the combination with radiotherapy induced much more cell death in tumor cells than irradiation alone. Cell death was confirmed by the release of lactate dehydrogenase from dead and dying tumor cells. Conclusion: Biocompatible GO and its derivatives can be successfully used in graphene-induced hyperthermia to elicit tumor cell death.
CRIS-Team WoS Importer:2020-05-15

Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice - Omata, Yasunori; Frech, Michael; Primbs, Tatjana; Lucas, Sebastien; Andreev, Darja; Scholtysek, Carina; Sarter-Zaiss, Kerstin; Kindermann, Markus; Yeremenko, Nataliya; Baeten, Dominique L.; Andreas, Nico; Kamradt, Thomas; et al. (Cell Reports, 2018)
Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORαcre/GATA3fl/fl and Tie2cre/RORαfl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13-/- ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis.
EVALuna2:34467

Guidelines for the use of flow cytometry and cell sorting in immunological studies - Cossarizza, Andrea; Chang, Hyun-Dong; Radbruch, Andreas; Akdis, Mubeccel; Andrae, Immanuel; Annunziato, Francesco; Bacher, Petra; Barnaba, Vincenzo; Battistini, Luca; Bauer, Wolfgang M.; Baumgart, Sabine; Becher, Burkhard; et al. (European Journal of Immunology, 2017)
EVALuna2:13453

Guidelines for visualization and analysis of DC in tissues using multiparameter fluorescence microscopy imaging methods - Bayerl, Felix; Bejarano, David A.; Bertacchi, Giulia; Doffin, Anne Claire; Gobbini, Elisa; Hubert, Margaux; Li, Lijian; Meiser, Philippa; Pedde, Anna Marie; Posch, Wilfried; Rupp, Luise; Schlitzer, Andreas; et al. (European Journal of Immunology, 2023)
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various non-lymphoid tissues. Here, we provide detailed procedures for a variety of multiparameter fluorescence microscopy imaging methods to explore the spatial organization of DC in tissues and to dissect how DC migrate, communicate, and mediate their multiple functional roles in immunity in a variety of tissue settings. The protocols presented here entail approaches to study DC dynamics and T cell cross-talk by intravital microscopy, large-scale visualization, identification, and quantitative analysis of DC subsets and their functions by multiparameter fluorescence microscopy of fixed tissue sections, and an approach to study DC interactions with tissue cells in a 3D cell culture model. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
CRIS-Team Scopus Importer:2023-01-20

Guselkumab, a Selective Interleukin-23 p19 Subunit Inhibitor, Resolves Dactylitis in Patients With Active Psoriatic Arthritis: Pooled Results Through Week 52 From Two Phase 3 Studies - Mcgonagle, Dennis; Mcinnes, Iain B. B.; Deodhar, Atul; Schett, Georg; Shawi, May; Chakravarty, Soumya D. D.; Kollmeier, Alexa P. P.; Xu, Xie L. L.; Sheng, Shihong; Xu, Stephen; Ritchlin, Christopher T. T.; Rahman, Proton; et al. (ACR Open Rheumatology, 2023)
Objective: Previous analyses of pooled DISCOVER-1 and DISCOVER-2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year. Methods: Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0-3/digit; total = 0-60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER-2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52. Results: Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab-randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new-onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab-randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER-2). Conclusion: Through 1 year, approximately 75% of guselkumab-randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long-term patient outcomes.
CRIS-Team Scopus Importer:2023-03-31

GUSELKUMAB IMPROVES DACTYLITIS IN PSA PATIENTS WITH INADEQUATE RESPONSE TO TNFI: DATA FROM THE PHASE 3B COSMOS TRIAL - Marzo-Ortega, H.; Theander, E.; Neuhold, M.; Bergmans, P.; Shawi, M.; Perate, M.; Contre, C.; Mcinnes, I.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

GUSELKUMAB MAINTAINS RESOLUTION OF DACTYLITIS AND ENTHESITIS IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: RESULTS THROUGH 2 YEARS FROM A PHASE 3 STUDY - Rahman, P.; Mcinnes, I.; Deodhar, A.; Schett, Georg; Mease, P. J.; Shawi, M.; Cua, D.; Sherlock, J.; Kollmeier, A.; Xu, X. L.; Jiang, Y.; Sheng, S.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Guselkumab (TREMFYA (R)) Maintains Resolution of Dactylitis and Enthesitis in Patients with Active Psoriatic Arthritis: Results Through 2 Years from a Phase 3 Study - Rahman, Proton; Mcinnes, Iain; Deodhar, Atul; Schett, Georg; Mease, Philip; Shawi, May; Cua, Daniel; Sherlock, Jonathan; Kollmeier, Alexa; Xu, Xie; Jiang, Yusang; Sheng, Shihong; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Gut immune cell trafficking: inter-organ communication and immune-mediated inflammation - Zundler, Sebastian; Günther, Claudia; Kremer, Andreas E.; Rothhammer, Veit; Neurath, Markus; Zaiss, Mario (Nature Reviews Gastroenterology & Hepatology, 2022)
Immune cell trafficking is a complex and tightly regulated process that is indispensable for the body’s fight against pathogens. However, it is also increasingly acknowledged that dysregulation of cell trafficking contributes to the pathogenesis of immune-mediated inflammatory diseases (IMIDs) in gastroenterology and hepatology, such as inflammatory bowel disease and primary sclerosing cholangitis. Moreover, altered cell trafficking has also been implicated as a crucial step in the immunopathogenesis of other IMIDs, such as rheumatoid arthritis and multiple sclerosis. Over the past few years, a central role of the gut in mediating these disorders has progressively emerged, and the partly microbiota-driven imprinting of particular cell trafficking phenotypes in the intestine seems to be crucially involved. Therefore, this Review highlights achievements in understanding immune cell trafficking to, within and from the intestine and delineates its consequences for immune-mediated pathology along the gut–liver, gut–joint and gut–brain axes. We also discuss implications for current and future therapeutic approaches that specifically interfere with homing, retention, egress and recirculation of immune cells.
CRIS-Team Scopus Importer:2022-08-26

GUT MICROBIOME, BONE AND JOINT - Schett, Georg (OSTEOPOROSIS INTERNATIONAL, 2021)
CRIS-Team WoS Importer:2022-03-04

Gut-to-brain spreading of pathology in synucleinopathies: A focus on molecular signalling mediators - Schmitt, Verena; Masanetz, Rebecca Katharina; Weidenfeller, Martin; Ebbinghaus, Lara Savannah; Süß, Patrick; Rosshart, Stephan Patrick; von Hörsten, Stephan; Zunke, Friederike; Winkler, Jürgen; Xiang, Wei (Behavioural Brain Research, 2023)
Synucleinopathies are a group of neurodegenerative disorders, classically characterized by the accumulation of aggregated alpha synuclein (aSyn) in the central nervous system. Parkinson's disease (PD) and multiple system atrophy (MSA) are the two prominent members of this family. Current treatment options mainly focus on the motor symptoms of these diseases. However, non-motor symptoms, including gastrointestinal (GI) symptoms, have recently gained particular attention, as they are frequently associated with synucleinopathies and often arise before motor symptoms. The gut-origin hypothesis has been proposed based on evidence of an ascending spreading pattern of aggregated aSyn from the gut to the brain, as well as the comorbidity of inflammatory bowel disease and synucleinopathies. Recent advances have shed light on the mechanisms underlying the progression of synucleinopathies along the gut-brain axis. Given the rapidly expanding pace of research in the field, this review presents a summary of the latest findings on the gut-to-brain spreading of pathology and potential pathology-reinforcing mediators in synucleinopathies. Here, we focus on 1) gut-to-brain communication pathways, including neuronal pathways and blood circulation, and 2) potential molecular signalling mediators, including bacterial amyloid proteins, microbiota dysbiosis-induced alterations in gut metabolites, as well as host-derived effectors, including gut-derived peptides and hormones. We highlight the clinical relevance and implications of these molecular mediators and their possible mechanisms in synucleinopathies. Moreover, we discuss their potential as diagnostic markers in distinguishing the subtypes of synucleinopathies and other neurodegenerative diseases, as well as for developing novel individualized therapeutic options for synucleinopathies.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Alpha synuclein; Gut-to-brain communication; Inflammatory bowel disease; Multiple system atrophy; Parkinson's disease

GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways - López-Isac, Elena; Acosta-Herrera, Marialbert; Kerick, Martin; Assassi, Shervin; Satpathy, Ansuman T.; Granja, Jeffrey; Mumbach, Maxwell R.; Beretta, Lorenzo; Simeón, Carmen P.; Carreira, Patricia; Ortego-Centeno, Norberto; Castellvi, Ivan; et al. (Nature Communications, 2019)
Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.
CRIS-Team Scopus Importer:2019-11-08

HAND FUNCTION IS IMPAIRED IN PATIENTS WITH RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS, AND PSORIASIS COMPARED TO HEALTHY CONTROLS - Liphardt, Anna-Maria; Liehr, Sonja; Manger, Eva; Bieniek, Lisa; Kleyer, Arnd; Simon, David; Tascilar, Koray; Sticherling, Michael; Rech, Jürgen; Schett, Georg; Hueber, Axel (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Hard palate hyperpigmentation - a rare side effect of antimalarials - Manger, Karin; von Streitberg, Ulrich; Seitz, Gerhard; Kleyer, Arnd; Manger, Bernhard (Arthritis and Rheumatology, 2017)
A 50-year old female Caucasian patient with marked xerostomia, xerophthalmia, relapsing parotid swelling, arthralgias, and fatigue had been treated with chloroquine diphosphate (250 mg/day) for four years, when a painless bluish-grey hyperpigmentation of her hard palate was noticed during one of her rheumatologic follow-up visits (A). To rule out malignancy or infection, a mucosal biopsy was performed and histology showed subepithelial granular pigment depositions among collagen fibres and within macrophages (B). Perl's Prussian blue staining confirmed that these deposits contained hemosiderin (C). This article is protected by copyright. All rights reserved.
EVALuna2:13448

Head and Neck Kaposi Sarcoma: Clinicopathological Analysis of 11 Cases - Agaimy, Abbas; Müller, Sarina Katrin; Harrer, Thomas; Bauer, Sebastian; Thompson, Lester D. R. (Head and Neck Pathology, 2018)
Kaposi sarcoma (KS) of the head and neck area is uncommon with limited published case series. Our routine and consultation files were reviewed for histologically and immunohistochemically proven KS affecting any cutaneous or mucosal head and neck site. Ten males and one female aged 42-78 years (median, 51 years; mean, 52 years) were retrieved. Eight patients were HIV-positive and three were HIV-negative. The affected sites were skin (n = 5), oral/oropharyngeal mucosa (n = 5), and lymph nodes (n = 3) in variable combination. The ear (pinna and external auditory canal) was affected in two cases; both were HIV-negative. Multifocal non-head and neck KS was reported in 50% of patients. At last follow-up (12-94 months; median, 46 months), most of patients were either KS-free (n = 8) or had ongoing remission under systemic maintenance therapy (n = 2). One patient was alive with KS (poor compliance). Histopathological evaluation showed classical features of KS. One case was predominantly sarcomatoid with prominent inflammation mimicking undifferentiated sarcoma. Immunohistochemistry showed consistent expression of CD31, CD34, ERG, D2-40 and HHV8 in all cases. This is one of the few series devoted to head and neck KS showing high prevalence of HIV-positivity, but also unusual presentations in HIV-negative patients with primary origin in the skin of the ear and the auditory canal. KS should be included in the differential diagnosis of difficult-to-classify spindle cell lesions at this uncommon location.
EVALuna2:207378

Healthcare utilization and unmet needs of patients with antisynthetase syndrome: An international patient survey - Weiß, Marina; Holzer, M. T.; Muehlensiepen, F.; Ignatyev, Y.; Fiehn, C.; Bauhammer, J.; Schmidt, J.; Schlüter, S.; Dihkan, A.; Scheibner, D.; Schneider, U.; Valor-Mendez, L.; et al. (Rheumatology International, 2023)
Antisynthease syndrome (ASSD) is a rare, complex and understudied autoimmune disease. Internet-based studies can overcome barriers of traditional on-site research and are therefore very appealing for rare diseases. The aim of this study was to investigate patient-reported symptoms, diagnostic delay, symptoms, medical care, health status, working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey. The multilingual questionnaire was created by an international group of rheumatologists and patients and distributed online. 236 participants from 22 countries completed the survey. 184/236 (78.0%) were female, mean age (SD) was 49.6 years (11.3) and most common antisynthetase antibody was Jo-1 (169/236, 71.6%). 79/236 (33.5%) reported to work full-time. Median diagnostic delay was one year. The most common symptom at disease onset was fatigue 159/236 (67.4%), followed by myalgia 130/236 (55.1%). The complete triad of myositis, arthritis and lung involvement verified by a clinician was present in 42/236 (17.8%) at disease onset and in 88/236 (37.3%) during the disease course. 36/236 (15.3%) reported to have been diagnosed with fibromyalgia and 40/236 (16.3%) with depression. The most reported immunosuppressive treatments were oral corticosteroids 179/236 (75.9%), followed by rituximab 85/236 (36.0%). 73/236 (30.9%) had received physiotherapy treatment. 71/236 (30.1%) reported to know useful online information sources related to ASSD. 223/236 (94.5%) were willing to share health data for research purposes once a year. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases.
CRIS-Team Scopus Importer:2023-08-25
Keywords: Autoantibodies; Diagnosis; Health services research; Myositis; Therapeutics

Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-? signalling to prevent fibrosis - Tomcik, Michal; Zerr, Pawel; Pitkowski, Jana; Palumbo-Zerr, Katrin; Avouac, Jerome; Distler, Oliver; Becvar, Radim; Senolt, Ladislav; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-? signalling and for the treatment of fibrosis in preclinical models of SSc.Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-? receptor I (T?RI).Expression of Hsp90? was increased in SSc skin and in murine models of SSc in a TGF-?-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-? signalling and completely prevented the stimulatory effects of TGF-? on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-? signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active T?RI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses.Hsp90 is upregulated in SSc and is critical for TGF-? signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-? in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications.
EVALuna2:12887

Herpes simplex infection in a patient with rheumatoid arthritis treated with baricitinib: a case report - Valor-Méndez, Larissa; Voskens, Caroline; Rech, Jürgen; Kleyer, Arnd; Schett, Georg (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-04-19

Hidradenitis Suppurativa and Concurrent Psoriasis: Comparison of Epidemiology, Comorbidity Profiles, and Risk Factors - Pinter, Andreas; Kokolakis, Georgios; Rech, Jürgen; Biermann, Mona H.C.; Häberle, Benjamin M.; Multmeier, Jan; Reinhardt, Maximilian (Dermatology and Therapy, 2020)
Introduction: Hidradenitis suppurativa (HS) is a chronic, debilitating, and inflammatory skin disease. The epidemiology of HS varies greatly, with an estimated prevalence ranging from 0.03% to 4% worldwide. Similar to psoriasis (PsO), HS also exhibits a systemic inflammatory nature with a spectrum of systemic comorbidities. A large health insurance claims (HICs) database is analyzed to determine the demography and epidemiology of HS, PsO, and HS with concurrent PsO (HS-PsO) patients. Furthermore, the comorbidity profiles, including the comorbidity risk of these patient populations, are analyzed. Methods: This is a noninterventional retrospective analysis of anonymized HICs data using a subset of the Institute of Applied Health Research Berlin (InGef) database. The primary outcome is the prevalence and incidence of HS, PsO, and HS-PsO. Secondary outcomes include comorbidity profiles and a comorbidity risk analysis. Results: The prevalence and incidence of HS were 0.0681% and 0.0101%, respectively. The prevalence of HS-PsO was 0.004% (6% of the total HS population). HS patients frequently suffered from arterial hypertension (45%), nicotine dependence (46%), obesity (41%), and depression (36%), which were more common in HS-PsO patients compared with HS alone. HS patients had an increased prevalence of metabolic, psychiatric, immune-mediated, and cardiovascular diseases, e.g., overweight/obesity [odds ratio (OR): 2.65, 95% confidence interval (CI) 2.37–2.96], depression (OR: 1.55, 95% CI 1.42–1.76), or seronegative rheumatoid arthritis (OR: 2.82, 95% CI 1.61–4.94) compared with the overall population. The increased risk of myocardial infarction in HS patients (OR: 4.1, 95% CI 3.5–4.8, adjusting for age/sex) was largely attributed to patient’s current smoking status (OR: 1.1, 95% CI 0.8–1.5, adjusting for smoking/age/sex). Conclusions: HS patients show a broad spectrum of inflammatory and metabolic syndrome-related comorbidities, with an increased risk by concurrent PsO. Important for clinical practice, the elevated cardiovascular risk of HS patients can be largely attributed to smoking.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Cardiovascular risk; Comorbidity; Epidemiology; Hidradenitis suppurativa; Psoriasis; Smoking

High Degree of Nonadherence to Disease-modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis - Rauscher, Veronika; Englbrecht, Matthias; Van Der Heijde, Desiree; Schett, Georg; Hueber, Axel (Journal of Rheumatology, 2015)
To test medication adherence using the Compliance-Questionnaire-Rheumatology (CQR).Invitation letter and CQR were sent to 240 patients with rheumatoid arthritis. Followup CQR was sent 3 months later. Adherence was evaluated using CQR 80% cutoff scores.Seventy-eight patients who were being treated with disease-modifying antirheumatic drugs provided full information on the CQR at both points in time. Eleven patients (14.1%) were classified as adherent based on taking compliance (TC), with only 3 patients (3.8%) adherent in regard to correct dosing (CD) [followup: 13 (16.7%) and 3 (3.8%) for TC and CD, respectively]. Nonadherence was not related to disease activity or side effects.We demonstrated low adherence, suggesting differences between doctors' records and patients' practice of antirheumatic drug therapy.
EVALuna2:13088

HIGH DIMENSIONAL ANALYSIS REVEAL A NETWORK OF CERTAIN TRANSCRIPTION FACTORS THAT LINK VASCULOPATHY AND ORGAN FIBROSIS IN SYSTEMIC SCLEROSIS - Anchang, Charles Gwellem; Lawaree, B. Matalobos; Weber, Stefanie; Rauber, S.; Wohlfahrt, T.; Luber, M.; Kreuter, A.; Schett, Georg; Distler, Jörg; Ramming, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Higher risk of short term COVID-19 vaccine adverse events in myositis patients with autoimmune comorbidities: results from the COVAD study - Dey, Mrinalini; Naveen, R.; Nikiphorou, Elena; Sen, Parikshit; Saha, Sreoshy; Lilleker, James B.; Agarwal, Vishwesh; Kardes, Sinan; Day, Jessica; Milchert, Marcin; Joshi, Mrudula; Gheita, Tamer; et al. (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-11-25

Higher serum levels of short-chain fatty acids are associated with non-progression to arthritis in individuals at increased risk of RA - Martinsson, Klara; Dürholz, Kerstin; Schett, Georg; Zaiss, Mario; Kastbom, Alf (Annals of the Rheumatic Diseases, 2021)
CRIS-Team WoS Importer:2021-12-03

High Fat Diet Alleviates Antigen-Induced Arthritis Severity in Male Mice By Enhancing Both Treg and B10 Cells - Luo, Yubin; Engdahl, Cecilia; Yi Zaho,; Liu, Yi; Schett, Georg; Bozec, Aline (2016)
EVALuna2:35060

High-fat-diet-associated intestinal microbiota exacerbates psoriasis-like inflammation by enhancing systemic γδ T cell IL-17 production - Sonomoto, Koshiro; Song, Rui; Eriksson, Daniel; Hahn, Anne Maria; Meng, Xianyi; Lyu, Pang; Cao, Shan; Liu, Ning; Taudte, Verena; Wirtz, Stefan; Tanaka, Yoshiya; Winkler, Thomas; et al. (Cell Reports, 2023)
Although it is known that psoriasis is strongly associated with obesity, the mechanistic connection between diet and skin lesions is not well established. Herein, we showed that only dietary fat, not carbohydrates or proteins, exacerbates psoriatic disease. Enhanced psoriatic skin inflammation was associated with changes in the intestinal mucus layer and microbiota composition by high-fat diet (HFD). Change of intestinal microbiota by vancomycin treatment effectively blocked activation of psoriatic skin inflammation by HFD, inhibited the systemic interleukin-17 (IL-17) response, and led to increased mucophilic bacterial species such as Akkermansia muciniphila. By using IL-17 reporter mice, we could show that HFD facilitates IL-17-mediated γδ T cell response in the spleen. Notably, oral gavage with live or heat-killed A. muciniphila effectively inhibited HFD-induced enhancement of psoriatic disease. In conclusion, HFD exacerbates psoriatic skin inflammation through changing the mucus barrier and the intestine microbial composition, which leads to an enhanced systemic IL-17 response.
CRIS-Team Scopus Importer:2023-07-28
Keywords: CP: Immunology; CP: Microbiology; high-fat diet; psoriasis; γδT cell

High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6 - Chen, Guangliang; Luo, Yubin; Eriksson, Daniel; Meng, Xianyi; Qian, Cheng; Bäuerle, Tobias; Chen, Xiao-Xiang; Schett, Georg; Bozec, Aline (Oncotarget, 2016)
The impact of metabolic stress induced by obesity on the bone marrow melanoma niche is largely unknown. Here we employed diet induced obese mice model, where mice received high-fat (HFD) or normal diet (ND) for 6 weeks before challenge with B16F10 melanoma cells. Tumor size, bone loss and osteoclasts numbers were assessed histologically in the tibial bones. For defining the molecular pathway, osteopontin knock-out mice, interleukin 6 neutralizing antibody or Janus kinase 2 inhibition were carried out in the same model. Mechanistic studies such as adipocyte-melanoma co-cultures for defining adipocyte induced changes of tumor cell proliferation and expression profiles were also performed. As results, HFD enhanced melanoma burden in bone by increasing tumor area and osteoclast numbers. This process was associated with higher numbers of bone marrow adipocytes expressing IL-6 in direct vicinity to tumor cells. Inhibition of IL-6 or of downstream JAK2 blocked HFD-induced tumor progression. Furthermore, the phenotypic changes of melanoma cells triggered macrophage and osteoclast accumulation accompanied by increased osteopontin expression. Osteopontin triggered osteoclastogenesis and also exerted a positive feedback loop to tumor cells, which was abrogated in its absence. Metabolic stress by HFD promotes melanoma growth in the bone marrow by an increase in bone marrow adipocytes and IL-6-JAK2-osteopontin mediated activation of tumor cells and osteoclast differentiation.
EVALuna2:13267

