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.
EVALuna2:213221

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

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

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

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-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes - Raulien, Nora; Friedrich, Kathleen; Strobel, Sarah; Raps, Stefanie; Hecker, Friederike; Pierer, Matthias; Schilling, Erik; Lainka, Elke; Kallinich, Tilmann; Baumann, Sven; Fritz-Wallace, Katarina; Rolle-Kampczyk, Ulrike; et al. (Science Signaling, 2024)
Hypoxia and low glucose abundance often occur simultaneously at sites of inflammation. In monocytes and macrophages, glucose-oxygen deprivation stimulates the assembly of the NLRP3 inflammasome to generate the proinflammatory cytokine IL-1β. We found that concomitant glucose deprivation and hypoxia activated the NLRP3 inflammasome by constraining the function of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate kinase pathway. HMGCR is involved in the synthesis of geranylgeranyl pyrophosphate (GGPP), which is required for the prenylation and lipid membrane integration of proteins. Under glucose-oxygen deprivation, GGPP synthesis was decreased, leading to reduced prenylation of the small GTPase Rac1, increased binding of nonprenylated Rac1 to the scaffolding protein IQGAP1, and enhanced activation of the NLRP3 inflammasome. In response to restricted oxygen and glucose supply, patient monocytes with a compromised mevalonate pathway due to mevalonate kinase deficiency or Muckle-Wells syndrome released more IL-1β than did control monocytes. Thus, reduced GGPP synthesis due to inhibition of HMGCR under glucose-oxygen deprivation results in proinflammatory innate responses, which are normally kept in check by the prenylation of Rac1. We suggest that this mechanism is also active in inflammatory autoimmune conditions.
CRIS-Team Scopus Importer:2024-07-26

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

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

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

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

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 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

Harnessing the potential of CAR-T cell in lupus treatment: From theory to practice - Alsuliman, Tamim; Marjanovic, Zora; Rimar, Doron; Tarte, Karin; Avcin, Tadej; Hagen, Melanie; Schett, Georg; Farge, Dominique (Autoimmunity Reviews, 2024)
Systemic Lupus Erythematosus (SLE) is a rare, heterogeneous, potentially life-threatening autoimmune disease. Presence of kidney or other major organ (brain, heart or lung) involvement are predictors of poor outcome and in a subset of patients resistant to 1st or 2nd line conventional treatment. The 10-year mortality remains around 10–15 %. Chimeric Antigen Receptors (CAR) are molecules that allow to redirect the engineered immune cells towards specific target antigens and to simultaneously boost their activation. Following breakthrough results observed in the treatment of hematological malignancies, conventional CAR T-cell therapy has recently been applied to refractory SLE patients. Compared to the use of monoclonal antibodies, anti-CD19 CAR T-cells allow to achieve deeper depletion of autoreactive B cells, notably at site of inflamed tissues and lymphoid organs (i.e. lymph node), to suppress interferon signature and to restore the immune tolerance with the reemergence of naïve B-cells with a new repertoire. All clinical data reported in SLE patients so far showed that autologous anti-CD19 CAR T-cell treatment allowed impressive short- and longer-term resolution of lupus nephritis and other severe disease-related manifestations, without major toxicities and only mild cytokine-release syndrome. These clinical effects persisted after B-cell reconstitution and were associated with normalization of double-stranded DNA antibodies and complement levels in drug-free patients until three years after the procedure. Overall, these pioneering experiences show unique clinical and immunological response to CAR T-cell therapy in SLE, and the need for extended follow-up to determine its long-term efficacy.
CRIS-Team Scopus Importer:2024-11-22
Keywords: B and T lymphocytes; Cell and gene therapies; Chimeric antigen receptors (CAR); Immune tolerance; Plasma cells; Systemic lupus erythematosus

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

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 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 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 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 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

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

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 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

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

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; 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 TFG- and Autophagy-Regulated Proteins and Glycerophospholipids in B Cells - Steinmetz, Tobit; Thomas, Jana; Reimann, Lena; Himmelreich, Ann-Kathrin; Schulz, Sebastian; Golombek, Florian; Castiglione, Kathrin; Jäck, Hans-Martin; Brodesser, Susanne; Warscheid, Bettina; Mielenz, Dirk (Journal of Proteome Research, 2024)
Keywords: metabolism; lysosome; JCHAIN; immunoglobulin; TRK-fused gene; ribosome; plasma cell; phosphatidylglycerol; autophagy; BCL10; endoplasmic reticulum stress; autophagy flux; B cell

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

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; 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-1 Inhibitors in the Treatment of Familial Mediterranean Fever: Treatment Indications and Clinical Features in a Large Real-World Cohort - Yalcin-Mutlu, Melek; Icacan, Ozan Cemal; Yildirim, Fatih; Temiz, Selahattin Alp; Fagni, Filippo; Schett, Georg; Tascilar, Koray; Minopoulou, Ioanna; Burul, Gokhan; Bes, Cemal (Journal of Clinical Medicine, 2024)
Background: The accruing evidence about the efficacy of anti-IL-1 agents in Familial Mediterranean Fever (FMF) patients led to their widespread off-label use. Therefore, identifying precise indications and clinical characteristics of IL-1i-warranting patients are important. This study investigated the clinical characteristics and treatment indications of patients with FMF requiring interleukin 1 inhibition therapy (IL-1i). Methods: Hospital records of FMF patients attending a tertiary care center at the Department of Rheumatology, University of Health Sciences, Basaksehir Cam and Sakura City Hospital were retrospectively analyzed. Data on symptoms and disease manifestations, age of symptom onset, time to diagnosis, MEFV variants, type of treatment, and their indications were collected. Results: Between June 2020 and March 2023, 312 FMF patients were identified. The mean age at the onset of symptoms was 14.0, and the mean time to diagnosis was 11.9 years. In total, 87.1% of patients were receiving colchicine monotherapy, while the remaining 11.8% warranted IL-1i. Clinical symptoms and flare manifestations did not show a significant difference between the two groups. However, patients receiving IL-1i started having symptoms at younger age (11.5 vs. 14.5, p = 0.042) and time to diagnosis was longer (18.2 vs. 11.0, p < 0.01). M694V homozygosity was more common in patients receiving IL-1i. Indications for patients receiving IL-1i were colchicine resistance (8.0%), secondary amyloidosis (5.1%), and colchicine intolerance (2.2%). Conclusions: This study shows that a subset of FMF patients, particularly those with a more severe phenotype with an earlier disease onset and M694V homozygosity, require IL-1i treatment despite the overall good efficacy and tolerability of colchicine, primarily due to colchicine resistance, intolerance, or complications such as amyloidosis.
CRIS-Team Scopus Importer:2024-07-12
Keywords: amyloidosis; colchicine intolerance; colchicine resistance; familial mediterranean fever; interleukin-1 inhibitors