HIGH FATIGUE SCORES IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHIES: A MULTIGROUP COMPARATIVE STUDY FROM THE COVAD E-SURVEY. - Grignaschi, S.; Cavagna, L.; Kim, M.; R, N.; Lilleker, J. B.; Sen, P.; Agarwal, V.; Kardes, S.; Day, J.; Makol, A.; Milchert, M.; Gheita, T. A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

High fatigue scores in patients with idiopathic inflammatory myopathies: a multigroup comparative study from the COVAD e-survey - Grignaschi, Silvia; Kim, Minchul; Zanframundo, Giovanni; Ravichandran, Naveen; Lilleker, James B.; Sen, Parikshit; Joshi, Mrudula; Agarwal, Vishwesh; Kardes, Sinan; Day, Jessica; Makol, Ashima; Milchert, Marcin; et al. (Rheumatology International, 2023)
Idiopathic inflammatory myopathies (IIMs) confer a significant risk of disability and poor quality of life, though fatigue, an important contributing factor, remains under-reported in these individuals. We aimed to compare and analyze differences in visual analog scale (VAS) scores (0–10 cm) for fatigue (VAS-F) in patients with IIMs, non-IIM systemic autoimmune diseases (SAIDs), and healthy controls (HCs). We performed a cross-sectional analysis of the data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) international patient self-reported e-survey. The COVAD survey was circulated from December 2020 to August 2021, and details including demographics, COVID-19 history, vaccination details, SAID details, global health, and functional status were collected from adult patients having received at least one COVID-19 vaccine dose. Fatigue experienced 1 week prior to survey completion was assessed using a single-item 10 cm VAS. Determinants of fatigue were analyzed in regression models. Six thousand nine hundred and eighty-eight respondents (mean age 43.8 years, 72% female; 55% White) were included in the analysis. The overall VAS-F score was 3 (IQR 1–6). Patients with IIMs had similar fatigue scores (5, IQR 3–7) to non-IIM SAIDs [5 (IQR 2–7)], but higher compared to HCs (2, IQR 1–5; P < 0.001), regardless of disease activity. In adjusted analysis, higher VAS-F scores were seen in females (reference female; coefficient −0.17; 95%CI −0.21 to −13; P < 0.001) and Caucasians (reference Caucasians; coefficient −0.22; 95%CI −0.30 to −0.14; P < 0.001 for Asians and coefficient −0.08; 95%CI −0.13 to 0.30; P = 0.003 for Hispanics) in our cohort. Our study found that patients with IIMs exhibit considerable fatigue, similar to other SAIDs and higher than healthy individuals. Women and Caucasians experience greater fatigue scores, allowing identification of stratified groups for optimized multidisciplinary care and improve outcomes such as quality of life.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Autoimmune diseases; COVID-19; Fatigue; Myositis; Surveys and questionnaires

High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice - Starke, Charlotte; Frey, Silke; Wellmann, Ute; Urbonaviciute, Vilma; Herrmann, Martin; Amann, Kerstin Ute; Schett, Georg; Winkler, Thomas; Voll, Reinhard E. (European Journal of Immunology, 2011)
Autoantibodies to double-stranded (ds) DNA represent a serological hallmark of systemic lupus erythematosus (SLE) and may critically contribute to the pathogenesis of lupus nephritis. Self-reactive antibodies might be partially produced by long-lived plasma cells (PCs), which mainly reside within the bone marrow and spleen. In contrast to short-lived PCs, long-lived PCs are extremely resistant to therapy and may sustain refractory disease courses. Recently, antibody-secreting cells were found within the inflamed kidneys of New Zealand black/white (NZB/W) F1 lupus mice as well as of patients with SLE. To analyze the longevity of the IgG-producing cells present in nephritic kidneys of NZB/W F1 mice we performed in vivo BrdU-labeling. We identified a higher frequency of long-lived than short-lived renal PCs, indicating that survival niches for long-lived PCs also exist within inflamed kidneys. Using ELISPOT assays, we found that on average 31% of renal IgG-producing cells reacted with dsDNA and 24% with nucleolin. Moreover, the frequencies of IgG-secreting cells specific for the autoantigens dsDNA and nucleolin were higher in the kidneys compared with those in the spleen and bone marrow.
Keywords: Autoantibody-secreting cells; Autoimmunity; Long-lived plasma cells; Lupus nephritis

High Impact Sports Leads to Inflammatory Responses at Entheseal Sites Results of the BEAT Study (Badminton Enthesitis Arthrosonography Study) - Simon, David; Kleyer, Arnd; Tascilar, Koray; Bayat, Sara; Knitza, Johannes; Valor-Mendez, Larissa; Schweiger, Marina; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

High incidence of disease recurrence after discontinuation of disease-modifying antirheumatic drug treatment in patients with psoriatic arthritis in remission - Araujo, Elizabeth G.; Finzel, Stephanie; Englbrecht, Matthias; Schreiber, Dominik A.; Faustini, Francesca; Hueber, Axel; Nas, Kemal; Rech, Juergen; Schett, Georg (Annals of the Rheumatic Diseases, 2015)
To investigate the possibility of drug-free remission in patients with psoriatic arthritis (PsA) in continuous remission.Prospective observational study in disease-modifying antirheumatic drug (DMARD)-treated PsA patients in continuous disease remission (no musculoskeletal symptoms, no or minimal skin/nail disease) for at least 6 months. Demographic, disease-specific and ultrasound parameters were assessed at baseline. DMARDs (traditional or biologic) were discontinued at the initial visit, and patients were followed for a maximum of 6 months for recurrence of disease.26 patients (methotrexate monotherapy: N=14; tumour necrosis factor inhibitors: N=12) with a mean age of 55.2 years, absence of musculoskeletal symptoms and minimal skin disease (mean Psoriasis Area Severity Index (PASI): 0.21) were enrolled. Incidence of recurrence of disease was high (N=20, 76.9%) and occurred rapidly (74.50±51.72 days) after treatment discontinuation. Male PsA patients were significantly more likely to lose remission. Long disease duration, more severe skin involvement and the presence of synovial hypertrophy by ultrasonographic examination at baseline decreased the likelihood for drug-free remission. Reinitiation of DMARDs promptly restored remission in all PsA patients with recurrence of disease.This study shows that the chance to reach drug-free remission in PsA patients is low. Discontinuation of DMARD therapy cannot be recommended in patients with PsA.
EVALuna2:12954

High levels of SOX5 decrease proliferative capacity of human B cells, but permit plasmablast differentiation - Rakhmanov, Mirzokhid; Sic, Heiko; Kienzler, Anne-Kathrin; Fischer, Beate; Rizzi, Marta; Seidl, Maximilian; Melkaoui, Kerstina; Unger, Susanne; Moehle, Luisa; Schmit, Nadine E.; Deshmukh, Sachin D.; Ayata, Cemil Korcan; et al. (PLoS ONE, 2014)
Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.
EVALuna2:13622

High Na+ Environments Impair Phagocyte Oxidase-Dependent Antibacterial Activity of Neutrophils - Krampert, Luka; Bauer, Katharina; Ebner, Stefan; Neubert, Patrick; Ossner, Thomas; Weigert, Anna; Schatz, Valentin; Toelge, Martina; Schröder, Agnes; Herrmann, Martin; Schnare, Markus; Dorhoi, Anca; et al. (Frontiers in Immunology, 2021)
Infection and inflammation can augment local Na+ abundance. These increases in local Na+ levels boost proinflammatory and antimicrobial macrophage activity and can favor polarization of T cells towards a proinflammatory Th17 phenotype. Although neutrophils play an important role in fighting intruding invaders, the impact of increased Na+ on the antimicrobial activity of neutrophils remains elusive. Here we show that, in neutrophils, increases in Na+ (high salt, HS) impair the ability of human and murine neutrophils to eliminate Escherichia coli and Staphylococcus aureus. High salt caused reduced spontaneous movement, degranulation and impaired production of reactive oxygen species (ROS) while leaving neutrophil viability unchanged. High salt enhanced the activity of the p38 mitogen-activated protein kinase (p38/MAPK) and increased the interleukin (IL)-8 release in a p38/MAPK-dependent manner. Whereas inhibition of p38/MAPK did not result in improved neutrophil defense, pharmacological blockade of the phagocyte oxidase (PHOX) or its genetic ablation mimicked the impaired antimicrobial activity detected under high salt conditions. Stimulation of neutrophils with phorbol-12-myristate-13-acetate (PMA) overcame high salt-induced impairment in ROS production and restored antimicrobial activity of neutrophils. Hence, we conclude that high salt-impaired PHOX activity results in diminished antimicrobial activity. Our findings suggest that increases in local Na+ represent an ionic checkpoint that prevents excessive ROS production of neutrophils, which decreases their antimicrobial potential and could potentially curtail ROS-mediated tissue damage.
CRIS-Team Scopus Importer:2021-10-08
Keywords: infection; neutrophils; phagocyte oxidase; reactive oxygen species; sodium

HIGH PREVALENCE OF INFLAMMATORY AND STRUCTURAL SIGNS OF KNEE OSTEOARTHRITIS IN THE GENERAL POPULATION AGED OVER 60 YEARS - Iagnocco, A.; Perricone, C.; Kleyer, Arnd; Sahinbegovic, E.; Aegerter, P.; Willeit, J.; Kiechl, S.; Schett, Georg; D'Agostino, M. -A. (2013)
EVALuna2:34464

High prevalence of tenosynovial inflammation before onset of rheumatoid arthritis and its link to progression to RA-A combined MRI/CT study - Kleyer, Arnd; Krieter, Manuel; Oliveira, Isabelle; Faustini, Francesca; Simon, Dominic; Kämmerer, Nadine; Cavalcante, Alan; Tabosa, Taiane; Rech, Juergen; Hueber, Axel; Schett, Georg (Seminars in Arthritis and Rheumatism, 2016)
To define the anatomic distribution of the earliest inflammatory and structural changes in individuals with anti-citrullinated protein antibody (ACPA+) positivity but no signs of arthritis.ACPA+ individuals (N = 20) and healthy controls (N = 13) received simultaneous gadolinium-enhanced magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of the hands. MRI sequences were scored for synovitis, osteitis, and bone erosions according to the RAMRIS method as well as for presence, localization, and extent of tenosynovitis. Bone erosions were validated by HR-pQCT scanning and related to the inflammatory changes found in the MRI.Tenosynovitis was the most prevalent inflammatory pathology, affecting 80% of ACPA+ individuals but none of the controls. Tenosynovitis at two or more anatomical sites was associated with later development of RA. Synovitis (65%) and osteitis (35%) were present in ACPA+ individuals as well, but at a lower frequency than tenosynovitis. MRI bone erosions were found in 65% of the individuals and additionally confirmed by HR-pQCT. Presence of MRI osteitis was the inflammatory pathology most strongly associated with bone erosions.Tenosynovitis is highly prevalent in ACPA+ individuals without arthritis and associated with later development of RA. Small erosions, often linked to osteitis, are also found in ACPA+ individuals without arthritis.
EVALuna2:13297

High rates of therapeutic changes in patients with psoriatic arthritis receiving treatment with disease-modifying antirheumatic drugs: A cross-sectional study - Behrens, Frank; Rech, Jürgen; Thaci, Diamant; Zinke, Silke; Rothnie, Kieran J.; (Oefner) Daamen, Carolin; Leipe, Jan (Modern Rheumatology, 2021)
Objectives To characterize treatment patterns for patients with psoriatic arthritis (PsA) currently receiving any disease-modifying antirheumatic drug (DMARD). Methods The Strategy for Psoriatic Arthritis In Germany (SPAIG) study was a retrospective observational study conducted from May to November 2017 at 46 rheumatology centers. Current and previous treatment data were collected at a single visit from adult patients with PsA and psoriasis who received DMARD treatment for >= 6 of the previous 12 months. The primary outcome was the proportion of patients receiving a biologic DMARD (bDMARD). Multinomial logistic regression analysis was used to evaluate associations between current characteristics and initial choice of therapy. Results Mean age of the 316 patients was 55.1 years and mean PsA disease duration was 9.9 years. PsA activity was generally comparable across treatment groups. In this cohort, 57.3% of patients were currently treated with bDMARDs, 37.7% with conventional synthetic DMARDs, and 4.4% with targeted synthetic DMARDs. Almost half (48.4%) of patients reported DMARD modifications in the previous 12 months. Specific comorbidities and patient/disease characteristics were associated with initial therapy. Conclusion DMARD treatment of PsA is frequently modified, suggesting the need for more effective therapies and assessment tools.
CRIS-Team WoS Importer:2021-09-10

HIGH REMISSION RATES IN RA - REAL LIFE DATA FROM BARITICINIB - Bayat, Sara; Tascilar, K.; Kaufmann, V.; Kleyer, Arnd; Simon, David; Knitza, Johannes; Hartmann, F.; Adam, Susanne; Hueber, A.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

High-resolution in vivo imaging of bone and joints: a window to microarchitecture - Geusens, Piet; Chapurlat, Roland; Schett, Georg; Ghasem-Zadeh, Ali; Seeman, Ego; De Jong, Joost; Van Den Bergh, Joop (Nature Reviews Rheumatology, 2014)
Imaging is essential to the evaluation of bone and joint diseases, and the digital era has contributed to an exponential increase in the number of publications on noninvasive analytical techniques for the quantification of changes to bone and joints that occur in health and in disease. One such technique is high-resolution peripheral quantitative CT (HR-pQCT), which has introduced a new dimension in the imaging of bone and joints by providing images that are both 3D and at high resolution (82 ?m isotropic voxel size), with a low level of radiation exposure (3-5 ?Sv). HR-pQCT enables the analysis of cortical and trabecular properties separately and to apply micro-finite element analysis for calculating bone biomechanical competence in vivo at the distal sites of the skeleton (distal radius and distal tibia). Moreover, HR-pQCT makes possible the in vivo assessment of the spatial distribution, dimensions and delineation of cortical bone erosions, osteophytes, periarticular cortical and trabecular microarchitecture, and 3D joint-space volume of the finger joints and wrists. HR-pQCT is, therefore, a technique with a high potential for improving our understanding of bone and joint diseases at the microarchitectural level.
EVALuna2:12936

High-resolution peripheral quantitative CT (HR-pQCT). New insights into arthritis - Finzel, Stephanie; Rech, Jürgen; Kleyer, Arnd (Zeitschrift für Rheumatologie, 2013)
The detection of periarticular bone lesions is of crucial importance in the diagnosis and treatment monitoring of chronic inflammatory diseases such as, but not limited to, rheumatoid arthritis (RA). High-resolution peripheral quantitative computed tomography (HR-pQCT) was initially developed for the meticulous assessment of bone microstructure with a focus on bone density parameters. With an isotropic voxel size of 82 µm HR-pQCT is, however, also well suited for quantitative evaluation of periarticular bone lesions, such as erosion, osteophytes as well as bone surface changes in arthritis. The present article gives an overview of the manifold possibilities of application of this novel imaging modality and addresses potential benefits of this technique for rheumatology in the future.
EVALuna2:12960

High-resolution quantitative computed tomography demonstrates structural defects in cortical and trabecular bone in IBD patients. - Haschka, Judith; Hirschmann, Simon; Kleyer, Arnd; Englbrecht, Matthias; Faustini, Francesca; Simon, David; Figueiredo, Camille P; Schuster, Louis; Muschitz, Christian; Kocijan, Roland; Resch, Heinrich; Atreya, Raja; et al. (Journal of Crohns & Colitis, 2016)
Background and Aims To investigate the macro- and microstructural changes of bone in patients with inflammatory bowel disease (IBD) and to define the factors associated with bone loss in IBDMethods A total of148 subjects, 59 with Crohn's Disease (CD), 39 with Ulcerative Colitis (UC) and 50 healthy controls were assessed for the geometric, volumetric and microstructural properties of bone using high-resolution peripheral quantitative computed tomography. In addition, demographic and disease-specific characteristics of IBD patients were recorded.Results IBD patients and controls were comparable in age, sex and body mass index. Total (p=0.001), cortical (p<0.001) and trabecular volumetric BMD (p=0.03) were significantly reduced in IBD patients compared to healthy controls. Geometric and microstructure analysis revealed significantly lower cortical area (p=0.001) and cortical thickness (p<0.001) without differences in cortical porosity, pore volume or pore diameter. CD showed a more severe bone phenotype than UC: While cortical bone loss was observed in both diseases, CD additionally showed profound trabecular bone loss with reduced trabecular BMD (p=0.008), bone volume (p=0.008) and trabecular thickness (p=0.009).Multivariate regression models identified the diagnosis of CD, female sex, lower body mass index and the lack of remission as factors independently associated with bone loss in IBD.Conclusion IBD patients develop significant cortical bone loss impairing bone strength. Trabecular bone loss is limited to CD patients, which exhibits a more severe bone phenotype compared to UC patients.
EVALuna2:2046

Hippocampal structure and function are maintained despite severe innate peripheral inflammation - Süß, Patrick; Kalinichenko, Liubov; Baum, Wolfgang; Reichel, Martin; Kornhuber, Johannes; Loskam, Sandra; Ettle, Benjamin; Distler, Jörg; Schett, Georg; Winkler, Jürgen; Müller, Christian P.; Schlachetzki, Johannes (Brain Behavior and Immunity, 2015)
Chronic peripheral inflammation mediated by cytokines such as TNF?, IL-1?, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-? transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1? and IL-6 expression in tarsal joints with highly elevated human TNF-? levels in the serum. Intriguingly, IL-1? and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation.
EVALuna2:12865

Histamine promotes angiogenesis through a histamine H1 receptor-PKC-VEGF-mediated pathway in human endothelial cells - Hatipoglu, Omer Faruk; Nishinaka, Takashi; Nishibori, Masahiro; Watanabe, Masahiro; Toyomura, Takao; Mori, Shuji; Yaykasli, Kürsat Oguz; Wake, Hidenori; Takahashi, Hideo (Journal of Pharmacological Sciences, 2023)
Histamine is a well-known inflammatory mediator, but how histamine induces angiogenesis remains poorly understood. In the present study, we demonstrated a dose-dependent dynamic tube formation in the human endothelial cell line EA.hy926 in the presence of histamine that was completely blocked by histamine H1 receptor (H1R) and protein kinase C (PKC) inhibitors. However, histamine H2, H3, and H4 receptor inhibitors did not inhibit tube formation, suggesting that H1R–PKC signaling is involved in histamine-induced tube formation. Moreover, we found an H1-specific induction of vascular endothelial growth factor (VEGF) expression. Inhibition of VEGF receptor 2 (VEGFR2) suppressed the histamine-induced tube formation, indicating that VEGF is downstream of histamine signaling. Additionally, we demonstrated that histamine stimulation induces the expression of critical regulators of angiogenesis such as matrix metalloproteinase (MMP)-9 and MMP-14 metalloproteases, as histamine-induced tube formation is blocked by MMP inhibitors. In summary, our study indicates that histamine can activate the H1R in human endothelial cells and thereby promote tube formation through the PKC, MMP, and VEGF signaling pathways.
CRIS-Team Scopus Importer:2023-03-10
Keywords: H1R; Histamine; MMPs; Tube formation; VEGF

HIV-1 mRNA electroporation of PBMC: A simple and efficient method to monitor T-cell responses against autologous HIV-1 in HIV-1-infected patients - Etschel, Jennifer K.; Hueckelhoven, Angela G.; Hofmann, Christian; Zitzelsberger, Kathrin; Maurer, Katja; Bergmann, Silke; Müller-Schmucker, Sandra; Wittmann, Jürgen; Spriewald, Bernd; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (Journal of Immunological Methods, 2012)
Efficient monitoring of HIV-1-specific T-cells is crucial for the development of HIV-1 vaccines and immunotherapies. Currently, mainly peptides and vaccinia vectors are used for detection of HIV-1-specific cytotoxic T-lymphocytes (CTL), however, as HIV-1 is a variable virus, it is unknown to what extent the T-cell response against the autologous virus is under- or overestimated by using antigens from heterologous viral strains. Therefore, we established a new method for immunomonitoring of CTL using electroporation of peripheral blood mononuclear cells (PBMC) with mRNA derived from autologous viral strains. From six HIV-1-infected patients virus derived mRNA was produced after PCR-based cloning of autologous gag (n = 5) and/or nef genes (n = 3) from plasma and electroporated into PBMC from patients and healthy donors. Electroporation of PBMC with mRNA resulted in efficient protein expression with good induction of γ-interferon (γ-IFN) release by specific T-cells comparable to peptide pools and better than recombinant vaccinia viruses. Three mRNA encoded autologous Gag proteins and one autologous mRNA encoded Nef protein were better recognized by autologous PBMC in comparison to heterologous mRNA encoded Gag or Nef proteins (SF2 or HXB2). However, in one case each, mRNA encoded autologous Gag or Nef, respectively, was recognized less efficiently due to the presence of CTL escape mutations. In summary, electroporation of PBMC with mRNA is a very efficient, easy and rapid method for immunomonitoring of HIV-1-specific T-cell responses against autologous viral strains. Our data demonstrate that patients' CTL responses against autologous viral strains may be under- or overestimated by using antigens from heterologous viral strains. © 2012 Elsevier B.V.
CRIS-Team Scopus Importer:2021-10-01
Keywords: CTL; HIV-1; Immunomonitoring; MRNA electroporation

HIV Activates the Tyrosine Kinase Hck to Secrete ADAM Protease-Containing Extracellular Vesicles - Lee, J. H.; Zhao, Z.; Ostalecki, Christian; Kesti, T.; Bruns, Heiko; Simon, B.; Harrer, Thomas; Saksela, K.; Baur, A. S. (EBioMedicine, 2018)
EVALuna2:13527