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-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

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

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 mass cytometry-based characterisation of fibroblast subsets and their cellular niches in systemic sclerosis - Rigau, Aleix Rius; Liang, Minrui; Devakumar, Veda; Neelagar, Ranjana; Matei, Alexandru Emil; Györfi, Andrea Hermina; Bergmann, Christina; Filla, Tim; Fedorchenko, Vladyslav; Schett, Georg; Distler, Jörg; Li, Yi Nan (Annals of the Rheumatic Diseases, 2024)
Objectives Transcriptomic data demonstrated that fibroblasts are heterogeneous with functionally diverse subpopulations. Although fibroblasts are key effector cells of fibrotic diseases such as systemic sclerosis (SSc), they have not yet been characterised spatially at the cellular level. Here, we aimed to investigate fibroblast subpopulations using imaging mass cytometry (IMC) as a proteomic-based, spatially resolved omics approach. Methods We applied IMC to deconvolute the heterogeneity of 49 969 cells including 6501 fibroblasts at the single-cell level, to analyse their spatial distribution and to characterise their cellular niches in skin sections of patients with SSc and controls in situ. Results We identified 13 different subpopulations of fibroblasts in SSc and control skin, the proportion increases in five fibroblast subpopulations (myofibroblasts, FAPhigh, S1PR+, Thy1+;ADAM12high;PU.1high and ADAM12+;GLI1+ fibroblasts) and decreases in three subpopulations (TFAMhigh, PI16+;FAP+ and Thy1+;ADAM12low fibroblasts). Several fibroblast subpopulations demonstrated spatial enrichment and altered cellular interactions in SSc. The proportion of S1PR+-fibroblast positively correlated with more extensive skin fibrosis, whereas high numbers of PI16+;FAP–-fibroblasts were associated with milder skin fibrosis. The frequency of aberrant cellular interaction between S1PR+ and ADAM12+;GLI1+-fibroblasts also positively associated with the extent of skin fibrosis in SSc. Conclusion Using IMC, we demonstrated profound changes in composition and localisation of the majority of fibroblast subpopulations in SSc skin. These findings may provide a rationale for specific targeting of deregulated fibroblast subpopulations in SSc. Quantification of S1PR+-fibroblast and PI16+;FAP–fibroblasts may offer potential for patient stratification according to severity of skin fibrosis.
CRIS-Team Scopus Importer:2025-02-04

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

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 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

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; 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

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; Schönau, 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 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 intravenous CT contrast agents on internal calibration techniques to determine trabecular BMD of the lumbar spine - Bartenschlager, Stefan; Cavallaro, Alexander Josef; Pogarell, Tobias; Uder, Michael; Chaudry, Oliver; Schett, Georg; Engelke, Klaus (European Journal of Radiology, 2025)
Objectives: Contrast agents are frequently administered in computed tomography (CT) scans used for opportunistic screening of osteoporosis. The objective of this study is to compare the impact of contrast-related bone mineral density (BMD) increase between phantom-based and internal CT calibration techniques. Materials and Methods: Phantom-based and internal CT calibration techniques were used to determine trabecular BMD in 93 existing clinical CT scans of the lumbar spine of 34 subjects, scanned before and after administration of contrast agents. BMD differences between native (Nat) and contrast-enhanced scans in arterial (Art) and portal venous (PV) phases were compared among calibration methods. Three pairs of internal reference materials were investigated: blood/air, subcutaneous adipose tissue (SAT)/air and muscle tissue/air. Results: Contrast agents increased CT values of blood in the aorta and the inferior vena cava in the Art phase by 210 ± 99HU and 47 ± 35HU, respectively and in the PV phase by 110 ± 49HU and 73 ± 28HU, respectively. Effects on CT values of muscle and SAT were < 5HU in the Art phase and < 10HU in the PV phase. BMD obtained with phantom calibration increased significantly (p < 0.01) in Art and PV phases by 8.6 ± 14.7 mg/cm3 and 14.4 ± 16.3 mg/cm3, respectively. If SAT/air or muscle/air were used as internal reference materials, increases in internally calibrated BMD (<12 mg/cm3 in AT phase and < 17 mg/cm3 in PV phase) did not significantly differ (p > 0.1 for Art and PV phases) from increases of phantom-calibrated BMD. Conclusions: Although CT values of internal reference materials increased following the administration of contrast, internal calibration was unable to mitigate the contrast-related BMD increases observed in phantom-based calibration.
CRIS-Team Scopus Importer:2025-01-31
Keywords: Computed tomography; Contrast agents; Internal BMD calibration; Lumbar spine; Osteoporosis; Opportunistic screening

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 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 the digital health application ViViRA on spinal mobility, physical function, quality of life and pain perception in spondyloarthritides patients: a randomized controlled trial - Palm von Alten Blaskowitz, Paloma Alexandra; Liphardt, Anna-Maria; Bouzas, Claudia; Coppers, Birte; Petit, Pascal; Vuillerme, Nicolas; Bundle, Vanessa; Rudolf, Sebastian; Knitza, Johannes; Raimondo, Maria Gabriella; Labinsky, Hannah; Hatscher, Lukas; et al. (Arthritis Research & Therapy, 2024)
Background: Spondyloarthritides (SpAs) are a group of common rheumatic diseases that often cause limited mobility and lower back pain. Physiotherapy is an integral part of treatment, but access to physiotherapy limits treatment success. Digital health applications (DHAs) enable home-based physiotherapy and could significantly improve access for SpAs patients. The aim is to investigate the clinical effects of the DHA ViViRA compared with those of standard physiotherapy. Methods: SpAs patients with chronic back pain were enrolled in a randomized controlled trial. The intervention group received ViViRA DHA, whereas the control group received standard physiotherapy. Pain (verbal rating scale, PAIN-Detect), quality of life (SF-36) and mobility (BASMI) were assessed at baseline and after 12 weeks as the primary outcomes. Results: Data from 59 participants (71.2% female, mean age 45.2 years) were analyzed. The intervention group showed a significant improvement in mobility (average BASMI score: baseline: 1.1 [range 0.7–1.5]; follow-up: 1.0 [range 0.5–1.4]; p = 0.05), whereas the control group showed a significant decrease in mobility (baseline: 1.5 [range 1.1–1.9]; follow-up: 1.8 [range 1.4–2.2]; p = 0.00). The intervention group demonstrated lower pain intensity (VRS pain level at week 3.5 ± 2.8) than did the control group (VRS pain level at week 4.5 ± 2) after 12 weeks. Conclusion: Our results highlight the efficacy of DHAs such as ViViRA in the treatment of lower back pain in SpAs patients. Compared with the current gold standard, physiotherapy, DHA use results in superior outcomes. However, further larger studies are needed to confirm these promising results. Trial registration: The study is registered in the German clinical trial registry (DRKS) under the following ID: DRKS00031254.
CRIS-Team Scopus Importer:2025-02-04
Keywords: DHA; Digital health application; E-Health; Mobility; Physical function; Psoriatic spondylitis; Spondyloarthritides; Spondyloarthropathy; ViViRA

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 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

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

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

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

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 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 human herpesvirus-8 neutralizing response during remission from Kaposi’s sarcoma - Byren, Hannah; Holzer, Angela; Müller, Alexander; Korn, Klaus; Backovic, Marija; Harrer, Ellen; Bergmann, Silke; Harrer, Thomas; Neipel, Frank (Journal of General Virology, 2024)
Human herpesvirus-8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, is a human oncogenic herpesvirus that is responsible for several diseases including Kaposi’s sarcoma (KS). KS prevalence varies dramatically, although emergence increases considerably with human immunodeficiency virus -1 (HIV-1) co-infection, making it one of the most common cancers in HIV-1 patients and sub-Saharan African men, even prior to the HIV-1 epidemic in Africa. Studies have shown that neutralizing antibodies exist in HHV-8-infected sera, which are most likely targeted to viral lytic surface glycoproteins, such as glycoprotein K8.1 (gpK8.1) and gHgL. Fifty-eight HHV-8-positive serum samples were tested for the levels of gpK8.1- and gHgL-binding antibodies and in vitro HHV-8-neutralizing capacity. Each sample was then categorized according to the disease status, which included asymptomatic infection, active KS and remission from KS, and the three measured parameters were compared between the disease groups. We show that neutralizing capacity in infected patient sera increases with remission of KS. Interestingly, antibodies targeting gpK8.1, but not gHgL, were also found to be increased during active disease and remission. Comparison of neutralizing capacity and antibody levels on an individual patient basis revealed that antibody levels, primarily targeting gHgL, are correlated with serum neutralizing response in sub-lingual Kaposi sarcoma (SLK) cells. Adsorption of gHgL or gpK8.1 antibodies from human sera removed the neutralizing response in SLK cells, although some non-specific removal of antibodies from the sera means that this result should be interpreted with caution. Taken collectively, these results suggest that glycoproteins, such as gHgL, are targets for neutralizing antibodies. Furthermore, our data imply that recovery from KS is associated with increased neutralizing capacity, suggesting that neutralizing antibodies may contribute to KS resolution. However, it is vital for further work to be completed in order to elucidate this relationship.
CRIS-Team Scopus Importer:2024-12-13
Keywords: gHgL; gpk8.1; HHV-8; Kaposi's sarcoma; neutralizing antibodies; remission

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

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

Independent development of inflammation and new bone formation in ankylosing spondylitis - Schett, Georg (Arthritis & Rheumatism-Arthritis Care & Research, 2012)
EVALuna2:13248

In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation - Jensen, Björn Erik Ole; Knops, Elena; Cords, Leon; Lübke, Nadine; Salgado, Maria; Busman-Sahay, Kathleen; Estes, Jacob D.; Huyveneers, Laura E.P.; Perdomo-Celis, Federico; Wittner, Melanie; Gálvez, Cristina; Mummert, Christiane; et al. (Nature Medicine, 2023)
Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.
CRIS-Team Scopus Importer:2023-03-03

Individually Tailored Predictions of Flare Probability for Rheumatoid Arthritis Patients on Biologic DMARDs Based on Machine Learning Stacking Meta-Classifier - Vodencarevic, Asmir; Simon, David; Hartmann, Fabian; Reiser, Michaela; Hueber, Axel; Tascilar, Koray; Kleyer, Arnd; Zimmermann-Rittereiser, Marcus; Schett, Georg (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Induction of apoptosis in circulating angiogenic cells by microparticles. - Distler, Jörg; Akhmetshina, Alfiya; Dees, Clara; Juengel, Astrid; Stürzl, Michael; Gay, Steffen; Pisetsky, David S.; Schett, Georg; Distler, Oliver (Arthritis & Rheumatism-Arthritis Care & Research, 2011)
Systemic sclerosis (SSc) is an autoimmune disease marked by aberrant activation and apoptosis of endothelial cells (ECs) and decreased numbers of circulating angiogenic cells (CACs). The aim of this study was to analyze whether microparticles might link pathologic activation and apoptosis of ECs with reduced numbers of CACs. Apoptosis was quantified by staining for annexin V and measurement of caspase 3 activity. The uptake of microparticles by CACs was determined by fluorescence-activated cell sorting and by fluorescence microscopy. Tritiated arachidonic acid and phosphatidylinositol 3,5-bisphosphate were used to demonstrate the transfer of arachidonic acid and highlight the role of the acid sphingomyelinase in microparticle-induced apoptosis of endothelial progenitor cells. Microparticles derived from activated or apoptotic ECs, the expression of which is strongly increased in the blood of patients with SSc, induce apoptosis in CACs in a dose-dependent manner. Microparticles, which are rich in arachidonic acid, are phagocytosed by CACs. Inhibition of phagocytosis prevents the induction of apoptosis in CACs by microparticles. Microparticles can transport arachidonic acid from ECs to CACs, and purified arachidonic acid mimics the proapoptotic effects of microparticles. Arachidonic acid activates the acid sphingomyelinase, and inhibition of acid sphingomyelinase prevents microparticle-induced apoptosis of CACs. Thus, phagocytosis of microparticles might stimulate the activity of acid sphingomyelinase and activate the apoptotic machinery. The induction of apoptosis in CACs by microparticles derived from ECs provides a novel link between aberrant activation or apoptosis of ECs, decreased numbers of CACs, and impaired formation of new vessels in SSc. OBJECTIVE METHODS RESULTS CONCLUSION