HIV-Nef and ADAM17-Containing Plasma Extracellular Vesicles Induce and Correlate with Immune Pathogenesis in Chronic HIV Infection - Lee, Jung-Hyun; Schierer, Stephan; Blume, Katja; Dindorf, Jochen; Wittki, Sebastian; Xiang, Wei; Ostalecki, Christian; Koliha, Nina; Wild, Stefan; Schuler, Gerold; Fackler, Oliver T.; Saksela, Kalle; et al. (EBioMedicine, 2016)
Antiretroviral therapy (ART) efficiently suppresses HIV replication but immune activation and low CD4 T cell counts often persist. The underlying mechanism of this ART-resistant pathogenesis is not clear. We observed that levels of plasma extracellular vesicles (pEV) are strongly elevated in HIV infection and do not decline during ART. Surprisingly, these vesicles contained the viral accessory proteins Nef and Vpu, which are assumed to be not expressed under efficient ART, as well as pro-inflammatory effectors, including activated ADAM17. HIV pEV were characterized by the presence of activated ?v?3 and absence of CD81 and Tsg101. Correlating with immune activation, peripheral monocytes ingested large amounts of pEV, giving rise to an increased population of CD1c(+) CD14(+) cells that secreted inflammatory cytokines. Importantly, the pro-inflammatory content, particularly ADAM17 activity, correlated with low T cell counts. Preliminary evidence suggested that HIV pEV derived from peripheral mononuclear cells and from an unknown myeloid cell population. In summary we propose an important role of pro-inflammatory pEV in chronic HIV infection due to ongoing viral Nef activity.
EVALuna2:4716

HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection - Ostalecki, Christian; Wittki, Sebastian; Lee, Jung-Hyun; Geist, Miriam M.; Tibroni, Nadine; Harrer, Thomas; Schuler, Gerold; Fackler, Oliver T.; Baur, Andreas (EBioMedicine, 2016)
Tumor necrosis factor (TNF) is a key cytokine in HIV replication and pathogenesis. For reasons that are not entirely clear, the cytokine remains upregulated despite anti-retroviral therapy (ART). Here we demonstrate that HIV Nef induces an alternative TNF secretion mechanism that remains active in chronic infection. Ingestion of Nef-containing plasma extracellular vesicles (pEV) from ART patients by primary immune cells, but also Nef expression, induced intracellular proTNF cleavage and secretion of vesicular TNF endosomes. Key event was the Nef-mediated routing of the TNF-converting enzyme ADAM17 into Rab4+ early endosomes and the Rab27+ secretory pathway. Analysis of lymph-node tissue by multi-epitope-ligand-cartography (MELC) confirmed a vesicular TNF secretion phenotype that co-localized with persistent Nef expression, and implicated Notch1 as an essential co-factor. Surprisingly Notch1 had no transcriptional effect but was required for the endosomal trafficking of ADAM17. We conclude that Nef expression and Nef-containing pEV mobilize TNF from endosomal compartments in acute and chronic infection.
EVALuna2:13372

HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases - Lee, Jung-Hyun; Wittki, Sebastian; Braeu, Tanja; Dreyer, Florian; Kraetzel, Kirsten; Dindorf, Jochen; Johnston, Ian C. D.; Gross, Stefanie; Kremmer, Elisabeth; Zeidler, Reinhard; Schlötzer-Schrehardt, Ursula; Lichtenheld, Mathias; et al. (Molecular Cell, 2013)
The HIV Nef protein recruits the polycomb protein Eed and mimics an integrin receptor signal for reasons that are not entirely clear. Here we demonstrate that Nef and Eed complex with the integrin effector paxillin to recruit and activate TNF? converting enzyme (TACE alias ADAM 17) and its close relative ADAM10. The activated proteases cleaved proTNF? and were shuttled into extracellular vesicles (EVs). Peripheral blood mononuclear cells that ingested these EVs released TNF?. Analyzing the mechanism, we found that Pak2, an established host cell effector of Nef, phosphorylated paxillin on Ser272/274 to induce TACE-paxillin association and shuttling into EVs via lipid rafts. Conversely, Pak1 phosphorylated paxillin on Ser258, which inhibited TACE association and lipid raft transfer. Interestingly, melanoma cells used an identical mechanism to shuttle predominantly ADAM10 into EVs. We conclude that HIV-1 and cancer cells exploit a paxillin/integrin-controlled mechanism to release TACE/ADAM10-containing vesicles, ensuring better proliferation/growth conditions in their microenvironment.
EVALuna2:12854

HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia - Baron, F.; Labopin, M.; Tischer, J.; Ciceri, F.; Raiola, A. M.; Blaise, D.; Sica, S.; Vydra, J.; Fanin, R.; Diez-Martin, J. L.; Bulabois, C. E.; Stolzel, F.; et al. (BONE MARROW TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-11-25

Höhere Prävalenz von depressiven und ängstlichen Symptomen bei Früharthritispatienten im Vergleich zur Normalbevölkerung - Freier, D.; Englbrecht, Matthias; Höhne-Zimmer, V.; Detert, J.; Burmester, G. R. (Zeitschrift für Rheumatologie, 2019)
Background: Many studies and registry data confirm that depression, often associated with anxiety disorders is very often found in patients with rheumatoid arthritis (RA). To what extent these psychiatric disorders are already relevant at a very early stage of the disease, has currently not been adequately investigated. Methods: In this study 176 patients with early joint symptoms (<1 year) were surveyed in an early arthritis consultation (EAC). The hospital anxiety and depression scale (HADS) was completed by the patients to examine the prevalence of depressive and anxiety symptoms. The results were compared to normative data of the general German population and between the diagnosis groups. Results: With 47.7% the prevalence of global distress for EA patients was almost twice as high compared to the corresponding group from the general population. This was also confirmed for depressive and anxiety symptoms. The EA patients without confirmed evidence of musculoskeletal inflammatory rheumatic disease (RD) showed nearly the same point prevalence as patients with confirmed RD. In multiple logistic regression the health assessment questionnaire (HAQ) was positively associated with global distress (odds ratio, OR 3.63) while the visual analogue scale (VAS) for global disease activity was positively associated with symptoms of depression (OR 1.03). Female EA patients (OR 5.45) appear to have a higher probability for experiencing corresponding symptoms, whereas patients over 60 years old appear to have less anxiety than younger patients (OR 0.11). Conclusion: The high prevalence of symptoms of depression and anxiety in EA patients compared to the general population is a challenge for rheumatologists, orthopedists and general practitioners, particularly with respect to the differentiation of possible psychosomatic components in noninflammatory joint complaints. The results suggest that screening for psychiatric problems in patients with rheumatism should be evaluated as soon as possible as these can have a great impact on the perception of pain and physical functional status from the very beginning.
CRIS-Team Scopus Importer:2019-11-12
Keywords: Anxiety; Depression; Early arthritis; HADS; Pain; Stress

Host cell entry and neutralisation sensitivity of the SARS-CoV-2 XBB.1.16 lineage - Nehlmeier, Inga; Kempf, Amy; Arora, Prerna; Cossmann, Anne; Dopfer-Jablonka, Alexandra; Stankov, Metodi V.; Schulz, Sebastian; Jäck, Hans-Martin; Behrens, Georg M.N.; Pöhlmann, Stefan; Hoffmann, Markus (Cellular & Molecular Immunology, 2023)
CRIS-Team Scopus Importer:2023-05-19

Host Cell Entry and Neutralization Sensitivity of SARS-CoV-2 Lineages B.1.620 and R.1 - Sidarovich, Anzhalika; Krueger, Nadine; Rocha, Cheila; Graichen, Luise; Kempf, Amy; Nehlmeier, Inga; Lier, Martin; Cossmann, Anne; Stankov, Metodi; Schulz, Sebastian; Behrens, Georg M. N.; Jäck, Hans-Martin; et al. (Viruses, 2022)
The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitates viral entry into host cells and is the key target for neutralizing antibodies. The SARS-CoV-2 lineage B.1.620 carries fifteen mutations in the S protein and is spread in Africa, the US and Europe, while lineage R.1 harbors four mutations in S and infections were observed in several countries, particularly Japan and the US. However, the impact of the mutations in B.1.620 and R.1 S proteins on antibody-mediated neutralization and host cell entry are largely unknown. Here, we report that these mutations are compatible with robust ACE2 binding and entry into cell lines, and they markedly reduce neutralization by vaccine-induced antibodies. Our results reveal evasion of neutralizing antibodies by B.1.620 and R.1, which might have contributed to the spread of these lineages.
CRIS-Team Scopus Importer:2022-11-25
Keywords: ACE2 binding; antibody evasion; B.1.620; cell entry; neutralization; R.1; SARS-CoV-2; spike protein

Host DNases prevent vascular occlusion by neutrophil extracellular traps - Jimenez-Alcazar, Miguel; Rangaswamy, Chandini; Panda, Rachita; Bitterling, Josephine; Simsek, Yashin J.; Long, Andy T.; Bilyy, Rostyslav; Krenn, Veit; Renne, Christoph; Renne, Thomas; Kluge, Stefan; Panzer, Ulf; et al. (Science, 2017)
Platelet and fibrin clots occlude blood vessels in hemostasis and thrombosis. Here we report a noncanonical mechanism for vascular occlusion based on neutrophil extracellular traps (NETs), DNA fibers released by neutrophils during inflammation. We investigated which host factors control NETs in vivo and found that two deoxyribonucleases (DNases), DNase1 and DNase1-like 3, degraded NETs in circulation during sterile neutrophilia and septicemia. In the absence of both DNases, intravascular NETs formed clots that obstructed blood vessels and caused organ damage. Vascular occlusions in patients with severe bacterial infections were associated with a defect to degrade NETs ex vivo and the formation of intravascular NET clots. DNase1 and DNase1-like 3 are independently expressed and thus provide dual host protection against deleterious effects of intravascular NETs.
EVALuna2:13518

How Autoantibodies Regulate Osteoclast Induced Bone Loss in Rheumatoid Arthritis - Steffen, Ulrike; Schett, Georg; Bozec, Aline (Frontiers in Immunology, 2019)
Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by autoimmunity that triggers joint inflammation and tissue destruction. Traditional concepts of RA pathogenesis have strongly been focused on inflammation. However, more recent evidence suggests that autoimmunity per se modulates the disease and in particular bone destruction during the course of RA. RA-associated bone loss is caused by increased osteoclast differentiation and activity leading to rapid bone resorption. Autoimmunity in RA is based on autoantibodies such as rheumatoid factor (RF) and autoantibodies against citrullinated proteins (ACPA). These autoantibodies exert effector functions on immune cells and on bone resorbing osteoclasts, thereby facilitating bone loss. This review summarizes potential pathways involved in increased destruction of bone tissue in RA, particularly focusing on the direct and indirect actions of autoantibodies on osteoclast generation and function.
CRIS-Team WoS Importer:2019-07-16

How the COVID-19 pandemic has affected rheumatology research - Moreyra, Paula Alba; Berenbaum, Francis; Danda, Debashish; Grötsch, Bettina; Stones, Simon R.; Viswanathan, Sowmya (Nature Reviews Rheumatology, 2022)
The COVID-19 pandemic has put pressure on researchers around the world. In this Viewpoint, six rheumatology researchers at different career stages and from different regions discuss the difficulty of conducting research during the pandemic, and also reflect on how the pandemic has changed their attitudes towards research and their plans for the future.
CRIS-Team WoS Importer:2022-01-21

HOW THE GUT INFLUENCES THE IMMUNE SYSTEM - Zaiss, Mario (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

HOW THE GUT MICROBIOTA AND ITS METABOLITES IMPACT ON BONE HOMEOSTASIS - Zaiss, Mario (2018)
EVALuna2:34983

How Well Does Ultrasound-assessed Synovitis in Reduced Joint Sets Predict the Response to Secukinumab in Patients with Active Psoriatic Arthritis and Inadequate Response to Conventional DMARDs? - Exploratory Results from a Phase 3b Study - D'Agostino, Maria-Antonietta; Conaghan, Philip G.; Gaillez, Corine; Naredo, Esperanza; Mandl, Peter; Carron, Philippe; Senolt, Ladislav; Eduardo Rosa, Javier; Lopez Rdz, Alejandra; Goyanka, Punit; Sahoo, Braja Gopal; Bao, Weibin; et al. (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

HR-pQCT in vivo imaging of periarticular bone changes in chronic inflammatory diseases: Data from acquisition to impact on treatment indications - Figueiredo, Camille P.; Perez, Mariana O.; Sales, Lucas Peixoto; Schett, Georg; Pereira, Rosa M. R. (Modern Rheumatology, 2020)
Imaging is essential for the assessment of bone and inflammatory joint diseases. There are several imaging techniques available that differ regarding resolution, radiation exposure, time expending, precision, cost, availability or ability to predict disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) that was introduced in 2004 allows the in vivo evaluation of peripheral bone microarchitecture and demonstrated high precision in assessing bone changes in inflammatory musculoskeletal diseases. This review summarizes the use of HR-pQCT for the evaluation of the hand skeleton in inflammatory joint diseases. We conducted a review of the literature regarding the protocols that involve hand joints assessment and evaluation of bone changes as erosions and osteophytes in chronic inflammatory diseases. Apart from measuring bone density and structure of the radius and the tibia, HR-pQCT has contributed to assessment of bone erosions and osteophytes, considered the hallmark of diseases as rheumatoid arthritis and psoriatic arthritis, respectively. In this way, there are some conventions recently established by rheumatic study groups that we just summarized here in order to standardize HR-pQCT measurements.
CRIS-Team Scopus Importer:2020-09-18
Keywords: Arthritis; bone erosion; bone spur; computed tomography

Hsp90 as a Potential Biomarker of Lung and Skin Involvement in Patients with Systemic Sclerosis - Storkanova, Hana; Oreska, Sabina; Spiritovic, Maja; Hermankova, Barbora; Bubova, Kristyna; Komarc, Martin; Pavelka, Karel; Vencovsky, Jiri; Distler, Jörg; Senolt, Ladislav; Becvar, Radim; Tomcik, Michal (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in lyme arthritis - Danzer, Heike; Glaesner, Joachim; Baerenwaldt, Anne; Reitinger, Carmen; Lux, Anja; Heger, Lukas; Dudziak, Diana; Harrer, Thomas; Gessner, Andre; Nimmerjahn, Falk (eLife, 2020)
Pathogen-specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that balancing of immune responses through inhibitory receptors is an important quality control checkpoint. Genetic differences between inbred mouse models and the outbred human population and allelic receptor variants not present in mice; however, argue for caution when directly translating these findings to the human system. By studying Borrelia burgdorferi infection in humanized mice reconstituted with human hematopoietic stem cells from donors homozygous for a functional or a non-functional FcγRIIb allele, we show that the human inhibitory FcγRIIb is a critical checkpoint balancing protective and autoreactive immune responses, linking infection with induction of autoimmunity in the human immune system.
CRIS-Team Scopus Importer:2020-09-11
Keywords: arthritis; autoimmunity; borrelia burgdorferi; Fc-receptor; humanized mouse; immunology; inflammation; mouse

Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. - Schreiner, Philipp; Harrer, Thomas; Scheibenbogen, Carmen; Lamer, Stephanie; Schlosser, Andreas; Naviaux, Robert; Prusty, Bhupesh K. (ImmunoHorizons, 2020)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)-6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, including pyruvate dehydrogenase, were strongly inhibited. Adoptive transfer of U2-OS cell supernatants after reactivation of HHV-6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 cell assay. In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism.
EVALuna2:424186

Humanized CD22 transgenic mouse model for in vivo analysis of anti-CD22-based immunotherapy - Brandl, Carolin; Angermüller, Sieglinde; Nitschke, Lars (European Journal of Immunology, 2020)
CRIS-Team Scopus Importer:2020-07-24

Human T cells expressing two additional receptors (TETARs) specific for HIV-1 recognize both epitopes - Hofmann, Christian; Hoefflin, Sandra; Hueckelhoven, Angela; Bergmann, Silke; Harrer, Ellen; Schuler, Gerold; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (Blood, 2011)
Adoptive TCR transfer against rapidly mutating targets, such as HIV-1 or cancer, must counteract corresponding immune escape. Hence, we generated T cells expressing two additional receptors (TETARs) specific for HIV-1 by TCR mRNA electroporation. An HLA-A2-restricted gag-specific TCR and an HLA-B13-restricted nef-specific TCR were chosen. When both TCRs were transfected simultaneously, strong competitive effects occurred that were overcome by replacing the human constant domains of one TCR with murine counterparts and adapting the amounts of TCR-RNA used for transfection. The resulting TETAR responded to both epitopes with cytokine secretion and cytotoxic function. Cell sorting revealed that one individual cell indeed recognized both epitopes. The T cells diminished their reactivity to each epitope after stimulation but sequentially killed targets that presented the gag epitope and then targets that presented the nef epitope, or vice versa. Taken together, TETARs represent a sophisticated tool to study TCR functionality and might be a useful strategy in immunotherapy. © 2011 by The American Society of Hematology.
CRIS-Team Scopus Importer:2021-10-01

Humoral and Cellular Immune Responses to SARS–CoV-2 Infection and Vaccination in Autoimmune Disease Patients With B Cell Depletion - Simon, David; Tascilar, Koray; Schmidt, Katja; Manger, Bernhard; Weckwerth, Leonie; Sokolova, Maria; Bucci, Laura; Fagni, Filippo; Manger, Karin; Schuch, Florian; Ronneberger, Monika; Hueber, Axel; et al. (Arthritis and Rheumatology, 2021)
Objective: B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS–CoV-2 in patients with B cell depletion and controls who are B cell–competent. Methods: Antibody responses (tested using enzyme-linked immunosorbent assay) and T cell responses (tested using interferon-γ enzyme-linked immunospot assay) against the SARS–CoV-2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls. Results: As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS–CoV-2 spike S1 were found after both infection and vaccination. A SARS–CoV-2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS–CoV-2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls. Conclusion: These data show that B cell depletion completely blocks humoral but not T cell SARS–CoV-2 vaccination response. Furthermore, limited humoral immune responses are found after SARS–CoV-2 infection in patients with B cell depletion.
CRIS-Team Scopus Importer:2021-12-03

Humoral Immune Responses to SARS-CoV2 Infections and upon Vaccination Against SARS-CoV2 - Finzel, Stephanie; Peter, Nicole; Brand, Chiara; Fischer, Beate; Keller, Barbel; Weigang, Sebastian; Kochs, Georg; Schwemmle, Martin; Rieg, Siegbert; Mathe, Philipp; Kern, Winfried; Van Der Hoek, Lia; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Hydroxyapatite-Coated SPIONs and Their Influence on Cytokine Release - Friedrich, Bernhard; Auger, Jean-Philippe; Dutz, Silvio; Cicha, Iwona; Schreiber, Eveline; Band, Julia; Boccaccini, Aldo R.; Krönke, Gerhard; Alexiou, Christoph; Tietze, Rainer (International Journal of Molecular Sciences, 2021)
Hydroxyapatite- or calcium phosphate-coated iron oxide nanoparticles have a high potential for use in many biomedical applications. In this study, a co-precipitation method for the synthesis of hydroxyapatite-coated nanoparticles (SPIONHAp), was used. The produced nanoparticles have been characterized by dynamic light scattering, X-ray diffraction, vibrating sample magnetometry, Fourier transform infrared spectrometry, atomic emission spectroscopy, scanning electron microscopy, transmission electron microscopy, selected area diffraction, and energy-dispersive X-ray spectroscopy. The results showed a successful synthesis of 190 nm sized particles and their stable coating, resulting in SPIONHAp. Potential cytotoxic effects of SPIONHAp on EL4, THP-1, and Jurkat cells were tested, showing only a minor effect on cell viability at the highest tested concentration (400 mu g Fe/mL). The results further showed that hydroxyapatite-coated SPIONs can induce minor TNF-alpha and IL-6 release by murine macrophages at a concentration of 100 mu g Fe/mL. To investigate if and how such particles interact with other substances that modulate the immune response, SPIONHAp-treated macrophages were incubated with LPS (lipopolysaccharides) and dexamethasone. We found that cytokine release in response to these potent pro- and anti-inflammatory agents was modulated in the presence of SPIONHAp. Knowledge of this behavior is important for the management of inflammatory processes following in vivo applications of this type of SPIONs.
CRIS-Team WoS Importer:2021-05-14

Hyperoxaluria Requires TNF Receptors to Initiate Crystal Adhesion and Kidney Stone Disease - Mulay, Shrikant R.; Eberhard, Jonathan N.; Desai, Jyaysi; Marschner, Julian A.; Kumar, Santhosh V.R.; Weidenbusch, Marc; Grigorescu, Melissa; Lech, Maciej; Eltrich, Nuru; Müller, Lisa; Hans, Wolfgang; Hrabě de Angelis, Martin; et al. (Journal of the American Society of Nephrology, 2016)
Intrarenal crystals trigger inflammation and renal cell necroptosis, processes that involve TNF receptor (TNFR) signaling. Here, we tested the hypothesis that TNFRs also have a direct role in tubular crystal deposition and progression of hyperoxaluria-related CKD. Immunohistochemical analysis revealed upregulated tubular expression of TNFR1 and TNFR2 in human and murine kidneys with calcium oxalate (CaOx) nephrocalcinosis-related CKD compared with controls. Western blot and mRNA expression analyses in mice yielded consistent data. When fed an oxalate-rich diet, wild-type mice developed progressive CKD, whereas Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice did not. Despite identical levels of hyperoxaluria, Tnfr1-, Tnfr2-, and Tnfr1/2-deficient mice also lacked the intrarenal CaOx deposition and tubular damage observed in wild-type mice. Inhibition of TNFR signaling prevented the induced expression of the crystal adhesion molecules, CD44 and annexin II, in tubular epithelial cells in vitro and in vivo, and treatment with the small molecule TNFR inhibitor R-7050 partially protected hyperoxaluric mice from nephrocalcinosis and CKD. We conclude that TNFR signaling is essential for CaOx crystal adhesion to the luminal membrane of renal tubules as a fundamental initiating mechanism of oxalate nephropathy. Furthermore, therapeutic blockade of TNFR might delay progressive forms of nephrocalcinosis in oxalate nephropathy, such as primary hyperoxaluria.
EVALuna2:13343