Induction of Ocular Surface Inflammation and Collection of Involved Tissues - Singh, Jeeshan; Shan, Xiaomei; Mahajan, Aparna; Herrmann, Martin; Schauer, Christine; Knopf, Jasmin; Munoz Becerra, Luis (Journal of Visualized Experiments, 2022)
Ocular surface diseases include a range of disorders that disturb the functions and structures of the cornea, conjunctiva, and the associated ocular surface gland network. Meibomian glands (MG) secrete lipids that create a covering layer that prevents the evaporation of the aqueous part of the tear film. Neutrophils and extracellular DNA traps populate MG and the ocular surface in a mouse model of allergic eye disease. Aggregated neutrophil extracellular traps (aggNETs) formulate a mesh-like matrix composed of extracellular chromatin that occludes MG outlets and conditions MG dysfunction. Here, a method for inducing ocular surface inflammation and MG dysfunction is presented. The procedures for collecting organs related to the ocular surface, such as the cornea, conjunctiva, and eyelids, are described in detail. Using established techniques for processing each organ, the major morphological and histopathological features of MG dysfunction are also shown. Ocular exudates offer the opportunity to assess the inflammatory state of the ocular surface. These procedures enable the investigation of topical and systemic anti-inflammatory interventions at the preclinical level.
CRIS-Team Scopus Importer:2022-09-02

Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. - Harre, Ulrike; Georgess, Dan; Bang, Holger; Bozec, Aline; Axmann, Roland; Ossipova, Elena; Jakobsson, Per-Johan; Baum, Wolfgang; Nimmerjahn, Falk; Szarka, Eszter; Sarmay, Gabriella; Krumbholz, Grit; et al. (Journal of Clinical Investigation, 2012)
Autoimmunity is complicated by bone loss. In human rheumatoid arthritis (RA), the most severe inflammatory joint disease, autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. We therefore hypothesized that these autoantibodies directly influence bone metabolism. Here, we found a strong and specific association between autoantibodies against citrullinated proteins and serum markers for osteoclast-mediated bone resorption in RA patients. Moreover, human osteoclasts expressed enzymes eliciting protein citrullination, and specific N-terminal citrullination of vimentin was induced during osteoclast differentiation. Affinity-purified human autoantibodies against mutated citrullinated vimentin (MCV) not only bound to osteoclast surfaces, but also led to robust induction of osteoclastogenesis and bone-resorptive activity. Adoptive transfer of purified human MCV autoantibodies into mice induced osteopenia and increased osteoclastogenesis. This effect was based on the inducible release of TNF-α from osteoclast precursors and the subsequent increase of osteoclast precursor cell numbers with enhanced expression of activation and growth factor receptors. Our data thus suggest that autoantibody formation in response to citrullinated vimentin directly induces bone loss, providing a link between the adaptive immune system and bon

Induction of proliferation and pro-inflammatory cytokine production in rheumatoid arthritis peripheral blood mononuclear cells by a 65 KDa chondrocyte membrane-specific, constitutive target autoantigen (CH65) - Alsalameh, Rayya J.; Casey, Rachael C.; Mollenhauer, Jürgen; Kalden, Joachim; Burmester, Gerd R.; Alsalameh, Saifeddin M. (International Journal of Rheumatic Diseases, 2013)
To analyze proliferation and pro-inflammatory cytokine production of peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis (RA) patients following stimulation with a purified chondrocyte membrane-associated autoantigen (CH65).CH65 was highly purified from bovine chondrocyte membranes by solubilization and ion exchange chromatography. PBMC of RA patients (n = 37; 28 seropositive, nine seronegative) and non-arthritic donors (n = 20) were isolated by ficoll centrifugation and used in cell proliferation assays. The levels of interleukin (IL)-1, tumo necrosis factor (TNF) and IL-6 produced after stimulation with CH65 were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using Mann-Whitney U-test and Spearman rank test and the software SPSS 13.0(TM) (SPSS Inc.; Chicago, IL, USA).Peripheral blood mononuclear cells exhibited a strong proliferative response to purified CH65 in approximately 50% of the RA patients (seropositive > seronegative), with a maximum reactivity at 0.15 or 0.30 ?g/mL culture medium. In contrast, PBMC from normal donors did not show a proliferative response to CH65 at any dose. The proliferative response in RA patients peaked at days 7-9 and returned to control levels at day 13, indicating an antigen-driven process. CH65-stimulated RA PBMC produced moderate to high amounts of IL-1, TNF and IL-6. This was comparable to the response after exposure to isolated whole chondrocyte membranes or purified collagen type II.These results demonstrate a significant cellular immune response to CH65 protein in RA patients. Given the high similarity between bovine and human CH65, the results suggest a pathogenetic involvement of this molecule as a cartilage-specific potential target autoantigen in RA.
EVALuna2:7644

INDUCTION OF SUSTAINED REMISSION IN EARLY INFLAMMATORY ARTHRITIS WITH THE COMBINATION OF INFLIXIMAB PLUS METHOTREXATE, METHOTREXATE ALONE OR PLACEBO: THE DINORA TRIAL - Stamm, T. A.; Machold, K.; Aletaha, D.; Alasti, F.; Lipsky, P.; Pisetsky, D.; Landewe, R.; Van Der Heijde, D.; Sepriano, A.; Aringer, M.; Boumpas, D.; Burmester, G.; et al. (2017)
EVALuna2:35030

Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial - Stamm, Tanja Alexandra; Machold, Klaus Peter; Aletaha, Daniel; Alasti, Farideh; Lipsky, Peter; Pisetsky, David; Landewe, Robert; Van Der Heijde, Desiree; Sepriano, Alexandre; Aringer, Martin; Boumpas, Dimitri; Burmester, Gerd; et al. (Arthritis Research & Therapy, 2018)
BACKGROUND: In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. METHODS: In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423 ), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0-2 tender joints, and an acute-phase reactant within the normal range. RESULTS: Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p < 0.05 over all three groups) was statistically significant for IFX + MTX vs PL (p < 0.05), but not for IFX + MTX vs MTX (p = 0.10), nor for MTX vs PL (p = 0.31). Remission was maintained during the second year on no therapy in 75% of the IFX + MTX patients compared with 20% of the MTX-only patients. CONCLUSIONS: These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone, suggesting that intensive treatment can alter the disease evolution. TRIAL REGISTRATION: The trial was registered at http://www.isrctn.com/ISRCTN21272423 on 4 October 2007 (date applied)/12 December 2007 (date assigned). The first patient was included on 24 October 2007.
EVALuna2:34478