Hyperthermia with 44 degrees C enhances danger signal-mediated activation of dendritic cells, while immune cell infiltration into tumors is particularly fostered by hyperthermia with lower temperatures - Vogl, P.; Frey, Benjamin; Rueckert, M.; Maueröder, Christian; Fietkau, Rainer; Gaipl, Udo; Derer, Anja (2017)
EVALuna2:32897

Hypoxia-immune-related microenvironment prognostic signature for osteosarcoma - Zhang, Wenshuo; Lyu, Pang; Andreev, Darja; Jia, Yewei; Zhang, Fulin; Bozec, Aline (Frontiers in Cell and Developmental Biology, 2022)
Introduction: Increasing evidences have shown that hypoxia and the immune microenvironment play vital roles in the development of osteosarcoma. However, reliable gene signatures based on the combination of hypoxia and the immune status for prognostic prediction of osteosarcoma have so far not been identified. Methods: The individual hypoxia and immune status of osteosarcoma patients were identified with transcriptomic profiles of a training cohort from the TARGET database using ssGSEA and ESTIMATE algorithms, respectively. Lasso regression and stepwise Cox regression were performed to develop a hypoxia-immune-based gene signature. An independent cohort from the GEO database was used for external validation. Finally, a nomogram was constructed based on the gene signature and clinical features to improve the risk stratification and to quantify the risk assessment for individual patients. Results: Hypoxia and the immune status were significantly associated with the prognosis of osteosarcoma patients. Seven hypoxia- and immune-related genes (BNIP3, SLC38A5, SLC5A3, CKMT2, S100A3, CXCL11 and PGM1) were identified to be involved in our prognostic signature. In the training cohort, the prognostic signature discriminated high-risk patients with osteosarcoma. The hypoxia-immune-based gene signature proved to be a stable and predictive method as determined in different datasets and subgroups of patients. Furthermore, a nomogram based on the prognostic signature was generated to optimize the risk stratification and to quantify the risk assessment. Similar results were validated in an independent GEO cohort, confirming the stability and reliability of the prognostic signature. Conclusion: The hypoxia-immune-based prognostic signature might contribute to the optimization of risk stratification for survival and personalized management of osteosarcoma patients.
CRIS-Team WoS Importer:2023-01-13

Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease - Meng, Xianyi; Groetsch, Bettina; Luo, Yubin; Knaup, Karl; Wiesener, Michael Sean; Chen, Xiao-Xiang; Jantsch, Jonathan; Fillatreau, Simon; Schett, Georg; Bozec, Aline (Nature Communications, 2018)
Hypoxia-inducible factors (HIFs) are key elements for controlling immune cell metabolism and functions. While HIFs are known to be involved in T cells and macrophages activation, their functions in B lymphocytes are poorly defined. Here, we show that hypoxia-inducible factor-1? (HIF-1?) contributes to IL-10 production by B cells. HIF-1? regulates IL-10 expression, and HIF-1?-dependent glycolysis facilitates CD1dhiCD5+ B cells expansion. Mice with B cell-specific deletion of Hif1a have reduced number of IL-10-producing B cells, which result in exacerbated collagen-induced arthritis and experimental autoimmune encephalomyelitis. Wild-type CD1dhiCD5+ B cells, but not Hif1a-deficient CD1dhiCD5+ B cells, protect recipient mice from autoimmune disease, while the protective function of Hif1a-deficient CD1dhiCD5+ B cells is restored when their defective IL-10 expression is genetically corrected. Taken together, this study demonstrates the key function of the hypoxia-associated transcription factor HIF-1? in driving IL-10 expression in CD1dhiCD5+ B cells, and in controlling their protective activity in autoimmune disease.
EVALuna2:13529

Hypoxia-Inducible Factors Regulate Osteoclasts in Health and Disease - Meng, Xianyi; Wielockx, Ben; Rauner, Martina; Bozec, Aline (Frontiers in Cell and Developmental Biology, 2021)
Hypoxia-inducible factors (HIFs) have become key transcriptional regulators of metabolism, angiogenesis, erythropoiesis, proliferation, inflammation and metastases. HIFs are tightly regulated by the tissue microenvironment. Under the influence of the hypoxic milieu, HIF proteins allow the tissue to adapt its response. This is especially critical for bone, as it constitutes a highly hypoxic environment. As such, bone structure and turnover are strongly influenced by the modulation of oxygen availability and HIFs. Both, bone forming osteoblasts and bone resorbing osteoclasts are targeted by HIFs and modulators of oxygen tension. Experimental and clinical data have delineated the importance of HIF responses in different osteoclast-mediated pathologies. This review will focus on the influence of HIF expression on the regulation of osteoclasts in homeostasis as well as during inflammatory and malignant bone diseases.
CRIS-Team Scopus Importer:2021-04-16
Keywords: bone homeostasis; HIF; hypoxia; inflammation; malignant bone disease; osteoblast; osteoclast

Hypoxia Promotes Neutrophil Survival After Acute Myocardial Infarction - Dölling, Maximilian; Eckstein, Markus; Singh, Jeeshan; Schoen, Janina; Shan, Xiaomei; Bozec, Aline; Knopf, Jasmin; Schett, Georg; Munoz Becerra, Luis; Herrmann, Martin; Schauer, Christine (Frontiers in Immunology, 2022)
Phagocytosis, degranulation, and neutrophil extracellular traps (NETs) formation build the armory of neutrophils for the first line of defense against invading pathogens. All these processes are modulated by the microenvironment including tonicity, pH and oxygen levels. Here we investigated the neutrophil infiltration in cardiac tissue autopsy samples of patients with acute myocardial infarction (AMI) and compared these with tissues from patients with sepsis, endocarditis, dermal inflammation, abscesses and diseases with prominent neutrophil infiltration. We observed many neutrophils infiltrating the heart muscle after myocardial infarction. Most of these had viable morphology and only few showed signs of nuclear de-condensation, a hallmark of early NET formation. The abundance of NETs was the lowest in acute myocardial infarction when compared to other examined diseases. Since cardiac oxygen supply is abruptly abrogated in acute myocardial infarction, we hypothesized that the resulting tissue hypoxia increased the longevity of the neutrophils. Indeed, the viable cells showed increased nuclear hypoxia inducible factor-1α (HIF-1α) content, and only neutrophils with low HIF-1α started the process of NET formation (chromatin de-condensation and nuclear swelling). Prolonged neutrophil survival, increased oxidative burst and reduced NETs formation were reproduced under low oxygen tensions and by HIF-1α stabilization in vitro. We conclude that nuclear HIF-1α is associated with prolonged neutrophil survival and enhanced oxidative stress in hypoxic areas of AMI.
CRIS-Team Scopus Importer:2022-03-04
Keywords: acute myocardial infarction; DNA decondensation; hypoxia inducible factor 1; NET formation; neutrophil extracellular traps; neutrophils

Identification, localization and differentiation of erosions and physiological bone channels by ultrasound in rheumatoid arthritis patients - Finzel, Stephanie; Aegerter, Philippe; Schett, Georg; D'Agostino, Maria-Antonietta (Rheumatology, 2020)
Objectives. Ultrasound (US) can detect cortical bone lesions in RA. However, not all cortical bone lesions are erosions. Herein, we aimed to define whether US can differentiate between physiological bone channels and pathological erosions in RA and to provide topographic description of their differential localization.
CRIS-Team WoS Importer:2021-01-29

Identification of a Distinct Monocyte-Driven Signature in Systemic Sclerosis Using Biophysical Phenotyping of Circulating Immune Cells - Matei, Alexandru-Emil; Kubankova, Marketa; Xu, Liyan; Györfi, Andrea-Hermina; Boxberger, Evgenia; Soteriou, Despina; Papava, Maria; Prater, Julia; Hong, Xuezhi; Bergmann, Christina; Kraeter, Martin; Schett, Georg; et al. (Arthritis and Rheumatology, 2023)
Objective Pathologically activated circulating immune cells, including monocytes, play major roles in systemic sclerosis (SSc). Their functional characterization can provide crucial information with direct clinical relevance. However, tools for the evaluation of pathologic immune cell activation and, in general, of clinical outcomes in SSc are scarce. Biophysical phenotyping (including characterization of cell mechanics and morphology) provides access to a novel, mostly unexplored layer of information regarding pathophysiologic immune cell activation. We hypothesized that the biophysical phenotyping of circulating immune cells, reflecting their pathologic activation, can be used as a clinical tool for the evaluation and risk stratification of patients with SSc.Methods We performed biophysical phenotyping of circulating immune cells by real-time fluorescence and deformability cytometry (RT-FDC) in 63 SSc patients, 59 rheumatoid arthritis (RA) patients, 28 antineutrophil cytoplasmic antibody-associated vasculitis (AAV) patients, and 22 age- and sex-matched healthy donors.Results We identified a specific signature of biophysical properties of circulating immune cells in SSc patients that was mainly driven by monocytes. Since it is absent in RA and AAV, this signature reflects an SSc-specific monocyte activation rather than general inflammation. The biophysical properties of monocytes indicate current disease activity, the extent of skin or lung fibrosis, and the severity of manifestations of microvascular damage, as well as the risk of disease progression in SSc patients.Conclusion Changes in the biophysical properties of circulating immune cells reflect their pathologic activation in SSc patients and are associated with clinical outcomes. As a high-throughput approach that requires minimal preparations, RT-FDC-based biophysical phenotyping of monocytes can serve as a tool for the evaluation and risk stratification of patients with SSc.
CRIS-Team WoS Importer:2023-04-14

Identification of CDT1 as a prognostic marker in human lung adenocarcinoma using bioinformatics approaches - Jiang, Jing; Zhang, Yu; Wang, Jun; Yang, Xuefei; Ren, Xingchang; Huang, Hai; Wang, Jue; Lu, Jinhua; Zhong, Yazhen; Lin, Zechen; Lin, Xianlei; Jia, Yewei; et al. (PeerJ, 2023)
Background: Lung cancer has the highest cancer-related mortality worldwide. Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC). Chromatin licensing and DNA replication factor 1 (CDT1), a key regulator of cell cycle control and replication in eukaryotic cells, has been implicated in various cancer-related processes. Given its significant role in cancer, the focus on CDT1 in this study is justified as it holds promise as a potential biomarker or therapeutic target for cancer treatment. However, its prognostic value in lung adenocarcinoma (LUAD) remains unclear. Methods: Bioinformatics analysis was conducted using data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were utilized to predict biological processes and signaling pathways, respectively. The LinkedOmics database was employed to identify differentially expressed genes (DEGs) associated with CDT1. Nomograms and Kaplan-Meier plots were generated to assess the survival rates of patients with lung adenocarcinoma (LUAD). To determine the RNA and protein expression levels of CDT1 in LUAD and adjacent normal tissues, quantitative polymerase chain reaction (qPCR) and immunohistochemistry techniques were employed, respectively. Results: CDT1 was upregulated in the vast majority of cancer tissues, based on pan-cancer analysis in TCGA and GEO datasets, as to lung cancer, the level of CDT1 expression was much higher in LUAD tissue than in healthy lung tissue. Our clinical data supported these findings. In our study, we used a specific cutoff value to dichotomize the patient samples into high and low CDT1 expression groups. The Kaplan–Meier survival curve revealed poor survival rates in CDT1 high expression group than the low expression group. To determine if CDT1 expression was an independent risk factor in LUAD patients, univariate and multivariate Cox regression analyses were performed. The result showed that CDT1 was a potential novel prognosis factor for LUAD patients, whose prognosis was poorer when CDT1 expression was higher. Based on functional enrichment analysis, highly expressed DEGs of CDT1-high patients were predicted to be involved in the cell cycle. According to our analysis of immune infiltration, CDT1 exhibited a strong correlation with specific immune cell subsets and was found to be a significant predictor of poor survival in patients with LUAD. Conclusions: Our research found that CDT1 was upregulated in LUAD and that high CDT1 expression predicted poor prognosis. We comprehensively and systematically analyzed the expression level in the datasets as well as in our own clinical samples, we also evaluated the prognostic and diagnostic value of CDT1, and finally, the potential mechanisms of CDT1 in the progression of LUAD. These results suggested that CDT1 may be a prognostic marker and therapeutic target for LUAD.
CRIS-Team Scopus Importer:2023-10-20
Keywords: Bioinformatics analysis; Biomarker; CDT1; Lung adenocarcinoma; Prognosis

Identification of circulating microRNA patterns in patients in psoriasis and psoriatic arthritis - Haschka, Judith; Simon, David; Bayat, Sara; Messner, Zora; Kampylafka, Eleni; Fagni, Filippo; Skalicky, Susanna; Hackl, Matthias; Resch, Heinrich; Zwerina, Jochen; Kleyer, Arnd; Cavallaro, Alexander Josef; et al. (Rheumatology, 2023)
Objective miRNAs are small non-coding RNAs that control gene expression. Specific intra- and extracellular miRNA signatures have been identified in various diseases. Whether certain miRNA signatures are associated with psoriasis (PsO) and PsA is currently unknown. We aimed to search for circulating miRNA signatures associated with PsO and PsA patients. Methods Expression of miRNAs was analysed by reverse transcription quantitative real-time PCR (RT-qPCR) in the serum of PsA, PsO patients and healthy controls. Demographic and disease-specific characteristics and imaging data from hand MRI were recorded. In the discovery phase, 192 miRNA assays were analysed in 48 samples (PsA, PsO, controls: each N = 16). For validation, 17 selected miRNAs were measured in the total population. Results A total of 141 patients and controls were analysed (51 PsA, 40 PsO, 50 controls). In the discovery phase 51 miRNAs in PsO and 64 miRNAs in PsA were down- or upregulated compared with controls, with 33 miRNAs being changed in both (adj. P < 0.05). The 17 top candidates from discovery were assessed in the validation phase, 9 of them discriminated PsA and PsO from controls [area under the curve (AUC) >= 0.70, all P < 0.05]. Four miRNAs (miR-19b-3p, miR-21-5p, miR-92a-3p and let-7b-5p) were significantly differently regulated between PsO and PsA. A combination of these miRNAs increased the AUC to 0.92 in multivariate regression model to discriminate PsO and PsA. Conclusion miRNA signatures in PsA and PsO patients differ from controls. Nine miRNAs were differentially regulated in PsA and PsO patients, five of them previously reported to be involved in bone and cartilage metabolism, indicating an intimate association of psoriatic inflammation and bone/cartilage changes.
CRIS-Team WoS Importer:2023-03-17

Identification of Circulating MicroRNA Signatures in Patients with Psoriasis and Psoriatic Arthritis to Develop Novel Strategies for Early Diagnosis of a Bone and Joint Involvement - Haschka, Judith; Simon, David; Bayat, Sara; Kleyer, Arnd; Kampylafka, Eleni; Muschitz, Christian; Skalicky, Susanna; Hackl, Matthias; Resch, Heinrich; Schett, Georg; Kocijan, Roland; Rech, Jürgen; et al. (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

IDENTIFICATION OF CIRCULATING MICRORNA SIGNATURES IN PATIENTS WITH PSORIASIS WITH SUBCLINICAL JOINT DISEASE AND PATIENTS WITH PSORIATIC ARTHRITIS - Haschka, J.; Simon, David; Bayat, Sara; Messner, Z.; Kampylafka, E.; Fagni, Filippo; Skalicky, S.; Hackl, M.; Resch, H.; Zwerina, J.; Kleyer, Arnd; Sticherling, Michael; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Identification of HLA-C restricted, HIV-1-specific CTL epitopes by peptide induced upregulation of HLA-C expression - Stoll, Andrej; Bergmann, Silke; Mummert, Christiane; Mueller-Schmucker, Sandra M.; Spriewald, Bernd M.; Harrer, Ellen G.; Harrer, Thomas (Journal of Immunological Methods, 2015)
HIV-1 negative regulatory factor (Nef) can inhibit CTL recognition by downregulation of HLA-A and HLA-B on the cell surface. In contrast, HLA-C is not affected by Nef and a growing number of studies demonstrate an important role of HLA-C for the control of HIV-1. So far, only a limited number of HLA-C restricted CTL epitopes are known. As the mapping of new CTL epitopes is time and labor intensive, we investigated a novel method for the identification of HLA-C restricted CTL epitopes. B-lymphoblastoid cell lines (B-LCLs) and T2-cells were incubated with HIV-1 specific peptides and subsequently stained for HLA-C surface expression using the HLA-C specific antibody DT9. Peptides that led to increased HLA-C surface expression were used for stimulation of PBMC from HIV-1-infected patients. Subsequently, outgrowing cells were tested for peptide recognition in IFN-? ELISPOT assays and HLA restriction of the recognized peptides was analyzed in ELISPOT assays using HLA-matched B-LCL. We observed that known HLA-C binding peptides increase HLA-C surface expression on T2-cells and on HLA-C*0102 and HLA-C*0702 homozygous B-LCL. Moreover, screening of HIV-1 Nef with overlapping peptides for potential C*0702 restricted epitopes using this method revealed a total of 8 peptides which considerably increased cell surface expression of HLA-C. By epitope mapping and functional analysis of peptide-stimulated T-cell lines we were able to define the peptide YPLTFGWCY as a new C*0702-restricted CTL epitope. These results show that the analysis of peptide induced HLA-C upregulation on B-LCL and T2-cells enables the efficient identification of new HLA-C restricted CTL epitopes.
EVALuna2:13104

Identification of the role of wnt/β-catenin pathway through integrated analyses and in vivo experiments in vitiligo - Zhao, Si-Jia; Jia, Hong; Xu, Xiu-Lian; Bu, Wen-Bo; Zhang, Qian; Chen, Xi; Ji, Juan; Sun, Jian-Fang (Clinical, Cosmetic and Investigational Dermatology, 2021)
Purpose: Vitiligo is an acquired depigmentation skin disease, which affects an average of 1% of the world’s population. The purpose of this study is to identify the key genes and pathways responsible for vitiligo and find new therapeutic targets. Methods: The datasets GSE65127, GSE53146, and GSE75819 were downloaded from the Gene Expression Omnibus (GEO) database. R language was used to identify the differentially expressed genes (DEGs) between lesional skin of vitiligo and non-lesional skin. Next, the key pathways were obtained by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The protein–protein interaction (PPI) networks were conducted by STRING database and Cytoscape software. Subsequently, module analysis was performed by Cytoscape. Among these results, the Wnt/β-catenin pathway and melanogenesis pathway caught our attention. The expression level of β-catenin, microphthalmia-associated transcription factor (MITF) and tyrosinase (TYR) was detected by immunofluorescence in vitiligo lesions and healthy skin. Moreover, zebrafish was treated with XAV-939, an inhibitor of the Wnt/β-catenin pathway. After that, the area of melanin granules as a percentage of the head area was measured. The mRNA expression of β-catenin, lymphoid-enhancing factor 1(lef1), tyr and mitf were detected by q-PCR (quantitative polymerase chain reaction) in zebrafish (Danio rerio). Results: A total of 2442 DEGs were identified, including 1068 upregulated and 1374 downregulated DEGs. The key pathways were identified by GO and KEGG analyses, such as “NOD-like receptor signaling pathway”, “Wnt signaling pathway”, “Melanogenesis”, “mTOR signaling pathway”, “PI3K-Akt signaling pathway”, “Calcium signaling pathway” and “Rap1 signaling pathway”. The immunofluorescence results showed that the level of βcatenin, MITF and TYR was significantly downregulated in vitiligo lesional skin. In zebrafish, the mean percentage area of melanin granules and the expression of β-catenin, lef1, tyr and mitf were decreased after treated with XAV-939. Conclusion: The present study identified key genes and signaling pathways associated with the pathophysiology of vitiligo. Among them, the Wnt/β-catenin pathway played an essential role in pigmentation and could be a breakthrough point in vitiligo treatment.
CRIS-Team Scopus Importer:2021-09-17
Keywords: Calcium signaling; Melanogenesis; Rap1; Vitiligo; Wnt/β-catenin; Zebrafish

IDENTIFYING ADULT HYPOPHOSPHATASIA IN THE RHEUMATOLOGY UNIT - Feurstein, J.; Behanova, M.; Haschka, J.; Roetzer, K.; Uyanik, G.; Witsch-Baumgartner, M.; Schett, Georg; Zwerina, J.; Kocijan, R. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

Identifying adult hypophosphatasia in the rheumatology unit - Feurstein, Julia; Behanova, Martina; Haschka, Judith; Roetzer, Katharina; Uyanik, Gökhan; Hadzimuratovic, Benjamin; Witsch-Baumgartner, Martina; Schett, Georg; Zwerina, Jochen; Kocijan, Roland (Orphanet Journal of Rare Diseases, 2022)
Background: The most frequent manifestation in adult hypophosphatasia (HPP) is musculoskeletal pain. The unspecific nature of its clinical presentation may prevent correct diagnosis. The aim of the study was to assess the prevalence of ALPL mutations in adult patients treated in rheumatological outpatient facilities with evident musculoskeletal symptoms typical for HPP. Methods: Over a period of 10 years 9,522 patients were screened in the rheumatology outpatient clinic of the Hanusch hospital Vienna. Serum ALP levels ≤ 40 U/L were found in 524 patients. After screening for secondary causes, 73 patients were invited for clinical evaluation. Genetic testing was performed in 23 patients with suspected HPP. Logistic regression models with Firth penalisation were used to estimate the unadjusted and BMI-adjusted association of each clinical factor with HPP. Results: Mutations in the ALPL gene were observed in 57% of genetically screened patients. Arthralgia, fractures, and pain were the leading symptoms in individuals with ALPL mutation. Chondrocalcinosis (OR 29.12; 95% CI 2.02–1593.52) and dental disease (OR 8.33; 95% CI 0.93–143.40) were associated with ALPL mutation, independent of BMI. Onset of symptoms in patients with ALPL mutation was at 35.1 (14.3) years, with a mean duration from symptoms to diagnosis of 14.4 (8.1) years. Bone mineral density (BMD) and trabecular bone score (TBS) as well as bone turnover markers were not indicative for HPP or ALPL mutation. Conclusion: HPP can mimic rheumatologic diseases. Thus, HPP should be considered as a possible diagnosis in adult patients presenting with musculoskeletal pain of unknown origin in rheumatology outpatient clinics. In patients with persistently low ALP serum levels and unclear musculoskeletal pain, HPP as the underlying cause has to be considered.
CRIS-Team Scopus Importer:2022-12-23
Keywords: Alkaline phosphatase; ALPL gene; Arthralgia; Hypophosphatasia; Musculoskeletal pain

Identifying 'non-progressors' among patients with arthralgia - Krönke, Gerhard; Hueber, Axel (Nature Reviews Rheumatology, 2020)
Patients with clinically suspect arthralgia have articular symptoms such as pain and stiffness of the small joints without clinical signs of arthritis. Some of these patients progress and develop 'true' disease, but how can we differentiate evolving chronic disease from disease that will resolve?
CRIS-Team WoS Importer:2020-03-13

IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin-directed vascular barrier disruption. - Langer, Victoria; Vivi, Eugenia; Regensburger, Daniela; Winkler, Thomas; Waldner, Maximilian; Rath, Timo; Schmid, Benjamin; Skottke, Lisa; Lee, Somin; Jeon, Noo Li; Wohlfahrt, Thomas; Kramer, Viktoria; et al. (Journal of Clinical Investigation, 2019)
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.

IgA2 Antibodies against SARS-CoV-2 Correlate with NET Formation and Fatal Outcome in Severely Diseased COVID-19 Patients - Staats, Leonie A. N.; Pfeiffer, Hella; Knopf, Jasmin; Lindemann, Aylin; Fürst, Julia; Kremer, Andreas; Hackstein, Holger; Neurath, Markus; Munoz, Luis Enrique; Achenbach, Susanne; Leppkes, Moritz; Herrmann, Martin; et al. (Cells, 2020)
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to an adaptive immune response in the host and the formation of anti-SARS-CoV-2 specific antibodies. While IgG responses against SARS-CoV-2 have been characterized quite well, less is known about IgA. IgA2 activates immune cells and induces inflammation and neutrophil extracellular trap (NET) formation which may contribute to organ injury and fatal outcome in SARS-CoV-2-infected patients. SARS-CoV-2 spike protein specific antibody levels were measured in plasma samples of 15 noninfected controls and 82 SARS-CoV-2-infected patients with no or mild symptoms, moderate symptoms (hospitalization) or severe disease (intensive care unit, ICU). Antibody levels were compared to levels of C-reactive protein (CRP) and circulating extracellular DNA (ecDNA) as markers for general inflammation and NET formation, respectively. While levels of SARS-CoV-2-specific IgG were similar in all patient groups, IgA2 antibodies were restricted to severe disease and showed the strongest discrimination between nonfatal and fatal outcome in patients with severe SARS-CoV-2 infection. While anti-SARS-CoV-2 IgG and IgA2 levels correlated with CRP levels in severely diseased patients, only anti-SARS-CoV-2 IgA2 correlated with ecDNA. These data suggest that the formation of anti-SARS-CoV-2 IgA2 during SARS-CoV-2 infection is a marker for more severe disease related to NET formation and poor outcome.
CRIS-Team WoS Importer:2021-01-15

IgA2 immune complexes selectively promote inflammation by human CD103+ dendritic cells - Mes, Lynn; Steffen, Ulrike; Chen, Hung-Jen; Veth, Jennifer; Hoepel, Willianne; Griffith, Guillermo Romeo; Schett, Georg; Den Dunnen, Jeroen (Frontiers in Immunology, 2023)
While immunoglobulin A (IgA) is well known for its neutralizing and anti-inflammatory function, it is becoming increasingly clear that IgA can also induce human inflammatory responses by various different immune cells. Yet, little is known about the relative role of induction of inflammation by the two IgA subclasses i.e. IgA1, most prominent subclass in circulation, and IgA2, most prominent subclass in the lower intestine. Here, we set out to study the inflammatory function of IgA subclasses on different human myeloid immune cell subsets, including monocytes, and in vitro differentiated macrophages and intestinal CD103+ dendritic cells (DCs). While individual stimulation with IgA immune complexes only induced limited inflammatory responses by human immune cells, both IgA subclasses strongly amplified pro-inflammatory cytokine production upon co-stimulation with Toll-like receptor (TLR) ligands such as Pam3CSK4, PGN, and LPS. Strikingly, while IgA1 induced slightly higher or similar levels of pro-inflammatory cytokines by monocytes and macrophages, respectively, IgA2 induced substantially more inflammation than IgA1 by CD103+ DCs. In addition to pro-inflammatory cytokine proteins, IgA2 also induced higher mRNA expression levels, indicating that amplification of pro-inflammatory cytokine production is at least partially regulated at the level of gene transcription. Interestingly, cytokine amplification by IgA1 was almost completely dependent on Fc alpha receptor I (FcαRI), whilst blocking this receptor only partially reduced cytokine induction by IgA2. In addition, IgA2-induced amplification of pro-inflammatory cytokines was less dependent on signaling through the kinases Syk, PI3K, and TBK1/IKKϵ. Combined, these findings indicate that IgA2 immune complexes, which are most abundantly expressed in the lower intestine, particularly promote inflammation by human CD103+ intestinal DCs. This may serve an important physiological function upon infection, by enabling inflammatory responses by this otherwise tolerogenic DC subset. Since various inflammatory disorders are characterized by disturbances in IgA subclass balance, this may also play a role in the induction or exacerbation of chronic intestinal inflammation.
CRIS-Team Scopus Importer:2023-04-21
Keywords: CD103; FcαRI; IgA subclasses; inflammation; intestine

IGA ACPA ARE ASSOCIATED WITH PROGRESSION TO RHEUMATOID ARTHRITIS IN INDIVIDUALS AT-RISK AND DECLINE IN LEVELS AROUND THE DISEASE ONSET - Sokolova, Maria; Hartmann, F.; Sieghart, D.; Steiner, G.; Kleyer, Arnd; Schett, Georg; Steffen, Ulrike (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

IgA anti-citrullinated protein antibodies are associated with flares during DMARD tapering in rheumatoid arthritis. - Sokolova, Maria; Hagen, Melanie; Bang, Holger; Schett, Georg; Rech, Jürgen; Steffen, Ulrike (Rheumatology, 2022)
OBJECTIVES: A substantial proportion of RA patients flare upon withdrawal of DMARDs, and thus the definition of prognostic markers is crucial. ACPA positivity has been identified as a risk factor for flare. However, only the role of IgG ACPA is established in this context, while the role of IgA ACPA is poorly defined. We thus aimed to investigate the role of IgA ACPA in flaring of RA. METHODS: Serum levels of IgA1 and IgA2 ACPA at baseline and after 12 months were measured in 108 patients from the randomized controlled RETRO study. RA patients in stable remission for at least 6 months at study recruitment were assigned to either one of the DMARD tapering arms or to continuation of DMARDs. RESULTS: In patients remaining in remission but not in the ones who flared, IgA2 ACPA levels and proportion of IgA2 in ACPA (IgA2% ACPA) significantly declined (median of 17.5%; P < 0.0001). This seemed to be independent of the treatment choice, as there was no difference in IgA2 ACPA dynamics between the study arms. IgA2% ACPA was associated with disease activity (DAS28) at flare (r = 0.36; P = 0.046). IgA and IgG ACPA showed a tendency towards independent contribution to the risk of flare with the highest risk if a patient had both antibody classes. CONCLUSION: In this study, IgA ACPA was identified as a risk factor for flare in combination with IgG ACPA. IgA2 ACPA levels were associated with flare severity and declined in patients in stable remission.
EVALuna2:474284

IgA Complexes Induce Neutrophil Extracellular Trap Formation More Potently Than IgG Complexes - Gimpel, Anna-Katharina; Maccataio, Antonio; Unterweger, Harald; Sokolova, Maria; Schett, Georg; Steffen, Ulrike (Frontiers in Immunology, 2022)
Neutrophil extracellular trap (NET) formation is a powerful instrument to fight pathogens, but may induce collateral damage in the affected tissues. Besides pathogen-derived factors, immune complexes are potent inducers of NET formation. Neutrophils express IgA and IgG specific Fc receptors (FcRs) and therefore respond to complexed IgA and IgG. Especially in the context of autoimmune diseases, IgA and IgG immune complexes have been shown to trigger NET formation, a process that putatively contributes to disease severity. However, it is of question if both antibody classes stimulate neutrophils to the same extent. In this study, we compared the capability of IgA and IgG complexes formed by heat aggregation to induce NET formation. While stimulation of neutrophils with IgA complexes robustly induced NET formation, complexed IgG only marginally increased the amount of NETs compared to the unstimulated control. Mixing IgA with IgG before heat aggregation did not increase the effect of complexed IgA on neutrophils. By contrast, the presence of IgG complexes seemed to disturb neutrophil stimulation by IgA complexes. The capacity of complexed IgG to induce NET formation could not be increased by the addition of autologous serum or the removal of terminal sialic acid in the Fc glycan. Together, our data show that IgA is a much more potent inducer of NET formation than IgG. IgA may thus be the main driving force in (auto)immune complex-mediated NET formation.
CRIS-Team Scopus Importer:2022-02-11
Keywords: IgA; IgG; immune complex; NET; neutrophil

IgA subclasses have different effector functions associated with distinct glycosylation profiles - Steffen, Ulrike; Koeleman, Carolien A.; Sokolova, Maria V.; Bang, Holger; Kleyer, Arnd; Rech, Jürgen; Unterweger, Harald; Schicht, Martin; Garreis, Fabian; Hahn, Jonas; Andes, Fabian T.; Hahn, Madelaine; et al. (Nature Communications, 2020)
Monomeric serum immunoglobulin A (IgA) can contribute to the development of various autoimmune diseases, but the regulation of serum IgA effector functions is not well defined. Here, we show that the two IgA subclasses (IgA1 and IgA2) differ in their effect on immune cells due to distinct binding and signaling properties. Whereas IgA2 acts pro-inflammatory on neutrophils and macrophages, IgA1 does not have pronounced effects. Moreover, IgA1 and IgA2 have different glycosylation profiles, with IgA1 possessing more sialic acid than IgA2. Removal of sialic acid increases the pro-inflammatory capacity of IgA1, making it comparable to IgA2. Of note, disease-specific autoantibodies in patients with rheumatoid arthritis display a shift toward the pro-inflammatory IgA2 subclass, which is associated with higher disease activity. Taken together, these data demonstrate that IgA effector functions depend on subclass and glycosylation, and that disturbances in subclass balance are associated with autoimmune disease.
CRIS-Team Scopus Importer:2020-01-21

IgG4 immune response in Churg-Strauss syndrome - Vaglio, Augusto; Strehl, Johanna D.; Manger, Bernhard; Maritati, Federica; Alberici, Federico; Beyer, Christian; Rech, Jürgen; Rech, Juergen; Sinico, Renato A.; Bonatti, Francesco; Battistelli, Luisita; Distler, Jörg; et al. (Annals of the Rheumatic Diseases, 2012)
Objective: T-helper type 2 responses are crucial in Churg-Strauss syndrome (CSS) and may enhance the production of IgG4 antibodies. The authors assessed the IgG4 immune response in CSS patients. Methods: The authors included 46 consecutive patients with CSS (24 with active and 22 with quiescent disease), 26 with granulomatosis with polyangiitis (GPA, Wegener's), 25 with atopic asthma and 20 healthy controls and determined serum IgG, IgM, IgA, IgE and IgG subclass levels. Tissue infiltration by IgG4 plasma cells was assessed in nine patients with CSS, 10 with GPA, 22 with chronic sinusitis (11 with and 11 without eosinophilia). Results: IgG4 levels were markedly higher in active CSS patients than in controls (p<0.001 vs all control groups). Serum IgG4 correlated with the number of disease manifestations (r=0.52, p=0.01) and the Birmingham vasculitis activity score (r=0.64, p=0.001). Longitudinal analysis in 12 CSS cases showed that both the IgG4 level and IgG4/IgG ratio dropped during disease remission (p=3×10 -5 and p=6×10 -4, respectively). Tissue analysis did not show an increased IgG4 plasma cell infiltration in CSS biopsies compared with control groups. Conclusions: Serum IgG4 levels are markedly elevated in active CSS and correlate with the number of organ manifestations and disease activity.
CRIS-Team Scopus Importer:2021-02-03

IgG4-related fasciitis - Morf, Harriet; Roemer, Frank; Agaimy, Abbas; Schett, Georg; Manger, Bernhard (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-02-18

IL-17-22-23 PATHWAYS IN PSORIATIC ARTHRITIS AND PSORIASIS - Nas, K.; Cevik, R.; Yildiz, I.; Rech, Jürgen; Schett, Georg (2017)
EVALuna2:35044

IL-17/23 IN THE TRANSITION FROM AUTOIMMUNITY TO INFLAMMATION - Pfeifle, R.; Rothe, Tobias; Scherer, H. U.; Wuhrer, M.; Rombouts, Y.; Koeleman, C. A.; Toes, R.; Holmdahl, R.; Herrmann, Martin; Blueml, S.; Nimmerjahn, Falk; Schett, Georg; et al. (2016)
EVALuna2:13361

IL-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation - Faas, Maria; Ipseiz, Natacha; Ackermann, Jochen; Culemann, Stephan; Grüneboom, Anika; Schröder, Fenja; Rothe, Tobias; Scholtysek, Carina; Eberhardt, Martin; Böttcher, Martin; Kirchner, Philipp; Stoll, Cornelia; et al. (Immunity, 2021)
Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.
CRIS-Team Scopus Importer:2021-11-19
Keywords: alternatively activated macrophage; GATA3; interleukin-33; itaconate; mitochondrial rewiring; resolution of inlammation; UCP2; uncoupling

IL-33 induces skin inflammation with mast cell and neutrophil activation - Hueber, Axel; Alves-Filho, Jose C.; Asquith, Darren L.; Michels, Chesney; Millar, Neal L.; Reilly, James H.; Graham, Gerry J.; Liew, Foo Y.; Miller, Ashley M.; Mcinnes, Iain B. (European Journal of Immunology, 2011)
Psoriasis is a common chronic autoimmune condition of the skin characterized by hyperplasia of epidermal keratinocytes associated with pro-inflammatory cytokines. IL-33 is a new member of the IL-1 superfamily that signals through the ST2 receptor and was originally defined as an inducer of T helper 2 (Th2) cytokines. Recently, broader immune activatory potential has been defined for IL-33 particularly via mast cell activation and neutrophil migration. Here, we show that ST2(-/-) mice exhibit reduced cutaneous inflammatory responses compared with WT mice in a phorbol ester-induced model of skin inflammation. Furthermore, injections of IL-33 into the ears of mice induce an inflammatory skin lesion. This inflammatory response was partially dependent on mast cells as mast cell-deficient mice (Kit(W-sh/W-sh) ) showed delayed responses to IL-33. IL-33 also recruited neutrophils to the ear, an effect mediated in part by increased production of the chemokine KC (CXCL1). Finally, we show that IL-33 expression is up-regulated in the epidermis of clinical psoriatic lesions, compared with healthy skin. These results therefore demonstrate that IL-33 may play a role in psoriasis-like plaque inflammation. IL-33 targeting may provide a new treatment strategy for psoriasis.
EVALuna2:13399

IL-36R signalling activates intestinal epithelial cells and fibroblasts and promotes mucosal healing in vivo - Scheibe, Kristina; Backert, Ingo; Wirtz, Stefan; Hueber, Axel; Schett, Georg; Vieth, Michael; Probst, Hans Christian; Bopp, Tobias; Neurath, Markus; Neufert, Clemens (Gut, 2016)
Interleukin (IL)-36R signalling plays a proinflammatory role in different organs including the skin, but the expression of IL-36R ligands and their molecular function in intestinal inflammation are largely unknown.We studied the characteristics of IL-36R ligand expression in IBDs and experimental colitis. The functional role of IL-36R signalling in the intestine was addressed in experimental colitis and wound healing models in vivo by using mice with defective IL-36R signalling (IL-36R-/-) or Myd88, neutralising anti-IL-36R antibodies, recombinant IL-36R ligands and RNA-seq genome expression analysis.Expression of IL-36? and IL-36? was significantly elevated in active human IBD and experimental colitis. While IL-36? was predominantly detected in nuclei of the intestinal epithelium, IL-36? was mainly found in the cytoplasm of CD14(+) inflammatory macrophages. Functional studies showed that defective IL-36R signalling causes high susceptibility to acute dextran sodium sulfate colitis and impairs wound healing. Mechanistically, IL-36R ligands released upon mucosal damage activated IL-36R(+) colonic fibroblasts via Myd88 thereby inducing expression of chemokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-6. Moreover, they induced proliferation of intestinal epithelial cells (IECs) and expression of the antimicrobial protein lipocalin 2. Finally, treatment of experimental intestinal wounds with IL-36R ligands significantly accelerated mucosal healing in vivo.IL-36R signalling is activated upon intestinal damage, stimulates IECs and fibroblasts and drives mucosal healing. Modulation of the IL-36R pathway emerges as a potential therapeutic strategy for induction of mucosal healing in IBD.
EVALuna2:2028

IL-3 orchestrates ulcerative colitis pathogenesis by controlling the development and the recruitment of splenic reservoir neutrophils - Benard, Alan; Mittelstädt, Anke; Klösch, Bettina; Glanz, Karolina; Müller, Jan; Schoen, Janina; Nüse, Björn; Brunner, Maximilian; Naschberger, Elisabeth; Stürzl, Michael; Mattner, Jochen; Munoz, Luis Enrique; et al. (Cell Reports, 2023)
Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis of IBDs has been investigated intensively, the etiology of IBDs remains enigmatic. Here, we report that interleukin-3 (Il-3)-deficient mice are more susceptible and exhibit increased intestinal inflammation during the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesenchymal stem cell phenotype and protects by promoting the early recruitment of splenic neutrophils with high microbicidal capability into the colon. Mechanistically, IL-3-dependent neutrophil recruitment involves CCL5+ PD-1high LAG-3high T cells, STAT5, and CCL20 and is sustained by extramedullary splenic hematopoiesis. During acute colitis, Il-3−/− show, however, increased resistance to the disease as well as reduced intestinal inflammation. Altogether, this study deepens our understanding of IBD pathogenesis, identifies IL-3 as an orchestrator of intestinal inflammation, and reveals the spleen as an emergency reservoir for neutrophils during colonic inflammation.
CRIS-Team Scopus Importer:2023-06-23
Keywords: CCL5; colitis; CP: Immunology; interleukin-3; neutrophils; spleen

IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells. - Ullrich, Karen; Derdau, Julia; Baltes, Carsten; Battistella, Alice; Rosso, Gonzalo; Uderhardt, Stefan; Schulze, Lisa; Liu, Lijuan; Dedden, Mark; Spocinska, Marta; Kainka, Lucina; Kubánková, Markéta; et al. (Gut, 2023)
IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of Il3 or Il3r deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of Il3r -/- and Il3r +/+ T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and in vitro and in vivo cell trafficking assays. We observed that, in patients with IBD, the levels of IL-3 in the inflamed mucosa were increased. In vivo, experimental chronic colitis on T cell transfer was exacerbated in the absence of Il-3 or Il-3r signalling. This was attributable to Il-3r signalling-induced changes in kinase phosphorylation and actin cytoskeleton structure, resulting in increased mechanical deformability and enhanced egress of Tregs from the inflamed colon mucosa. Similarly, IL-3 controlled mechanobiology in human Tregs and was associated with increased mucosal Treg abundance in patients with IBD. Collectively, our data reveal that IL-3 signaling exerts an important regulatory role at the interface of biophysical and migratory T cell features in intestinal inflammation and suggest that this might be an interesting target for future intervention.
EVALuna2:539503

IL9 MODULATION OF OSTEOCLASTS DIFFERENTIATION AND IMPACTS ON BONE METABOLISM - Saad, M.; Rauber, S.; Schett, Georg; Ramming, Andreas (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

IL-9-Producing Innate Lymphoid Cells - Keyplayers That Orchestrate Resolution of Chronic Inflammation in Arthritis - Rauber, Simon; Luber, Markus; Weber, Stefanie; Maul, Lisa; Soare, Alina; Wohlfahrt, Thomas; Bozec, Aline; Herrmann, Martin; Zaiss, Mario; Fearon, Ursula; Veale, Douglas J.; Canete, Juan; et al. (2017)
EVALuna2:33440

IL-9 Producing Tumor-Infiltrating Lymphocytes and Treg Subsets Drive Immune Escape of Tumor Cells in Non-Small Cell Lung Cancer - Heim, Lisanne; Yang, Zuqin; Tausche, Patrick; Hohenberger, Katja; Chiriac, Mircea-Teodor; Kölle, Julia; Geppert, Carol-Immanuel; Kachler, Katerina; Miksch, Sarah; Graser, Anna; Friedrich, Juliane; Kharwadkar, Rakshin; et al. (Frontiers in Immunology, 2022)
Although lung cancer is the leading cause of cancer deaths worldwide, the mechanisms how lung cancer cells evade the immune system remain incompletely understood. Here, we discovered IL-9-dependent signaling mechanisms that drive immune evasion in non-small cell lung cancer (NSCLC). We found increased IL-9 and IL-21 production by T cells in the tumoral region of the lung of patients with NSCLC, suggesting the presence of Th9 cells in the lung tumor microenvironment. Moreover, we noted IL-9 producing Tregs in NSCLC. IL-9 target cells in NSCLC consisted of IL-9R+ tumor cells and tumor-infiltrating lymphocytes. In two murine experimental models of NSCLC, and in vitro, IL-9 prevented cell death and controlled growth of lung adenocarcinoma cells. Targeted deletion of IL-9 resulted in successful lung tumor rejection in vivo associated with an induction of IL-21 and reduction of Treg cells. Finally, anti-IL-9 antibody immunotherapy resulted in suppression of tumor development even in established experimental NSCLC and was associated with reduced IL-10 production in the lung. In conclusion, our findings indicate that IL-9 drives immune escape of lung tumor cells via effects on tumor cell survival and tumor infiltrating T cells. Thus, strategies blocking IL-9 emerge as a new approach for clinical therapy of lung cancer.
CRIS-Team Scopus Importer:2022-05-20
Keywords: IL-9; immune escape; NSCLC; TIL; tumor immunotherapy