INDUCTION OF TH2 CELLS AND EOSINOPHIL BY INFECTION WITH NIPPOSTRONGYLUS BRASILIENSIS PROTECTS AGAINST RHEUMATOID ARTHRITIS - Chen, Zhu; Oeser, Katharina; Baum, Wolfgang; Vöhringer, David; Schett, Georg; Bozec, Aline (2014)
EVALuna2:13204

Inefficient clearance of dying cells in patients with SLE: Anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players - Kruse, Kristin; Janko, Christina; Urbonaviciute, Vilma; Mierke, Claudia T.; Winkler, Thomas; Voll, Reinhard E.; Schett, Georg; Munoz, Luis E.; Herrmann, Martin (Apoptosis, 2010)
Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease. © 2010 Springer Science+Business Media, LLC.
Keywords: ANA; Biophysical features; Clearance; CRP; HMGB-1; MFG-E8; Phosphatidylserine; Plasma membrane

Infection with a small intestinal helminth, Heligmosomoides polygyrus bakeri, consistently alters microbial communities throughout the murine small and large intestine - Rapin, Alexis; Chuat, Audrey; Lebon, Luc; Zaiss, Mario M.; Marsland, Benjamin J.; Harris, Nicola L.; Zaiss, Mario (International Journal For Parasitology, 2020)
Increasing evidence suggests that intestinal helminth infection can alter intestinal microbial communities with important impacts on the mammalian host. However, all of the studies to date utilize different techniques to study the microbiome and access different sites of the intestine with little consistency noted between studies. In the present study, we set out to perform a comprehensive analysis of the impact of intestinal helminth infection on the mammalian intestinal bacterial microbiome. For this purpose, we investigated the impact of experimental infection using the natural murine small intestinal helminth, Heligmosomoides polygyrus bakeri and examined possible alterations in both the mucous and luminal bacterial communities along the entire small and large intestine. We also explored the impact of common experimental variables including the parasite batch and pre-infection microbiome, on the outcome of helminth-bacterial interactions. This work provides evidence that helminth infection reproducibly alters intestinal microbial communities, with an impact of infection noted along the entire length of the intestine. Although the exact nature of helminth-induced alterations to the intestinal microbiome differed depending on the microbiome community structure present prior to infection, changes extended well beyond the introduction of new bacterial species by the infecting larvae. Moreover, striking similarities between different experiments were noted, including the consistent outgrowth of a bacterium belonging to the Peptostreptococcaceae family throughout the intestine. (C) 2019 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.
CRIS-Team WoS Importer:2020-02-18

Inflammatory activation of the FcγR and IFNγR pathways co-influences the differentiation and activity of osteoclasts - Grötsch, Bettina; Schachtschabel, Elisabeth; Tripal, Philipp; Schmid, Benjamin; Smith, Ana-Suncana; Schett, Georg; Bozec, Aline (Frontiers in Immunology, 2022)
Osteoclasts are polykaryons formed by cell–cell fusion of highly motile progenitors of the myeloid lineage. Osteoclast activity can preserve skeletal strength and bone homeostasis. However, osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA). Fc receptors activated by IgG immune complexes (IC) can boost osteoclast differentiation and bone loss in the course of RA. In contrast, interferon (IFN) γ secreted by immune cells blocks osteoclast activation. Despite their hypothetical importance in the regulation of osteoclast differentiation in RA, the interconnection between the two pathways has not been described so far. Here, we show by total internal reflection fluorescence (TIRF) microscopy that FcγR3 and IFNγ receptor (IFNγR) locate at close vicinity to each other on the human osteoclast surface. Moreover, the average distance increases during the differentiation process. Interestingly, FcγR and IFNγR activation shapes the position of both receptors to each other. Surprisingly, the inhibitory action of IFNγ on in-vitro human osteoclast differentiation depends on the osteoclast differentiation stage. Indeed, IFNγR activation in early osteoclast precursors completely inhibits the formation of polynucleated osteoclasts, while in premature osteoclasts, it further enhanced their fusion. In addition, gene expression analyses showed that IFNγR activation on early precursor cells but not on premature osteoclasts could induce FcγR expression, suggesting a co-regulation of both receptors on human osteoclast precursors. Phosphokinase array data of precursor cells demonstrate that the observed divergence of IFNγR signaling is dependent on the mitogen−activated protein kinase (MAPK) downstream signaling pathway. Overall, our data indicate that FcγR and IFNγR signaling pathways co-influence the differentiation and activity of osteoclasts dependent on the differentiation state, which might reflect the different stages in RA.
CRIS-Team Scopus Importer:2022-10-07
Keywords: FcγR3; IFNγR; IFNγR signaling; ITAM signaling; Osteoclast; rheumatoid arthritis (RA)

Inflammatory Arthritis and Bone Metabolism Regulated by Type 2 Innate and Adaptive Immunity - Omata, Yasunori; Frech, Michael; Saito, Taku; Schett, Georg; Zaiss, Mario; Tanaka, Sakae (International Journal of Molecular Sciences, 2022)
While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current evidence of the regulatory role of type 2 immunity in arthritis and bone. Key type 2 cytokines, like interleukin (IL)-4 and IL-13, but also others such as IL-5, IL-9, IL-25, and IL-33, exert regulatory properties on arthritis, dampening inflammation and inducing resolution of joint swelling. Furthermore, these cytokines share anti-osteoclastogenic properties and thereby reduce bone resorption and protect bone. Cellular effectors of this action are both T cells (i.e., Th2 and Th9 cells), but also non-T cells, like type 2 innate lymphoid cells (ILC2). Key regulatory actions mediated by type 2 cytokines and immune cells on both inflammation as well as bone homeostasis are discussed.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Osteoclast; Rheumatoid arthritis; Type 2 immunity; Type 2 innate lymphoid cells

Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal helminth parasites - Sarter, Kerstin; Kulagin, Manuel; Schett, Georg; Harris, Nicola L.; Zaiss, Mario M. (Autoimmunity, 2017)
Infections with different helminth species have been observed to ameliorate a variety of chronic inflammatory diseases. Herein, we show that the natural murine helminth species, Heligmosomoides polygyrus bakeri (Hp) is capable of attenuating disease severity in two different inflammatory arthritis models. Furthermore, we show that excretory-secretory (ES) products from Hp directly suppress osteoclast differentiation in vitro. Taken together, these results demonstrate that helminth infections can dampen autoimmune diseases and highlight a previously unrecognized and important role for ES products, by directly impacting on bone destruction.
EVALuna2:13389

Inflammatory bone spur formation in psoriatic arthritis is different from bone spur formation in hand osteoarthritis - Finzel, Stephanie; Sahinbegovic, Enijad; Kocijan, Roland; Engelke, Klaus; Englbrecht, Matthias; Schett, Georg (Arthritis and Rheumatology, 2014)
To investigate the different patterns of bone spur formation in psoriatic arthritis (PsA) and hand osteoarthritis (OA), using high-resolution peripheral quantitative computed tomography (QCT).The study group comprised 70 subjects (25 patients with PsA, 25 patients with hand OA, and 20 healthy controls). The 2 patient groups were similar with regard to age and sex distribution and clinical involvement of the metacarpophalangeal (MCP) joints. All patients underwent high-resolution peripheral QCT scanning of the second, third, and fourth MCP joints of the dominantly affected hand. Demographic and disease-specific data were recorded, and the number, size, and distribution of bone spurs were assessed and compared between patients with PsA and patients with hand OA.The overall number and size of bone spurs were similar in patients with PsA and patients with hand OA. However, localization of lesions within individual joints was substantially different between patients with PsA and those with hand OA. In PsA, bone spurs dominated the radial sides of the joints (for the metacarpal head of the second joint, P < 0.001 versus hand OA; for the base of the second phalangeal joint, P < 0.001 versus hand OA), whereas the palmar and dorsal quadrants were the predilection sites in hand OA. Detailed anatomic analysis showed that bone spurs in the entheseal regions were prominent in patients with PsA but rare in patients with hand OA, and that bone spurs in patients with hand OA typically emerged at the cartilage-bone interphase and the joint margins.Our findings show that the overall number and size of bone spurs are similar in patients with PsA and patients with hand OA. Nonetheless, the anatomic sites of bone proliferation are different between these 2 groups of patients.
EVALuna2:10082

Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. - Seeling, Michaela; Hillenhoff, Ulrike; David, Jean Pierre; Schett, Georg; Tuckermann, Jan; Lux, Anja; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2013)
Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFα and receptor-ligand interactions, such as the receptor activator of nuclear factor-kappa B-receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)γ receptors (FcγR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcγRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcγR-expressing innate immune cells. To address this question, we studied FcγR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcγRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction.

Inflammatory osteolysis: a conspiracy against bone - Mbalaviele, Gabriel; Novack, Deborah V.; Schett, Georg; Teitelbaum, Steven L. (Journal of Clinical Investigation, 2017)
There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of inflammatory cytokines on osteoclast formation and function was among the most important discoveries advancing the treatment of focal osteolysis, leading to development of therapeutic agents that either directly block the bone-resorptive cell or do so indirectly via cytokine arrest. Despite these advances, a substantial number of patients with inflammatory arthritis remain resistant to current therapies, and even effective anti-inflammatory drugs frequently do not repair damaged bone. Thus, insights into events such as those impacted by inflammasomes, which signal through cytokine-dependent and -independent mechanisms, are needed to optimize treatment of inflammatory osteolysis.
EVALuna2:13420

Infliximab therapy of relapsing tracheal stenosis in a pediatric patient with granulomatosis with polyangiitis: a case report - Schnell, Alexander; Ruppel, Renate; Tremel, Christina; Galiano, Matthias; Meßbacher, Maria-Elena; Krickau, Tobias (Journal of Medical Case Reports, 2022)
Background: Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases. Case presentation: We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters. Conclusions: The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Children; Granulomatosis with polyangiitis; TNF-α inhibitor; Tracheal stenosis

Influence of Antisynthetase Antibodies Specificities on Antisynthetase Syndrome Clinical Spectrum Time Course - Cavagna, Lorenzo; Trallero-Araguas, Ernesto; Meloni, Federica; Cavazzana, Ilaria; Rojas-Serrano, Jorge; Feist, Eugen; Zanframundo, Giovanni; Morandi, Valentina; Meyer, Alain; Pereira Da Silva, Jose Antonio; Matos Costa, Carlo Jorge; Molberg, Oyvind; et al. (Journal of Clinical Medicine, 2019)
Antisynthetase syndrome (ASSD) is a rare clinical condition that is characterized by the occurrence of a classic clinical triad, encompassing myositis, arthritis, and interstitial lung disease (ILD), along with specific autoantibodies that are addressed to different aminoacyl tRNA synthetases (ARS). Until now, it has been unknown whether the presence of a different ARS might affect the clinical presentation, evolution, and outcome of ASSD. In this study, we retrospectively recorded the time of onset, characteristics, clustering of triad findings, and survival of 828 ASSD patients (593 anti-Jo1, 95 anti-PL7, 84 anti-PL12, 38 anti-EJ, and 18 anti-OJ), referring to AENEAS (American and European NEtwork of Antisynthetase Syndrome) collaborative group's cohort. Comparisons were performed first between all ARS cases and then, in the case of significance, while using anti-Jo1 positive patients as the reference group. The characteristics of triad findings were similar and the onset mainly began with a single triad finding in all groups despite some differences in overall prevalence. The "ex-novo" occurrence of triad findings was only reduced in the anti-PL12-positive cohort, however, it occurred in a clinically relevant percentage of patients (30%). Moreover, survival was not influenced by the underlying anti-aminoacyl tRNA synthetase antibodies' positivity, which confirmed that antisynthetase syndrome is a heterogeneous condition and that antibody specificity only partially influences the clinical presentation and evolution of this condition.
CRIS-Team WoS Importer:2020-01-03