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure - Schulz-Kuhnt, Anja; Greif, Vicky; Hildner, Kai; Knipfer, Lisa; Döbrönti, Michael; Zirlik, Sabine; Fuchs, Florian; Atreya, Raja; Zundler, Sebastian; Lopez Posadas, Rocío; Neufert, Clemens; Ramming, Andreas; et al. (Frontiers in Immunology, 2020)
Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6+ ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions in vitro and in vivo using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.
CRIS-Team Scopus Importer:2020-06-02
Keywords: CCR6; cystic fibrosis; group-2 innate lymphoid cells; tissue remodeling; type-VI collagen

Imaging in inflammatory arthritis: progress towards precision medicine - Minopoulou, Ioanna; Kleyer, Arnd; Yalcin-Mutlu, Melek; Fagni, Filippo; Kemenes, Stephan; Schmidkonz, Christian; Atzinger, Armin; Pachowsky, Milena; Engel, Klaus; Folle, Lukas; Roemer, Frank; Waldner, Maximilian; et al. (Nature Reviews Rheumatology, 2023)
Imaging techniques such as ultrasonography and MRI have gained ground in the diagnosis and management of inflammatory arthritis, as these imaging modalities allow a sensitive assessment of musculoskeletal inflammation and damage. However, these techniques cannot discriminate between disease subsets and are currently unable to deliver an accurate prediction of disease progression and therapeutic response in individual patients. This major shortcoming of today’s technology hinders a targeted and personalized patient management approach. Technological advances in the areas of high-resolution imaging (for example, high-resolution peripheral quantitative computed tomography and ultra-high field MRI), functional and molecular-based imaging (such as chemical exchange saturation transfer MRI, positron emission tomography, fluorescence optical imaging, optoacoustic imaging and contrast-enhanced ultrasonography) and artificial intelligence-based data analysis could help to tackle these challenges. These new imaging approaches offer detailed anatomical delineation and an in vivo and non-invasive evaluation of the immunometabolic status of inflammatory reactions, thereby facilitating an in-depth characterization of inflammation. By means of these developments, the aim of earlier diagnosis, enhanced monitoring and, ultimately, a personalized treatment strategy looms closer.
CRIS-Team Scopus Importer:2023-09-29

Imaging in rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis: An international viewpoint on the current knowledge and future research priorities - Baraliakos, Xenofon; Conaghan, Philip G.; D'Agostino, Maria-Antonietta; Maksymowych, Walter; Naredo, Esperanza; Ostergaard, Mikkel; Schett, Georg; Emery, Paul (European Journal of Rheumatology, 2019)
Imaging is increasingly used in the routine management of rheumatic diseases as well as in the clinical trials of these disorders. This viewpoint, authored by a group of international imaging experts following two meetings dedicated to imaging in rheumatology, reports a consensus about the current knowledge and addresses where further research should be focused based on the views of the international imaging experts and discussion of the evidence with attending imaging practitioners. The goal was to maximize the potential of imaging to improve the clinical management of four rheumatic diseases. These rheumatic diseases include rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis.
CRIS-Team WoS Importer:2019-04-23

Imaging of gout: New tools and biomarkers? - Araujo, Elizabeth G.; Manger, Bernhard; Perez-Ruiz, Fernando; Thiele, Ralf G. (Best Practice & Research in Clinical Rheumatology, 2016)
While joint aspiration and crystal identification by polarizing microscopy remain the gold standard for diagnosing tophaceous gout, agreement among medical and ancillary health personnel examining synovial fluid using polarizing microscopy for the detection of monosodium urate (MSU) crystals appears to be poor. Imaging modalities, including conventional radiography (CR), ultrasonography (US), magnetic resonance imaging (MRI), and dual-energy computed tomography (DECT), have been found to provide information on the deposition of MSU crystals in tissues, and the consequences of such deposition. CR can demonstrate typical "punched out lesions" with marginal overhangs, but the sensitivity for erosion detection is better for DECT and US. US is inexpensive and can identify tophus deposition in and around joints, erosions, and tissue inflammation if power Doppler US is used. MRI can show tophi, bone marrow edema, and inflammation, but MRI findings of tophi may be nonspecific. DECT can identify and color-code tophaceous material, and provide an overview of the tophus burden of a joint area. Because of the lower number of available studies, the strength of evidence for the newer imaging can be improved through further research.
EVALuna2:13391

Imatinib-loaded gold nanoparticles inhibit proliferation of fibroblasts and macrophages from systemic sclerosis patients and ameliorate experimental bleomycin-induced lung fibrosis - Codullo, Veronica; Cova, Emanuela; Pandolfi, Laura; Breda, Silvia; Morosini, Monica; Frangipane, Vanessa; Malatesta, Manuela; Calderan, Laura; Cagnone, Maddalena; Pacini, Chiara; Cavagna, Lorenzo; Recalde, Helios; et al. (Journal of Controlled Release, 2019)
Interstitial lung involvement in Systemic Sclerosis (SSc-ILD) is a complication with high morbidity and mortality. Specifically, engineered gold nanoparticles (GNPs) are proposed as targeted delivery system increasing efficacy of drugs with antifibrotic effect, such as tyrosine kinases. We aimed to test in vitro and in vivo the activity of targeted Imatinib (Im)-loaded GNP on SSc-ILD patients derived cells and in experimental model of lung fibrosis. GNPs functionalized with anti-CD44 and loaded with Im (GNP-HCIm) were synthesized. Lung fibroblasts (LFs) and alveolar macrophages from bronchoalveolar lavage fluids of SSc-ILD patients were cultured in presence of nanoparticles. GNP-HCIm significantly inhibited proliferation and viability inducing apoptosis of LFs and effectively reduced IL-8 release, viability and M2 polarization in alveolar macrophages. Anti-fibrotic effect of tracheal instilled GNP-HCIm was evaluated on bleomycin lung fibrosis mouse model comparing effect with common route of Im administration. GNP-HCIm were able to reduce significantly lung fibrotic changes and collagen deposition. Finally, electron microscopy revealed the presence of GNPs inside alveolar macrophages. These data support the use of GNPs locally administered in the development of new therapeutic approaches to SSc-ILD.
CRIS-Team Scopus Importer:2019-10-01
Keywords: Gold nanoparticles; Imatinib; Inhalatory delivery; Interstitial lung fibrosis; Systemic sclerosis

IMATINIB-LOADED TARGETED GOLD NANOPARTICLES AMELIORATE EXPERIMENTAL LUNG FIBROSIS INDUCED BY BLEOMYCIN - Codullo, V.; Breda, S.; Meloni, F.; Cova, E.; Inghilleri, S.; Colombo, M.; Prosperi, Davide; Malatesta, M.; Calderan, L.; Montecucco, C.; Distler, Jörg (2017)
EVALuna2:35036

Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer's Disease: A Case Control Study - Oberstein, Timo; Taha, Lava; Spitzer, Philipp; Hellstern, Janina; Herrmann, Martin; Kornhuber, Johannes; Maler, Juan Manuel (Frontiers in Immunology, 2018)
The neuropathological hallmarks of Alzheimer's disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (Th) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCIAD, n = 14), with MCI unlikely due to AD (MCIother, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3+CD8-IL-17A+IFNγ- Th17 cells, CD3+CD8-IL-17A-IFNγ+ Th1 cells, and CD4+CD127lowCD25+ regulatory T cells (Tregs) were assessed by flow cytometry. In addition, the correlations of the proportions of Th subsets to cerebrospinal fluid biomarkers were studied. CD3+CD8-IL-17A+IFNγ- Th17 cells were significantly increased in subjects with MCIAD compared to age- and sex-matched subjects with MCIother and controls (MCIAD mean = 1.13, SD = 0.77; MCIother mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4+CD127lowCD25+ Tregs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (rTreg|totalTau = 0.43, p = 0.021, n = 28; rTreg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (rTreg|totalTau = -0.51, p = 0.007, n = 26). The increase of circulating CD3+CD8-IL-17A+IFNγ- Th17 cells in the early stages of AD and the association of CD4+CD127lowCD25+ Tregs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.
EVALuna2:211630

Immobilization by 21 days of bed rest results in type II collagen degradation in healthy individuals - Liphardt, Anna-Maria; Elie-Tino, Godonou; Dreiner, Maren; Mündermann, Annegret; Tascilar, Koray; Djalal, Nadja; Heer, Martina; Schett, Georg; Zaucke, Frank; Niehoff, Anja (Osteoarthritis and Cartilage, 2023)
Objective: To investigate the effects of 21 days of bed rest immobilization (with and without exercise and nutrition interventions) on type II collagen biomarker concentrations in healthy individuals. Design: Twelve healthy male participants (age 34.2 ± 8.3 years; body mass index 22.4 ± 1.7 kg/m²) were exposed to 6 days ambulatory baseline data collection (BDC), 21 days head-down-tilt bed rest (HDT, CON) + interventions (HDT + resistive vibration exercise (2 times/week, 25 minutes): RVE; HDT + RVE + whey protein (0.6 g/kg body weight/day) and bicarbonate supplementation (90 mmol KHCO3/day: NeX), and 6 days of re-ambulation (R) in a cross-over designed study. The starting HDT condition was randomized (CON-RVE-NEX, RVE-NEX-CON, NEX-CON-RVE). Blood and urine samples were collected before, during, and after HDT. Serum concentrations (s) of CPII, C2C, C1,2C, and urinary concentrations (u) of CTX-II and Coll2–1NO2 were measured. Results: Twenty-one days of HDT resulted in increased sCPII (p < 0.001), sC2C (p < 0.001), and sC1,2C (p = 0.001) (highest increases: sCPII (+24.2% - HDT5), sC2C (+24.4% - HDT7), sC1,2C (+13.5% - HDT2). sC2C remained elevated at R+1 (p = 0.002) and R+6 (p < 0.001) compared to baseline. NeX led to lower sCPII (p < 0.001) and sC1,2C (p = 0.003) compared to CON. uCTX-II (second void and 24-hour urine) increased during HDT (p < 0.001, highest increase on HDT21: second void +82.8% (p < 0.001); 24-hour urine + 77.8% (p < 0.001). NeX resulted in lower uCTX-II concentrations in 24-hour urine (p = 0.012) compared to CON. Conclusions: Twenty-one days of bed rest immobilization results in type II collagen degradation that does not recover within 6 days of resuming ambulation. The combination of resistive vibration exercise and protein/bicarbonate supplementation minimally counteracted this effect.
CRIS-Team Scopus Importer:2023-12-15
Keywords: Bed rest; Cartilage biomarkers; Collagen metabolism; Immobilization; MNX-study; Type II collagen

Immune checkpoint inhibitor-induced neurotoxicity is not associated with seroprevalence of neurotropic infections - Schmitt, C.; Hoefsmit, E. P.; Fangmeier, T.; Kramer, N.; Kabakci, C.; Vera González, Julio; Versluis, J. M.; Compter, A.; Harrer, Thomas; Mijočević, H.; Schubert, S.; Hundsberger, T.; et al. (Cancer Immunology, Immunotherapy, 2023)
Background: Immune checkpoint inhibitors (ICI) substantially improve outcome for patients with cancer. However, the majority of patients develops immune-related adverse events (irAEs), which can be persistent and significantly reduce quality of life. Neurological irAEs occur in 1–5% of patients and can induce severe, permanent sequelae or even be fatal. In order to improve the diagnosis and treatment of neurological irAEs and to better understand their pathogenesis, we assessed whether previous neurotropic infections are associated with neurological irAEs. Methods: Neurotropic infections that might predispose to ICI-induced neurological irAEs were analyzed in 61 melanoma patients from 3 countries, the Netherlands, Australia and Germany, including 24 patients with neurotoxicity and 37 control patients. In total, 14 viral, 6 bacterial, and 1 protozoal infections previously reported to trigger neurological pathologies were assessed using routine serology testing. The Dutch and Australian cohorts (NL) included pre-treatment plasma samples of patients treated with neoadjuvant ICI therapy (OpACIN-neo and PRADO trials; NCT02977052). In the Dutch/Australian cohort a total of 11 patients with neurological irAEs were compared to 27 control patients (patients without neurological irAEs). The German cohort (LMU) consisted of serum samples of 13 patients with neurological irAE and 10 control patients without any documented irAE under ICI therapy. Results: The association of neurological irAEs with 21 possible preceding infections was assessed by measuring specific antibodies against investigated agents. The seroprevalence of all the tested viral (cytomegalovirus, Epstein-Barr-Virus, varicella-zoster virus, measles, rubella, influenza A and B, human herpes virus 6 and 7, herpes simplex virus 1 and 2, parvovirus B19, hepatitis A and E and human T-lymphotropic virus type 1 and 2), bacterial (Borrelia burgdorferi sensu lato, Campylobacter jejuni, Mycoplasma pneumoniae, Coxiella burnetti, Helicobacter pylori, Yersinia enterocolitica and Y. pseudotuberculosis) and protozoal (Toxoplasma gondii) infections was similar for patients who developed neurological irAEs as compared to control patients. Thus, the analysis provided no evidence for an association of described agents tested for seroprevalence with ICI induced neurotoxicity. Conclusion: Previous viral, bacterial and protozoal neurotropic infections appear not to be associated with the development of neurological irAEs in melanoma patients who underwent therapy with ICI across 3 countries. Further efforts are needed to unravel the factors underlying neurological irAEs in order to identify risk factors for these toxicities, especially with the increasing use of ICI in earlier stage disease.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Checkpoint-inhibitor; Melanoma; Serology; Side effect

Immune deficiency vs. immune excess in inflammatory bowel diseases-STAT3 as a rheo-STAT of intestinal homeostasis - Leppkes, Moritz; Neurath, Markus; Herrmann, Martin; Becker, Christoph (Journal of Leukocyte Biology, 2016)
Genome-wide association studies have provided many genetic alterations, conferring susceptibility to multifactorial polygenic diseases, such as inflammatory bowel diseases. Yet, how specific genetic alterations functionally affect intestinal inflammation often remains elusive. It is noteworthy that a large overlap of genes involved in immune deficiencies with those conferring inflammatory bowel disease risk has been noted. This has provided new arguments for the debate on whether inflammatory bowel disease arises from either an excess or a deficiency in the immune system. In this review, we highlight the functional effect of an inflammatory bowel disease-risk allele, which cannot be deduced from genome-wide association studies data alone. As exemplified by the transcription factor signal transducer and activator of transcription 3 (STAT3), we show that a single gene can have a plethora of effects in various cell types of the gut. These effects may individually contribute to the restoration of intestinal homeostasis on the one hand or pave the way for excessive immunopathology on the other, as an inflammatory "rheo-STAT".
EVALuna2:1967

Immune mechanisms of depression in rheumatoid arthritis - Brock, James; Basu, Neil; Schlachetzki, Johannes C.M.; Schett, Georg; McInnes, Iain B.; Cavanagh, Jonathan (Nature Reviews Rheumatology, 2023)
Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression.
CRIS-Team Scopus Importer:2023-12-08

Immune response in COVID-19: what is next? - Li, Qing; Wang, Ying; Sun, Qiang; Knopf, Jasmin; Herrmann, Martin; Lin, Liangyu; Jiang, Jingting; Shao, Changshun; Li, Peishan; He, Xiaozhou; Hua, Fei; Niu, Zubiao; et al. (Cell Death and Differentiation, 2022)
The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future.
CRIS-Team WoS Importer:2022-06-03

Immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients receiving secukinumab: a literature review - Gisondi, Paolo; Simon, David; Alarcon, Ivette; Pournara, Effie; Puig, Lluís (Journal of Dermatological Treatment, 2023)
Purpose: There is a paucity of evidence on the impact of immune-mediated inflammatory disease (IMID) treatments on the immunogenicity of SARS-CoV-2 vaccination. The purpose of this literature review is to address the question of whether patients with IMIDs receiving secukinumab, a fully human anti–interleukin-17A monoclonal antibody, have an adequate immune response after SARS-CoV-2 vaccination. Materials and Methods: Clinical studies that evaluated the effect of secukinumab on immune responses in patients with IMIDs after SARS-CoV-2 vaccination were searched in publication databases, including Medline and Embase, until May 2022. Results: From the 53 articles identified, a total of 11 articles were included. Overall, the majority of the patients treated with secukinumab elicited an adequate immune response to SARS-CoV-2 vaccines. Patients receiving secukinumab for IMIDs developed cellular immune responses following vaccination with the BNT162b2 vaccine, and there were no significant differences in the overall humoral and cellular immune responses between patients and healthy individuals. The third dose of the BNT162b2 mRNA vaccine resulted in a positive antibody response in secukinumab-treated patients. Conclusion: The available data provide no evidence of impairment in immunological response to SARS-CoV-2 vaccines by secukinumab in patients with IMIDs.
CRIS-Team Scopus Importer:2023-02-10
Keywords: COVID-19; immune-mediated inflammatory diseases; SARS-CoV-2 vaccination; secukinumab

Immunizations with diverse sarbecovirus receptor-binding domains elicit SARS-CoV-2 neutralizing antibodies against a conserved site of vulnerability - Burnett, Deborah L.; Jackson, Katherine J.L.; Langley, David B.; Aggrawal, Anupria; Stella, Alberto Ospina; Johansen, Matt D.; Balachandran, Harikrishnan; Lenthall, Helen; Rouet, Romain; Walker, Gregory; Saunders, Bernadette M.; Singh, Mandeep; et al. (Immunity, 2021)
Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.
CRIS-Team Scopus Importer:2021-11-26
Keywords: antigenic variation; class 4 epitope site; cross-reactivity; epitope conservation; escape mutations; human antibodies; mouse model; neutralization; next generation vaccines; SARS-CoV-2; variants of concern

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis - Mayes, Maureen D.; Bossini-Castillo, Lara; Gorlova, Olga; Martin, Jose Ezequiel; Zhou, Xiaodong; Chen, Wei V.; Assassi, Shervin; Ying, Jun; Tan, Filemon K.; Arnett, Frank C.; Reveille, John D.; Guerra, Sandra; et al. (American Journal of Human Genetics, 2014)
In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.
EVALuna2:12882

Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1 - Seeling, Michaela; Pöhnl, Matthias; Kara, Sibel; Horstmann, Nathalie; Riemer, Carolina Daniela; Wöhner, Miriam; Liang, Chunguang; Brückner, Christin; Eiring, Patrick; Werner, Anja; Biburger, Markus; Altmann, Leon; et al. (Immunity, 2023)
Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.
CRIS-Team Scopus Importer:2023-05-12
Keywords: bone; Dectin-1; Fc-receptor; glycosylation; IgG; inflammation; osteoclast; rheumatoid arthritis

IMMUNOLOGICAL DIFFERENCES BETWEEN PSA PATIENTS WHO ARE TUMOR NECROSIS FACTOR INHIBITOR-NAIVE AND WHO HAVE INADEQUATE RESPONSE TO TUMOR NECROSIS FACTOR INHIBITORS - Siebert, S.; Coates, L.; Schett, Georg; Raychaudhuri, S. P.; Chen, W.; Gao, S.; Chakravarty, S. D.; Shawi, M.; Lavie, F.; Theander, E.; Neuhold, M.; Kollmeier, A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Immunology in Germany: 50th Anniversary of the German Society for Immunology (DGfI) - Giniewski, Agnes; Kalden, Joachim; Jäck, Hans-Martin (European Journal of Immunology, 2017)
EVALuna2:13648

Impact of clinical and psychological factors associated with depression in patients with rheumatoid arthritis: comparative study between Germany and Brazil - Morf, Harriet; da Rocha Castelar-Pinheiro, Geraldo; Vargas-Santos, Ana Beatriz; Baerwald, Christoph; Seifert, Olga (Clinical Rheumatology, 2020)
Objective: To investigate the prevalence of depressive symptoms and its association with clinical and psychological factors in patients with rheumatoid arthritis (RA) in Germany and in Brazil. Method: A convenience sample of 267 RA patients, 176 from Germany (age 62.4 ± 12.3 years) and 91 from Brazil (age 56.3 ± 12.6 years), was used in this cross-sectional study. The following questionnaires were used: Beck Depression Inventory (BDI), painDETECT test, Perceived Stress Questionnaire, fatigue questionnaire (FACIT), Health Assessment Questionnaire Disability Index (HAQ-DI), and the SF–36 questionnaires (Short-Form 36 Health Survey). Disease activity score (DAS 28-CRP) and visual analogue scale (VAS) for pain were also evaluated. Statistical analysis is based on comparison of means and proportions. Statistical significance for non-normal data was evaluated by non-parametrical tests. Results: Depressive symptoms were more prevalent in the Brazilian sample (44% vs 22.9%, p = 0.025). Compared to German patients, the Brazilian ones also experienced more pain (current pain status on VAS: 4.67 ± 3.4 vs 3.67 ± 2.31 respectively, p < 0.01), were physically more limited (1.89 ± 1.85 vs 1.01 ± 0.75, p = 0.012), and had higher C-reactive protein levels (7.78 ± 18.3 vs 5.82 ± 10.45, p = 0.028). Despite receiving a more intensive treatment, German patients presented similar disease activity when compared to Brazilian patients (DAS28-CRP: Brazil 3.4 ± 1.5 vs Germany 3.3 ± 1.3, p = 0.307). Conclusion: Depressive symptoms are frequent in RA patients from different countries and interact with psychological disorders and the experience of pain. They contribute negatively to their well-being suggesting the need for psychoeducational strategies. Key Points• New psychoeducational strategies for RA management.• Higher inflammation marker in rheumatoid arthritis patients is associated with depression.• Medical treatment in RA influences depressive symptoms.• Depressive symptoms are dependent on population group.• High disease activity is related to depression.
CRIS-Team Scopus Importer:2020-11-06
Keywords: Depressive symptoms; Psychoeducational strategies; Rheumatoid arthritis