Influence of antiTNF-alpha antibody treatment on fracture healing under chronic inflammation - Timmen, Melanie; Hidding, Heriburg; Wieskoetter, Britta; Baum, Wolfgang; Pap, Thomas; Raschke, Michael J.; Schett, Georg; Zwerina, Jochen; Stange, Richard (BMC Musculoskeletal Disorders, 2014)
The overexpression of tumor necrosis factor (TNF)-? leads to systemic as well as local loss of bone and cartilage and is also an important regulator during fracture healing. In this study, we investigate how TNF-? inhibition using a targeted monoclonal antibody affects fracture healing in a TNF-? driven animal model of human rheumatoid arthritis (RA) and elucidate the question whether enduring the anti TNF-? therapy after trauma is beneficial or not.A standardized femur fracture was applied to wild type and human TNF-? transgenic mice (hTNFtg mice), which develop an RA-like chronic polyarthritis. hTNFtg animals were treated with anti-TNF antibody (Infliximab) during the fracture repair. Untreated animals served as controls. Fracture healing was evaluated after 14 and 28 days of treatment by clinical assessment, biomechanical testing and histomorphometry.High levels of TNF-? influence fracture healing negatively, lead to reduced cartilage and more soft tissue in the callus as well as decreased biomechanical bone stability. Blocking TNF-? in hTNFtg mice lead to similar biomechanical and histomorphometrical properties as in wild type.High levels of TNF-? during chronic inflammation have a negative impact on fracture healing. Our data suggest that TNF-? inhibition by an anti-TNF antibody does not interfere with fracture healing.
EVALuna2:12972

INFLUENCE OF B-CATENIN ON THE PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS AND THE DEVELOPMENT OF CARDIAC ALLOGRAFT VASCULOPATHY IN MICE - Heim, Christian; Kuckhahn, Annika; Ramsperger-Gleixner, Martina; Distler, Jörg; Spriewald, Bernd M.; Weyand, Michael; Ensminger, Stephan M. (TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2021-03-05

INFLUENCE OF SEROTONIN (5-HT) RECEPTOR TYPE 2 ANTAGONISTS ON THE DEVELOPMENT OF TRANSPLANT VASCULOPATHY IN A MODEL OF MURINE AORTIC TRANSPLANTATION - Gocht, A.; Distler, Jörg; Ensminger, S.; Spriewald, B.; Ramsperger-Gleixner, Martina; Weyand, Michael; Heim, Christian (2016)
EVALuna2:35054

Influence of TYK2 in systemic sclerosis susceptibility: a new locus in the IL-12 pathway - Lopez-Isac, Elena; Campillo-Davo, Diana; Bossini-Castillo, Lara; Guerra, Sandra G.; Assassi, Shervin; Pilar Simeon, Carmen; Carreira, Patricia; Ortego-Centeno, Norberto; Garcia De La Pena, Paloma; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; et al. (Annals of the Rheumatic Diseases, 2016)
TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc.This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method.Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants.We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology.
EVALuna2:13153

Inhibited Arginase-1 Expression by Fra-1 in Myeloid Cells Enhance Rheumatoid Arthritis Inflammation - Hannemann, Nicole; Schnelzer, A.; Jordan, J.; Eberhardt, Martin; Schleicher, Ulrike; Uebe, Steffen; Ekici, Arif Bülent; Reid, Stephen; Sonnewald, Sophia; Bäuerle, Tobias; Bogdan, Christian; Vera, Julio; et al. (2017)
EVALuna2:33310

Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis - Avouac, Jerome; Palumbo, Katrin; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Horn, Angelika; Maurer, Britta; Akhmetshina, Alfiya; Beyer, Christian; Sadowski, Anika; Schneider, Holm; Shiozawa, Shunichi; et al. (Arthritis and Rheumatism, 2012)
Objective To investigate whether c-Jun and c-Fos contribute to the pathologic activation of fibroblasts in systemic sclerosis (SSc) and to evaluate the antifibrotic potential of selective activator protein 1 (AP-1) inhibition. Methods Expression of c-Jun and c-Fos was determined by real-time polymerase chain reaction (PCR) and immunohistochemical analysis. Fibroblasts were stimulated with transforming growth factor β (TGFβ) and incubated with T-5224, a small-molecule inhibitor of AP-1, or were transfected with small interfering RNA (siRNA) duplexes against c-Jun and c-Fos. Collagen synthesis was quantified by real-time PCR and hydroxyproline assay. Differentiation of resting fibroblasts into myofibroblasts was assessed by staining for α-smooth muscle actin and stress fibers. The antifibrotic potential of T-5224 was evaluated in mouse models of dermal fibrosis induced by bleomycin or by adenoviral overexpression of a constitutively active TGFβ receptor type I. Results Up-regulation of c-Jun and c-Fos was detected in mouse models of SSc and in the skin and dermal fibroblasts of patients with SSc. Stimulation of healthy fibroblasts with TGFβ induced the expression of c-Jun and c-Fos. Treatment with T-5224 or nucleofection with siRNA directed against c-Jun and c-Fos abrogated the profibrotic effects of TGFβ. T-5224 decreased the release of collagen selectively in SSc fibroblasts. T-5224 was well tolerated and prevented dermal fibrosis induced by bleomycin or by adenoviral activation of TGFβ signaling. Conclusion AP-1 is up-regulated in a TGFβ-dependent manner in SSc. The selective AP-1 inhibitor T-5224 reduced collagen synthesis selectively in SSc fibroblasts and efficiently prevented the development of experimental dermal fibrosis. Thus, AP-1 might be a promising new molecular target for the treatment of SSc. Copyright © 2012 by the American College of Rheumatology.
CRIS-Team Scopus Importer:2020-07-01

INHIBITION OF ARGINASE-1 EXPRESSION BY THE TRANSCRIPTION FACTOR FRA-1 IN MACROPHAGES EXACERBATES RHEUMATOID ARTHRITIS INFLAMMATION - Hannemann, Nicole; Cao, Shan; Schnelzer, A.; Jordan, J.; Eberhardt, Martin; Schleicher, Ulrike; Uebe, Steffen; Ekici, Arif Bülent; Rech, Jürgen; Bäuerle, Tobias; Bogdan, Christian; Vera, Julio; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-05-17