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort - Simon, David; Tascilar, Koray; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, Johanna; Liphardt, Anna-Maria; Schoenau, Verena; et al. (Arthritis and Rheumatology, 2022)
Objective To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. Results In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). Conclusion IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.
CRIS-Team WoS Importer:2022-04-08

Impact of dietary vitamin D on immunoregulation and disease pathology in lupus-prone NZB/W F1 mice - Kraemer, Antoine N.; Schäfer, Anna Lena; Sprenger, Dalina T.L.; Sehnert, Bettina; Williams, Johanna P.; Luo, Aileen; Riechert, Laura; Al-Kayyal, Qusai; Dumortier, Hélène; Fauny, Jean Daniel; Winter, Zoltan; Heim, Kathrin; et al. (Frontiers in Immunology, 2022)
Vitamin D (VD) deficiency is a highly prevalent worldwide phenomenon and is extensively discussed as a risk factor for the development of systemic lupus erythematosus (SLE) and other immune-mediated diseases. In addition, it is now appreciated that VD possesses multiple immunomodulatory effects. This study aims to explore the impact of dietary VD intake on lupus manifestation and pathology in lupus-prone NZB/W F1 mice and identify the underlying immunological mechanisms modulated by VD. Here, we show that low VD intake accelerates lupus progression, reflected in reduced overall survival and an earlier onset of proteinuria, as well higher concentrations of anti-double-stranded DNA autoantibodies. This unfavorable effect gained statistical significance with additional low maternal VD intake during the prenatal period. Among examined immunological effects, we found that low VD intake consistently hampered the adoption of a regulatory phenotype in lymphocytes, significantly reducing both IL-10-expressing and regulatory CD4+ T cells. This goes along with a mildly decreased frequency of IL-10-expressing B cells. We did not observe consistent effects on the phenotype and function of innate immune cells, including cytokine production, costimulatory molecule expression, and phagocytic capacity. Hence, our study reveals that low VD intake promotes lupus pathology, likely via the deviation of adaptive immunity, and suggests that the correction of VD deficiency might not only exert beneficial functions by preventing osteoporosis but also serve as an important module in prophylaxis and as an add-on in the treatment of lupus and possibly other immune-mediated diseases. Further research is required to determine the most appropriate dosage, as too-high VD serum levels may also induce adverse effects, possibly also on lupus pathology.
CRIS-Team Scopus Importer:2022-12-16
Keywords: autoimmune; autoimmunity; choleacliferol; diet; lupus; mice; SLE; vitamin D

IMPACT OF IMMOBILIZATION ON SERUM LEVELS OF CARTILAGE OLIGOMERIC MATRIX PROTEIN AND IMPLICATIONS FOR CLINICAL PRACTICE IN MUSCULOSKELETAL DISORDERS - Liphardt, A. -M.; Bruggemann, G. -P.; Zaucke, Frank; Eckstein, F.; Bloch, W.; Mundermann, A.; Mester, J.; Schett, Georg; Rech, Jürgen; Niehoff, Anja (2016)
EVALuna2:13473

IMPACT OF METHOTREXATE ON DISEASE PATTERN IN ACTIVE PSORIATIC ARTHRITIS PATIENTS ELIGIBLE FOR A RANDOMIZED CLINICAL TRIAL WITH USTEKINUMAB: COMPARATIVE BASELINE DATA FROM MULTICENTRE INVESTIGATOR-INITIATED MUST TRIAL - Rossmanith, T.; Koehm, M.; Kiltz, U.; Rech, Jürgen; Burmester, G. R.; Kellner, H.; Bulczak-Schadendorf, A.; Foldenauer, A. C.; Burkhardt, H.; Behrens, F. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

IMPACT OF PRIMARY HAND OSTEOARTHRITIS ON MICROSTRUCTURE AND BIOMECHANICS IN FINGER JOINTS - Simon, David; Tascilar, Koray; Unbehend, Sara; Bayat, Sara; Meinderink, Timo; Berlin, Andreas; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

IMPACT OF SECUKINUMAB TREATMENT ON PSORIATIC ARTHRITIS PATIENTS WITH OR WITHOUT ENTHESITIS AT BASELINE: POOLED DATA FROM FUTURE 2 AND FUTURE 3 PHASE 3 STUDIES - Mcinnes, Iain B.; Wallman, Johan K.; Schett, Georg; Quebe-Fehling, Erhard; Rasouliyan, Lawrence; Pricop, Luminita; Fasth, Andreas E.; Gaillez, Corine (2019)
EVALuna2:213229

Impact of secukinumab treatment on psoriatic arthritis patients with or without enthesitis at baseline: pooled data from two phase 3 studies (FUTURE 2 and FUTURE 3) - Wallman, J. K.; Schett, Georg; Mcinnes, I. B.; Quebe-Fehling, E.; Rasouliyan, L.; Pricop, L.; Gaillez, C.; Fasth, A. E. (2018)
EVALuna2:35014

Impact of Swiprosin-1/Efhd2 on Adult Hippocampal Neurogenesis - Regensburger, Martin; Prots, Iryna; Reimer, Dorothea; Brachs, Sebastian; Loskarn, Sandra; Lie, Dieter Chichung; Mielenz, Dirk; Winner, Beate (Stem Cell Reports, 2018)
Swiprosin-1/Efhd2 (Efhd2) is highly expressed in the CNS during development and in the adult. EFHD2 is regulated by Ca2+ binding, stabilizes F-actin, and promotes neurite extension. Previous studies indicated a dysregulation of EFHD2 in human Alzheimer's disease brains. We hypothesized a detrimental effect of genetic ablation of Efhd2 on hippocampal integrity and specifically investigated adult hippocampal neurogenesis. Efhd2 was expressed throughout adult neuronal development and in mature neurons. We observed a severe reduction of the survival of adult newborn neurons in Efhd2 knockouts, starting at the early neuroblast stage. Spine formation and dendrite growth of newborn neurons were compromised in full Efhd2 knockouts, but not upon cell-autonomous Efhd2 deletion. Together with our finding of severe hippocampal tauopathy in Efhd2 knockout mice, these data connect Efhd2 to impaired synaptic plasticity as present in Alzheimer's disease and identify a role of Efhd2 in neuronal survival and synaptic integration in the adult hippocampus.
EVALuna2:34019

Impact of switching from mycophenolate mofetil to enteric-coated mycophenolate sodium on gastrointestinal side effects in patients with autoimmune disease: a Phase III, open-label, single-arm, multicenter study - Manger, Bernhard; Hiepe, Falk; Schneider, Matthias; Worm, Margitta; Wimmer, Peter; Paulus, Eva Maria; Schwarting, Andreas (Clinical and Experimental Gastroenterology, 2015)
The purpose of this study was to assess changes in gastrointestinal symptom severity in patients with autoimmune disease who were switched from mycophenolate mofetil to enteric-coated mycophenolate sodium (EC-MPS).In this national, explorative, single-arm study, 111 patients were enrolled and switched to equimolar EC-MPS at baseline. The primary endpoint was change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6-8 weeks of treatment (Visit 2). The optional follow-up visit was 6-12 weeks after completion of the study (Visit 2). Secondary endpoints were changes in GSRS subscale score; changes in gastrointestinal-related quality of life measured by the Gastrointestinal Quality of Life Index (GIQLI); and general health-related quality of life (HRQoL) measured by Psychological General Well-Being Index and assessment of overall treatment effect (OTE). Change was evaluated by paired t-tests.At Visit 2, the mean ± standard deviation GSRS total score improved from 2.28±1.13 to 2.02±0.93 points. The change (-0.28±0.92 points, P=0.002) was statistically significant. The change at the follow-up visit (-0.36±0.94 points, P=0.001) was statistically significant and more than the minimal clinical important difference. GSRS subscores showed statistically significant and clinically relevant improvement for abdominal pain (-0.51±1.2 points, P<0.001) and indigestion (-0.42±1.33 points, P=0.002). Overall GIQLI score showed significant improvement from baseline to Visit 2 (-5.8±18.6 points, P=0.002). Per OTE, improvement was reported in 44.1% and 34.2% patients as rated by physicians and patients, respectively. The majority of patients (55%) reported OTE-HRQoL as unchanged. Diarrhea and nausea were the commonly reported adverse events.Patients switched to EC-MPS experienced less gastrointestinal symptom burden and showed improvement in HRQoL.
EVALuna2:13166

Impact of Systemic Sclerosis-Associated Interstitial Lung Disease With and Without Pulmonary Hypertension on Survival: A Large Cohort Study of the German Network for Systemic Sclerosis - Moinzadeh, Pia; Bonella, Francesco; Oberste, Max; Weliwitage, Jithmi; Blank, Nobert; Riemekasten, Gabriela; Müller-Ladner, Ulf; Henes, Jörg; Siegert, Elise; Günther, Claudia; Kötter, Ina; Pfeiffer, Christiane; et al. (Chest, 2024)
Background: Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD with pulmonary hypertension [ILD-PH]). The aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis. Research Question: Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact? Study Design and Methods: Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival. Results: Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk. Interpretation: ILD is the most prevalent pulmonary involvement in SSc, whereas the combination of ILD and PH is associated with the most detrimental survival.
CRIS-Team Scopus Importer:2024-01-12
Keywords: ILD; ILD-PH; ILD-w/o-PH; interstitial lung disease; overall survival; PAH; PH; pulmonary hypertension; scleroderma; SSc; survival; systemic sclerosis

IMPACT OF TOLL-LIKE RECEPTOR 9 IN INFLAMMATORY ARTHRITIS AND OSTEOCLASTOGENESIS - Fischer, Anita; Boehm, Christina; Koenders, Marije; Van Den Berg, Wim; Rothe, Tobias; Krönke, Gerhard; Dudziak, Diana; Steiner, Guenter (2017)
EVALuna2:34374

Impaired Mitochondrial Transcription Factor A Expression Promotes Mitochondrial Damage to Drive Fibroblast Activation and Fibrosis in Systemic Sclerosis - Zhou, Xiang; Trinh, Minh Thuong; TRAN MANH, CUONG; Gießl, Andreas; Bergmann, Christina; Györfi, Andrea-Hermina; Schett, Georg; Distler, Jörg (Arthritis and Rheumatology, 2022)
Objective Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation. Methods TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor beta type I receptor (TGF beta R Iota). Results TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGF beta mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGF beta RI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation. Conclusion Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGF beta and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.
CRIS-Team WoS Importer:2022-04-15

Impaired periodontium and temporomandibular joints in TNF-α transgenic mice - Dobsak, Toni; Heimel, Patrick; Tangl, Stefan; Schwarze, Uwe Y.; Schett, Georg; Gruber, Reinhard (Journal of Clinical Periodontology, 2017)
TNF-? is a pathological factor causing the characteristic symptoms of periodontal disease and rheumatoid arthritis. In this study we describe the phenotypes of human tumor necrosis factor (TNF)-? transgenic mice (hTNFtg) with respect to their periodontium and the temporomandibular joint (TMJ).Periodontal structures, TMJ, and skull shape of hTNFtg mice and wild-type (WT) littermates were assessed by micro computed tomography, automated segmentation, geometric morphometrics and histologic ground sections.We show that hTNFtg mice have an eroded lamina dura and reduced periodontal ligament space compared to (WT) littermates. Transgenic mice further exhibit severe destruction of the TMJ. Geometric morphometrics revealed that hTNFtg mice have a more laterally positioned TMJ with a concomitantly enlarged zygomatic process. Mandibular and maxillary teeth occluded properly.Our findings suggest that chronic inflammation in hTNFtg mice causes destructive changes of the periodontium and the TMJ. This article is protected by copyright. All rights reserved.
EVALuna2:13443

Impaired physical function in patients with idiopathic inflammatory myopathies: results from the multicentre COVAD patient-reported e-survey - Yoshida, Akira; Kim, Minchul; Kuwana, Masataka; Ravichandran, Naveen; Makol, Ashima; Sen, Parikshit; Lilleker, James B.; Agarwal, Vishwesh; Kardes, Sinan; Day, Jessica; Milchert, Marcin; Joshi, Mrudula; et al. (Rheumatology, 2022)
Objectives The assessment of physical function is fundamental in the management of patients with idiopathic inflammatory myopathies (IIMs). We aimed to investigate the physical function of patients with IIMs compared with those with non-IIM autoimmune rheumatic diseases (AIRDs) utilizing Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) data obtained in the COVAD study, an international self-reported e-survey assessing the safety of COVID-19 vaccines in AIRDs. Methods Demographics, AIRD diagnosis, disease activity, and PROMIS PF short form-10a data were extracted from the COVAD database. PROMIS PF-10a scores were compared between disease categories and stratified by disease activity. Factors affecting PROMIS PF-10a scores other than disease activity were identified by multivariable regression analysis in patients with inactive disease. Results A total of 1057 IIM patients, 3635 non-IIM AIRD patients and 3981 healthy controls (HCs) responded to the COVAD e-survey from April to August 2021. Using a binomial regression model, the predicted mean of PROMIS PF-10a scores was significantly lower in IIM patients compared with non-IIM AIRD patients or HCs [36.3 (95% CI 35.5, 37.1) vs 41.3 (95% CI 40.2, 42.5) vs 46.2 (95% CI 45.8, 46.6), P < 0.001], irrespective of disease activity. The independent factors for lower PROMIS PF-10a scores in patients with inactive disease were older age, female, longer disease duration, and a diagnosis of inclusion body myositis or polymyositis. Conclusion Physical function is significantly impaired in IIMs compared with non-IIM AIRDs or HCs, even in patients with inactive disease. Our study highlights a critical need for better strategies to minimize functional disability in patients with IIMs.
CRIS-Team WoS Importer:2022-09-02

IMPAIRED PROMIS PHYSICAL FUNCTION IN IDIOPATHIC INFLAMMATORY MYOPATHY PATIENTS: RESULTS FROM THE MULTICENTER COVAD PATIENT REPORTED E-SURVEY - Yoshida, A.; Kim, M.; Kuwana, M.; R, N.; Lilleker, J. B.; Sen, P.; Agarwal, V.; Kardes, S.; Day, J.; Makol, A.; Milchert, M.; Gheita, T. A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Impaired T-bet-pSTAT1? and perforin-mediated immune responses in the tumoral region of lung adenocarcinoma - Andreev, Katerina; Trufa, Denis; Siegemund, Raphaela; Rieker, Ralf; Hartmann, Arndt; Schmidt, Joachim; Sirbu, Horia; Finotto, Susetta (British Journal of Cancer, 2015)
In spite of modern therapies for non-small-cell lung cancer (NSCLC), prognosis for many patients is still poor and survival rates are low. Immunotherapy is the possibility to improve the lung immune response surrounding the tumour. However, this approach requires detailed understanding of the local immune-responses of NSCLC patients.We analysed samples from three different regions within the lungs of NSCLC patients, whereas we distinguished between patients suffering from adenocarcinoma and squamous cell carcinoma. Expression of type 1 T helper (Th1)/type 1 cytotoxic (Tc1) factors was assessed by quantitative real-time PCR, western blot analyses or immunohistochemistry. Cytotoxic cell activity of CD8(+) T cells was determined via co-culture with autologous tumour cells and apoptosis assay.We found decreased levels of the transcription factor T-box expressed in T cells (T-bet or Tbx21) and of the downstream activated IFN-?-dependent pSTAT1? isoform in the lung tumour areas of patients with NSCLC as compared with tumour-free control regions. In these patients, reduced T-bet and pSTAT1? levels were found associated with increased immunosuppressive markers like cytotoxic T lymphocyte-associated protein 4, programmed cell death 1 and with a suppression of the Th1 cell cytokine production and Tc1 cell activity.These findings confirm a central role of T-bet in targeted immunotherapy for patients with NSCLC.
EVALuna2:6728

Implementing an automated monitoring process in a digital, longitudinal observational cohort study - Lindner, Lisa; Weiss, Anja; Reich, Andreas; Kindler, Siegfried; Behrens, Frank; Braun, Juergen; Listing, Joachim; Schett, Georg; Sieper, Joachim; Strangfeld, Anja; Regierer, Anne C. (Arthritis Research & Therapy, 2021)
Background Clinical data collection requires correct and complete data sets in order to perform correct statistical analysis and draw valid conclusions. While in randomized clinical trials much effort concentrates on data monitoring, this is rarely the case in observational studies- due to high numbers of cases and often-restricted resources. We have developed a valid and cost-effective monitoring tool, which can substantially contribute to an increased data quality in observational research. Methods An automated digital monitoring system for cohort studies developed by the German Rheumatism Research Centre (DRFZ) was tested within the disease register RABBIT-SpA, a longitudinal observational study including patients with axial spondyloarthritis and psoriatic arthritis. Physicians and patients complete electronic case report forms (eCRF) twice a year for up to 10 years. Automatic plausibility checks were implemented to verify all data after entry into the eCRF. To identify conflicts that cannot be found by this approach, all possible conflicts were compiled into a catalog. This "conflict catalog" was used to create queries, which are displayed as part of the eCRF. The proportion of queried eCRFs and responses were analyzed by descriptive methods. For the analysis of responses, the type of conflict was assigned to either a single conflict only (affecting individual items) or a conflict that required the entire eCRF to be queried. Results Data from 1883 patients was analyzed. A total of n = 3145 eCRFs submitted between baseline (T0) and T3 (12 months) had conflicts (40-64%). Fifty-six to 100% of the queries regarding eCRFs that were completely missing were answered. A mean of 1.4 to 2.4 single conflicts occurred per eCRF, of which 59-69% were answered. The most common missing values were CRP, ESR, Schober's test, data on systemic glucocorticoid therapy, and presence of enthesitis. Conclusion Providing high data quality in large observational cohort studies is a major challenge, which requires careful monitoring. An automated monitoring process was successfully implemented and well accepted by the study centers. Two thirds of the queries were answered with new data. While conventional manual monitoring is resource-intensive and may itself create new sources of errors, automated processes are a convenient way to augment data quality.
CRIS-Team WoS Importer:2021-07-23

Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia - Ries, Jutta; Agaimy, Abbas; Wehrhan, Falk; Baran, Christoph; Bolze, Stella; Danzer, Eva; Frey, Silke; Jantsch, Jonathan; Möst, Tobias; Büttner-Herold, Maike; Wickenhauser, Claudia; Kesting, Marco Rainer; et al. (Biomedicines, 2021)
Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (PE = 0.001; PS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.
CRIS-Team WoS Importer:2021-03-19

IMPORTANT ROLE OF CD11C+CELLSIN INFLAMMATORY ARTHRITIS - Puchner, Antonia; Simader, Elisabeth; Saferding, Victoria; Krönke, Gerhard; Pfeifle, René; Aletaha, Daniel; Smolen, Josef S.; Blueml, Stephan (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

IMPORTANT ROLE OF CD11C+DENDRITIC CELLS IN INFLAMMATORY ARTHRITIS - Puchner, A.; Saferding, V.; Pfeifle, René; Krönke, Gerhard; Redlich, K.; Smolen, J.; Blueml, S. (2018)
EVALuna2:35010

Important Role of CD11c+Dendtritic Cells in Inflammatory Arthritis - Puchner, Antonia; Saferding, Victoria; Bonelli, Michael; Leiss, Harald; Krönke, Gerhard; Pfeifle, René; Smolen, Josef S.; Redlich, Kurt; Blueml, Stephan (2017)
EVALuna2:35019

IMPORTANT ROLE OF DENDRITIC CELLS IN INFLAMMATORY ARTHRITIS - Simader, E.; Puchner, A.; Saferding, V.; Goncalves-Alves, E.; Pfeifle, René; Krönke, Gerhard; Smolen, J.; Blueml, S. (2019)
EVALuna2:213241

Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation - Wedmann, Rudolf; Onderka, Constantin; Wei, Shengwei; Szijarto, Istvan Andras; Miljkovic, Jan; Mitrovic, Aleksandra; Lange, Mike; Savitsky, Sergey; Yadav, Pramod Kumar; Torregrossa, Roberta; Harrer, Ellen G.; Harrer, Thomas; et al. (Chemical Science, 2016)
Hydrogen sulfide (H2S) has emerged as a signalling molecule capable of regulating several important physiological functions such as blood pressure, neurotransmission and inflammation. The mechanisms behind these effects are still largely elusive and oxidative posttranslational modification of cysteine residues (protein persulfidation or S-sulfhydration) has been proposed as the main pathway for H2S-induced biological and pharmacological effects. As a signalling mechanism, persulfidation has to be controlled. Using an improved tag-switch assay for persulfide detection we show here that protein persulfide levels are controlled by the thioredoxin system. Recombinant thioredoxin showed an almost 10-fold higher reactivity towards cysteine persulfide than towards cystine and readily cleaved protein persulfides as well. This reaction resulted in H2S release suggesting that thioredoxin could be an important regulator of H2S levels from persulfide pools. Inhibition of the thioredoxin system caused an increase in intracellular persulfides, highlighting thioredoxin as a major protein depersulfidase that controls H2S signalling. Finally, using plasma from HIV-1 patients that have higher circulatory levels of thioredoxin, we could prove depersulfidase role in vivo.
EVALuna2:13290

IMPROVING THE STUDY OF BONE DISEASES BY CORRELATIVE ELECTRON-, ION- AND X-RAY MICROSCOPY INCLUDING THEIR ANALYTICAL TECHNIQUES - Christiansen, S. H.; Kling, L.; Sarau, G.; Keding, R.; Pillatsch, L.; Michler, Johann; Milovanovic, P.; Busse, B.; Herrmann, M.; Schett, Georg (2018)
EVALuna2:34982

IMU-838, a Developmental DHODH Inhibitor in Phase II for Autoimmune Disease, Shows Anti-SARS-CoV-2 and Broad-Spectrum Antiviral Efficacy In Vitro - Hahn, Friedrich; Wangen, Christina; Häge, Sigrun; Peter, Antonia Sophia; Dobler, Gerhard; Hurst, Brett; Julander, Justin; Fuchs, Jonas; Ruzsics, Zsolt; Überla, Klaus; Jäck, Hans-Martin; Ptak, Roger; et al. (Viruses, 2020)
The ongoing pandemic spread of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) demands skillful strategies for novel drug development, drug repurposing and cotreatments, in particular focusing on existing candidates of host-directed antivirals (HDAs). The developmental drug IMU-838, currently being investigated in a phase 2b trial in patients suffering from autoimmune diseases, represents an inhibitor of human dihydroorotate dehydrogenase (DHODH) with a recently proven antiviral activity in vitro and in vivo. Here, we established an analysis system for assessing the antiviral potency of IMU-838 and DHODH-directed back-up drugs in cultured cell-based infection models. By the use of SARS-CoV-2-specific immunofluorescence, Western blot, in-cell ELISA, viral yield reduction and RT-qPCR methods, we demonstrated the following: (i) IMU-838 and back-ups show anti-SARS-CoV-2 activity at several levels of viral replication, i.e., protein production, double-strand RNA synthesis, and release of infectious virus; (ii) antiviral efficacy in Vero cells was demonstrated in a micromolar range (IMU-838 half-maximal effective concentration, EC50, of 7.6 ± 5.8 µM); (iii) anti-SARS-CoV-2 activity was distinct from cytotoxic effects (half-cytotoxic concentration, CC50, >100 µM); (iv) the drug in vitro potency was confirmed using several Vero lineages and human cells; (v) combination with remdesivir showed enhanced anti-SARS-CoV-2 activity; (vi) vidofludimus, the active determinant of IMU-838, exerted a broad-spectrum activity against a selection of major human pathogenic viruses. These findings strongly suggest that developmental DHODH inhibitors represent promising candidates for use as anti-SARS-CoV-2 therapeutics.
CRIS-Team Scopus Importer:2020-12-25
Keywords: antiviral therapy; dihydroorotate dehydrogenase (DHODH) inhibitors; host-directed antivirals (HDAs); IMU-838; SARS-CoV-2; vidofludimus

INACTIVATION OF ALDEHYDE DEHYDROGENASE 3A2 INHIBITS FIBROBLAST ACTIVATION AND TISSUE FIBROSIS - Xu, Xiaohan; Li, Y. N.; Chen, Chih-Wei; Trinh-Minh, T.; Schett, Georg; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Inactivation of autophagy ameliorates glucocorticoid-induced and ovariectomy-induced bone loss - Lin, Neng-Yu; Chen, Chih-Wei; Kagwiria, Rosebeth; Liang, Ruifang; Beyer, Christian; Distler, Alfiya; Luther, Julia; Engelke, Klaus; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2016)
Autophagy has recently been shown to regulate osteoclast activity and osteoclast differentiation. Here, we aim to investigate the impact of autophagy inhibition as a potential therapeutic approach for the treatment of osteoporosis in preclinical models.Systemic bone loss was induced in mice by glucocorticoids and by ovariectomy (OVX). Autophagy was targeted by conditional inactivation of autophagy-related gene 7 (Atg7) and by treatment with chloroquine (CQ). Bone density was evaluated by microCT. The role of autophagy on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The quantification of receptor activator of nuclear factor ? B ligand and osteoprotegerin proteins in cocultures was performed using ELISA whereas that of osteoclast and osteoblast differentiation markers was by qPCR.Selective deletion of Atg7 in monocytes from Atg7(fl/fl)_x_LysM-Cre mice mitigated glucocorticoid-induced and OVX-induced osteoclast differentiation and bone loss compared with Atg7(fl/fl) littermates. Pharmacological inhibition of autophagy by treatment with CQ suppressed glucocorticoid-induced osteoclastogenesis and protected mice from bone loss. Similarly, inactivation of autophagy shielded mice from OVX-induced bone loss. Inhibition of autophagy led to decreased osteoclast differentiation with lower expression of osteoclast markers such as NFATc1, tartrate-resistant acid phosphatase, OSCAR and cathepsin K and attenuated bone resorption in vitro. In contrast, osteoblast differentiation was not affected by inhibition of autophagy.Pharmacological or genetic inactivation of autophagy ameliorated glucocorticoid-induced and OVX-induced bone loss by inhibiting osteoclastogenesis. These findings may have direct translational implications for the treatment of osteoporosis, since inhibitors of autophagy such as CQ are already in clinical use.
EVALuna2:10103

Inactivation of evenness interrupted (EVI) reduces experimental fibrosis by combined inhibition of canonical and non-canonical Wnt signalling - Distler, Alfiya; Ziemer, Clara; Beyer, Christian; Lin, Neng-Yu; Chen, Chih-Wei; Palumbo-Zerr, Katrin; Dees, Clara; Weidemann, Alexander; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
Canonical as well as non-canonical Wnt signalling pathways have emerged as core pathways of fibrosis. Their profibrotic effects are mediated via distinct intracellular cascades independently of each other. Thus, inhibition of both pathways may have additive antifibrotic effects. Here, we knocked down evenness interrupted (EVI) to simultaneously target for the first time canonical and non-canonical Wnt signalling in experimental fibrosis.The antifibrotic effects of siRNA-mediated knockdown of EVI were evaluated in the mouse models of bleomycin-induced skin fibrosis and in fibrosis induced by adenoviral overexpression of a constitutively active TGF-? receptor I (AdTBRI).Knockdown of EVI decreased the release of canonical and non-canonical Wnt ligands by fibroblasts and reduced the activation of canonical and non-canonical Wnt cascades in experimental fibrosis with decreased accumulation of ?-catenin and phosphorylated JNK and cJun. Inactivation of EVI exerted potent antifibrotic effects and reduced dermal thickening, myofibroblast differentiation and accumulation of collagen in the mouse models of bleomycin-induced and AdTBR-induced fibrosis.Inhibition of Wnt secretion by knockdown of EVI inhibits canonical and non-canonical Wnt signalling and effectively reduces experimental fibrosis in different preclinical models. Inhibition of Wnt secretion may thus be an interesting approach for the treatment of fibrosis.
EVALuna2:3691

Inactivation of tankyrases reduces experimental fibrosis by inhibiting canonical Wnt signalling - Akhmetshina, Alfiya; Deloch, Lisa; Huang, Jingang; Dees, Clara; Lin, Neng-Yu; Palumbo-Zerr, Katrin; Beyer, Christian; Weidemann, Alexander; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2013)

Incidence and predictors of cutaneous manifestations during the early course of systemic sclerosis: a 10-year longitudinal study from the EUSTAR database - Wirz, Elina G.; Jaeger, Veronika K.; Allanore, Yannick; Riemekasten, Gabriela; Hachulla, Eric; Distler, Oliver; Airò, Paolo; Carreira, Patricia E.; Tikly, Mohammed; Vettori, Serena; Gurman, Alexandra Balbir; Damjanov, Nemanja; et al. (Annals of the Rheumatic Diseases, 2015)
To longitudinally map the onset and identify risk factors for skin sclerosis and digital ulcers (DUs) in patients with systemic sclerosis (SSc) from an early time point after the onset of Raynaud's phenomenon (RP) in the European Scleroderma Trials and Research (EUSTAR) cohort.695 patients with SSc with a baseline visit within 1 year after RP onset were followed in the prospective multinational EUSTAR database. During the 10-year observation period, cumulative probabilities of cutaneous lesions were assessed with the Kaplan-Meier method. Cox proportional hazards regression analysis was used to evaluate risk factors.The median modified Rodnan skin score (mRSS) peaked 1 year after RP onset, and was 15 points. The 1-year probability to develop an mRSS >=2 in at least one area of the arms and legs was 69% and 25%, respectively. Twenty-five per cent of patients developed diffuse cutaneous involvement in the first year after RP onset. This probability increased to 36% during the subsequent 2 years. Only 6% of patients developed diffuse cutaneous SSc thereafter. The probability to develop DUs increased to a maximum of 70% at the end of the 10-year observation. The main factors associated with diffuse cutaneous SSc were the presence of anti-RNA polymerase III autoantibodies, followed by antitopoisomerase autoantibodies and male sex. The main factor associated with incident DUs was the presence of antitopoisomerase autoantibodies.Early after RP onset, cutaneous manifestations exhibit rapid kinetics in SSc. This should be accounted for in clinical trials aiming to prevent skin worsening.
EVALuna2:13167

Incidences and Risk Factors of Organ Manifestations in the Early Course of Systemic Sclerosis: A Longitudinal EUSTAR Study - Jaeger, Veronika K.; Wirz, Elina G.; Allanore, Yannick; Rossbach, Philipp; Riemekasten, Gabriela; Hachulla, Eric; Distler, Oliver; Airo, Paolo; Carreira, Patricia E.; Gurman, Alexandra Balbir; Tikly, Mohammed; Vettori, Serena; et al. (PLoS ONE, 2016)
Systemic sclerosis (SSc) is a rare and clinically heterogeneous autoimmune disorder characterised by fibrosis and microvascular obliteration of the skin and internal organs. Organ involvement mostly manifests after a variable period of the onset of Raynaud's phenomenon (RP). We aimed to map the incidence and predictors of pulmonary, cardiac, gastrointestinal (GI) and renal involvement in the early course of SSc.In the EUSTAR cohort, patients with early SSc were identified as those who had a visit within the first year after RP onset. Incident SSc organ manifestations and their risk factors were assessed using Kaplan-Meier methods and Cox regression analysis.Of the 695 SSc patients who had a baseline visit within 1 year after RP onset, the incident non-RP manifestations (in order of frequency) were: skin sclerosis (75%) GI symptoms (71%), impaired diffusing capacity for monoxide<80% predicted (65%), DU (34%), cardiac involvement (32%), FVC<80% predicted (31%), increased PAPsys>40mmHg (14%), and renal crisis (3%). In the heart, incidence rates were highest for diastolic dysfunction, followed by conduction blocks and pericardial effusion. While the main baseline risk factor for a short timespan to develop FVC impairment was diffuse skin involvement, for PAPsys>40mmHg it was higher patient age. The main risk factors for incident cardiac manifestations were anti-topoisomerase autoantibody positivity and older age. Male sex, anti-RNA-polymerase-III positivity, and older age were risk factors associated with incident renal crisis.In SSc patients presenting early after RP onset, approximately half of all incident organ manifestations occur within 2 years and have a simultaneous rather than a sequential onset. These findings have implications for the design of new diagnostic and therapeutic strategies aimed to 'widen' the still very narrow 'window of opportunity'. They may also enable physicians to counsel and manage patients presenting early in the course of SSc more accurately.
EVALuna2:13354

Inclusion of optical marker position data in optimal control simulations of a rigid body model of the human hand - Heinrich, Simon; Coppers, Birte; Liphardt, Anna-Maria; Leyendecker, Sigrid (conference, ECCOMAS - 11th Thematic Conference on Multibody Dynamics, 2023)

Incomplete recovery of bone strength and trabecular microarchitecture at the distal tibia 1 year after return from long duration spaceflight - Gabel, Leigh; Liphardt, Anna-Maria; Hulme, Paul A.; Heer, Martina; Zwart, Sara R.; Sibonga, Jean D.; Smith, Scott M.; Boyd, Steven K. (Scientific Reports, 2022)
Determining the extent of bone recovery after prolonged spaceflight is important for understanding risks to astronaut long-term skeletal health. We examined bone strength, density, and microarchitecture in seventeen astronauts (14 males; mean 47 years) using high-resolution peripheral quantitative computed tomography (HR-pQCT; 61 μm). We imaged the tibia and radius before spaceflight, at return to Earth, and after 6- and 12-months recovery and assessed biomarkers of bone turnover and exercise. Twelve months after flight, group median tibia bone strength (F.Load), total, cortical, and trabecular bone mineral density (BMD), trabecular bone volume fraction and thickness remained − 0.9% to − 2.1% reduced compared with pre-flight (p ≤ 0.001). Astronauts on longer missions (> 6-months) had poorer bone recovery. For example, F.Load recovered by 12-months post-flight in astronauts on shorter (< 6-months; − 0.4% median deficit) but not longer (− 3.9%) missions. Similar disparities were noted for total, trabecular, and cortical BMD. Altogether, nine of 17 astronauts did not fully recover tibia total BMD after 12-months. Astronauts with incomplete recovery had higher biomarkers of bone turnover compared with astronauts whose bone recovered. Study findings suggest incomplete recovery of bone strength, density, and trabecular microarchitecture at the weight-bearing tibia, commensurate with a decade or more of terrestrial age-related bone loss.
CRIS-Team Scopus Importer:2022-07-15

Increased bone density and resistance to ovariectomy-induced bone loss in FoxP3-transgenic mice based on impaired osteoclast differentiation. - Zaiss, Mario; Sarter, Kerstin; Heß, Andreas; Engelke, Klaus; Boehm, Christina; Nimmerjahn, Falk; Voll, Reinhard; Schett, Georg; David, Jean-Pierre (Arthritis and Rheumatism, 2010)
OBJECTIVE Immune activation triggers bone loss. Activated T cells are the cellular link between immune activation and bone destruction. The aim of this study was to determine whether immune regulatory mechanisms, such as naturally occurring Treg cells, also extend their protective effects to bone homeostasis in vivo. METHODS Bone parameters in FoxP3-transgenic (Tg) mice were compared with those in their wild-type (WT) littermate controls. Ovariectomy was performed in FoxP3-Tg mice as a model of postmenopausal osteoporosis, and the bone parameters were analyzed. The bones of RAG-1(-/-) mice were analyzed following the adoptive transfer of isolated CD4+CD25+ T cells. CD4+CD25+ T cells and CD4+ T cells isolated from FoxP3-Tg mice and WT mice were cocultured with monocytes to determine their ability to suppress osteoclastogenesis in vitro. RESULTS FoxP3-Tg mice developed higher bone mass and were protected from ovariectomy-induced bone loss. The increase in bone mass was found to be the result of impaired osteoclast differentiation and bone resorption in vivo. Bone formation was not affected. Adoptive transfer of CD4+CD25+ T cells into T cell-deficient RAG-1(-/-) mice also increased the bone mass, indicating that Treg cells directly affect bone homeostasis without the need to engage other T cell lineages. CONCLUSION These data demonstrate that Treg cells can control bone resorption in vivo and can preserve bone mass during physiologic and pathologic bone remodeling.

Increased Cartilage Damage in Metacarpophalangeal Joints of ACPA Positive Rheumatoid Arthritis (RA) Patients Using T2 Mapping in 3 Tesla Magnetresonance Imaging (MRI) - Renner, Nina; Kleyer, Arnd; Simon, David; Krönke, Gerhard; Rech, Jürgen; Schett, Georg; Welsch, Goetz; Pachowsky, Milena (2017)
EVALuna2:33441

Increased expression of guanylate binding protein-1 in lesional skin of patients with cutaneous lupus erythematosus - Naschberger, Elisabeth; Wenzel, Joerg; Kretz, Cosima C.; Herrmann, Martin; Stürzl, Michael; Kuhn, Annegret (Experimental Dermatology, 2011)
The large GTPase human guanylate binding protein-1 (GBP-1) is a key mediator of angiostatic effects of inflammation and is induced by interferon (IFN)-α and IFN-γ in endothelial cells (ECs). The aim of this study was to investigate whether GBP-1 is a marker of skin lesions in patients with cutaneous lupus erythematosus (CLE). Western blotting revealed that GBP-1 was in vitro induced by IFN-α and -γ in primary keratinocytes obtained from healthy controls. Moreover, we found that this protein was expressed by keratinocytes and ECs in primary and ultraviolet (UV)-induced skin lesions from patients with various subtypes of CLE, when compared to non-lesional skin. No GBP-1 expression was noted in skin biopsy specimens 24 or 72h after UV irradiation prior to lesion formation in patients with CLE or in healthy control specimens with or without UV irradiation. Initial findings suggest that GBP-1 is not expressed in other skin diseases with different inflammatory aetiology, such as atopic dermatitis. We conclude that GBP-1 expression is closely associated with skin lesions in patients with CLE, suggesting a contribution of GBP-1 in the pathogenesis of this disease. © 2011 John Wiley & Sons A/S.
Created from Fastlane, Scopus look-up
Keywords: Guanylate binding protein; Inflammation; Interferon; Lupus erythematosus; Skin; UV light

Increased expression of the Th17-IL-6R/pSTAT3/BATF/Ror?T-axis in the tumoural region of adenocarcinoma as compared to squamous cell carcinoma of the lung - Balabko, Liubov; Andreev, Katerina; Burmann, Nadine; Schubert, Melanie; Mathews, Martina; Trufa, Denis; Reppert, Sarah; Rau, Tilmann; Schicht, Martin; Sirbu, Horia; Hartmann, Arndt; Finotto, Susetta (Scientific Reports, 2014)
Here we describe increased expression of IL6R in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to squamous cell lung carcinoma. Moreover, here we found increased IL6R in the tumour free part of the lung. By using a murine model of lung adenocarcinoma, we discovered that few lung tumour cells expressed IL-6R and CD4+CD25+Foxp-3+ T regulatory cells down-regulated IL-6R in the tumour bearing lungs. Downstream of IL-6R, the Th17 lineage-specification factors: Signal transducer and activator of transcription 3 (STAT3), Basic leucine zipper transcription factor, BATF and a protein encoded by the RORC in human (RAR-related orphan receptor C) (ROR?T), were also found induced in the tumoural region of lung tissue from patients affected by lung adenocarcinoma as compared to those carrying squamous cell carcinoma. Moreover, pSTAT3 protein was found phosphorylated and auto-phosphorylated in the tumoural region of patients with adeno cell carcinoma of the lung as compared to the tumoural region of patients with squamous cell carcinoma of the lung. Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.
EVALuna2:4416

INCREASED PLASMA LEVELS OF HSP90 ARE ASSOCIATED WITH MORE SEVERE LUNG AND SKIN INVOLVEMENT IN PATIENTS WITH SYSTEMIC SCLEROSIS - Storkanova, H.; Oreska, S.; Spiritovic, M.; Hermankova, B.; Bubova, K.; Komarc, M.; Pavelka, K.; Vencovsky, J.; Distler, Jörg; Senolt, L.; Becvar, R.; Tomcik, M. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Increased Plasma Levels of Hsp90 Are Associated with More Severe Organ Involvement in Patients with Systemic Sclerosis - Storkanova, Hana; Oreska, Sabina; Spiritovic, Maja; Pavelka, Karel; Vencovsky, Jiri; Distler, Jörg; Senolt, Ladislav; Becvar, Radim; Tomcik, Michal (2017)
EVALuna2:35021

Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: possible association with microvascular abnormalities and extent of fibrosis - Legany, Nora; Toldi, Gergely; Distler, Jörg; Beyer, Christian; Szalay, Balazs; Kovacs, Laszlo; Vasarhelyi, Barna; Balog, Attila (Clinical Chemistry and Laboratory Medicine, 2015)
Urokinase plasminogen activator receptor (uPAR) is a key component of the fibrinolytic system involved in extracellular matrix remodeling and angiogenesis. Novel animal models supported the key role of uPAR not only in fibrosis but also in systemic sclerosis (SSc)-related microvascular abnormalities. The aim of this study was to investigate plasma soluble uPAR (suPAR) levels in SSc, and their association with organ-specific involvement.suPAR concentrations were measured by ELISA in SSc patient (n=83) and in healthy controls (n=29). Simultaneously, CRP and ESR were assessed. Detailed clinical data including skin, lung, heart and microvascular characteristics were evaluated at sampling.suPAR values were higher in SSc patients than in controls. Subgroup analysis showed higher suPAR values in diffuse cutaneous- than in limited cutaneous SSc and correlated with anti-Scl-70+. suPAR levels also associated with pulmonary function test parameters of fibrosis, presence of microvascular lesions (e.g., Raynaud phenomenon, naifold capillaroscopic abnormalities and digital ulcers) and arthritis.Our data indicate that suPAR might be a valuable early diagnostic marker of SSc which also correlates with disease severity.
EVALuna2:13154

Increased risk of chronic fatigue and hair loss following COVID-19 in individuals with hypohidrotic ectodermal dysplasia - Hennig, Verena; Schuh, Wolfgang; Neubert, Antje; Mielenz, Dirk; Jäck, Hans-Martin; Schneider, Holm (Orphanet Journal of Rare Diseases, 2021)
Background: Hypohidrotic ectodermal dysplasia (HED) is a group of genodermatoses in which deficient ectodysplasin A signalling leads to maldevelopment of skin appendages, various eccrine glands, and teeth. Individuals with HED often have disrupted epithelial barriers and, therefore, were suspected to be more susceptible to coronavirus infection. Methods: 56 households with at least one member who had coronavirus disease of 2019 (COVID-19) were enrolled in a longitudinal study to compare the course of illness, immune responses, and long-term consequences of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection in HED patients (n = 15, age 9–52 years) and control subjects of the same age group (n = 149). Results: In 14 HED patients, mild or moderate typical COVID-19 symptoms were observed that lasted for 4–45 days. Fever during the first days sometimes required external cooling measures. The course of COVID-19 was similar to that in control subjects if patients developed antibodies blocking the SARS-CoV-2 spike protein. Five out of six HED patients with completely abrogated ectodysplasin A signalling (83%) suffered from chronic, in two cases very severe fatigue following COVID-19, while only 25% of HED patients with residual activity of this pathway and 21% of control subjects recovering from COVID-19 experienced postinfectious fatigue. Hair loss after COVID-19 was also more frequent among HED patients (64%) than in the control group (13%). Conclusions: HED appears to be associated with an increased risk of long-term consequences of a SARS-CoV-2 infection. Preventive vaccination against COVID-19 should be recommended for individuals affected by this rare genetic disorder.
CRIS-Team Scopus Importer:2021-09-17
Keywords: Chronic fatigue; COVID-19; Hair loss; Hypohidrotic ectodermal dysplasia; SARS-CoV-2

INCREASE OF CORTICAL MICRO-CHANNELS (COMICS) AS A NEW FEATURE OF STRUCTURAL DAMAGE IN PAIENTS WITH RHEUMATOID ARTHRITIS - Werner, David; Simon, David; Englbrecht, Matthias; Stemmler, F.; Berlin, Andreas; Haschka, J.; Renner, Nina; Buder, Thomas; Rech, Jürgen; Engelke, Klaus; Hueber, Axel; Schett, Georg; et al. (2017)
EVALuna2:34454