Inhibition of bone remodeling in young mice by bisphosphonate displaces the plasma cell niche into the spleen - Teufel, Stefan; Groetsch, Bettina; Luther, Julia; Derer, Anja; Schinke, Thorsten; Amling, Michael; Schett, Georg; Mielenz, Dirk; David, Jean-Pierre (Journal of Immunology, 2014)
The bone marrow provides niches for early B cell differentiation and long-lived plasma cells. Therefore, it has been hypothesized that perturbing bone homeostasis might impact B cell function and Ab production. This hypothesis is highly relevant for patients receiving long-term treatment with antiresorptive drugs. We therefore analyzed the humoral immune response of mice chronically treated with ibandronate, a commonly used bisphosphonate. We confirmed the increased bone mass caused by inhibition of osteoclast activity and also the strongly reduced bone formation because of decreased osteoblast numbers in response to ibandronate. Thus, bisphosphonate drastically inhibited bone remodeling. When ibandronate was injected into mice after a primary immunization to mimic common antiosteoporotic treatments, the generation of the various B cell populations, the response to booster immunization, and the generation of plasma cells were surprisingly normal. Mice also responded normally to immunization when ibandronate was applied to naive mice. However, there, ibandronate shunted the homing of bone marrow plasma cells. Interestingly, ibandronate reduced the numbers of megakaryocytes, a known component of the bone marrow plasma cell niche. In line with normal Ab responses, increased plasma cell populations associated with increased megakaryocyte numbers were then observed in the spleens of the ibandronate-treated mice. Thus, although inhibition of bone remodeling disturbed the bone marrow plasma cell niche, a compensatory niche may have been created by relocating the megakaryocytes into the spleen, thereby allowing normal B cell responses. Therefore, megakaryocytes may act as a key regulator of plasma cell niche plasticity.
EVALuna2:12971

Inhibition of casein kinase II reduces TGF? induced fibroblast activation and ameliorates experimental fibrosis - Zhang, Yun; Dees, Clara; Beyer, Christian; Lin, Neng-Yu; Distler, Alfiya; Zerr, Pawel; Palumbo, Katrin; Susok, Laura; Kreuter, Alexander; Distler, Oliver; Schen, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2015)
Casein kinase II (CK2) is a constitutively active serine/threonine protein kinase that plays a key role in cellular transformation and tumorigenesis. The purpose of the study was to characterise whether CK2 contributes to the pathologic activation of fibroblasts in patients with SSc and to evaluate the antifibrotic potential of CK2 inhibition.Activation of CK2, JAK2 and STAT3 in human skin and in experimental fibrosis was analysed by immunohistochemistry. CK2 signalling was inhibited by the selective CK2 inhibitor 4, 5, 6, 7-Tetrabromobenzotriazole (TBB). The mouse models of bleomycin-induced and TGF? receptor I (TBR)-induced dermal fibrosis were used to evaluate the antifibrotic potential of specific CK2 inhibition in vivo.Increased expression of CK2 was detected in skin fibroblasts of SSc patients. Inhibition of CK2 by TBB abrogated the TGF?-induced activation of JAK2/STAT3 signalling and prevented the stimulatory effects of TGF? on collagen release and myofibroblasts differentiation in cultured fibroblasts. Inhibition of CK2 prevented bleomycin-induced and TBR-induced skin fibrosis with decreased dermal thickening, lower myofibroblast counts and reduced accumulation of collagen. Treatment with TBB also induced regression of pre-established fibrosis. The antifibrotic effects of TBB were accompanied by reduced activation of JAK2/STAT3 signalling in vivo.We provide evidence that CK2 is activated in SSc and contributes to fibroblast activation by regulating JAK2/STAT3 signalling. Inhibition of CK2 reduced the pro-fibrotic effects of TGF? and inhibited experimental fibrosis. Targeting of CK2 may thus be a novel therapeutic approach for SSc and other fibrotic diseases.
EVALuna2:12859

Inhibition of Hedgehog Acyltransferase Alleviates the Profibrotic Effects of Transforming Growth Factor beta in Systemic Sclerosis - Liang, Ruifang; Kagwiria, Rosebeth; Dees, Clara; Zhang, Yun; Distler, Oliver; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33436

Inhibition of Hsp90 counteracts the established experimental dermal fibrosis induced by bleomycin - Štorkánová, Hana; Štorkánová, Lenka; Navrátilová, Adéla; Bečvář, Viktor; Hulejová, Hana; Oreská, Sabína; Heřmánková, Barbora; Špiritović, Maja; Bečvář, Radim; Pavelka, Karel; Vencovský, Jiří; Distler, Jörg; et al. (Biomedicines, 2021)
Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Established dermal fibrosis; Heat shock protein 90; Systemic sclerosis; Treatment

INHIBITION OF HSP90 REDUCES PROGRESSION OF DERMAL FIBROSIS AND INDUCES REGRESSION OF ESTABLISHED EXPERIMENTAL DERMAL FIBROSIS INDUCED BY BLEOMYCIN - Storkanova, H.; Storkanova, L.; Oreska, S.; Spiritovic, M.; Hermankova, B.; Becvar, R.; Pavelka, K.; Vencovsky, J.; Distler, Jörg; Senolt, L.; Tomcik, M. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

INHIBITION OF NOTCH1 PROMOTES HEDGEHOG SIGNALING IN A HES1-DEPENDENT MANNER AND EXACERBATES EXPERIMENTAL OSTEOARTHRITIS - Lin, N. Y.; Distler, A.; Beyer, Christian; Philipi-Schobinger, A.; Stock, Michael; Niemeier, A.; Dell'Accio, F.; Schett, Georg; Distler, Jörg (2016)
EVALuna2:13490

Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis - Lin, Neng-Yu; Distler, Alfiya; Beyer, Christian; Philipi-Schöbinger, Ariella; Breda, Silvia; Dees, Clara; Stock, Michael; Tomcik, Michal; Niemeier, Andreas; Dell'Accio, Francesco; Gelse, Kolja; Mattson, Mark P; et al. (Annals of the Rheumatic Diseases, 2016)
Notch ligands and receptors have recently been shown to be differentially expressed in osteoarthritis (OA). We aim to further elucidate the functional role of Notch signalling in OA using Notch1 antisense transgenic (Notch1 AS) mice.Notch and hedgehog signalling were analysed by real-time PCR and immunohistochemistry. Notch-1 AS mice were employed as a model of impaired Notch signalling in vivo. Experimental OA was induced by destabilisation of the medial meniscus (DMM). The extent of cartilage destruction and osteophyte formation was analysed by safranin-O staining with subsequent assessment of the Osteoarthritis Research Society International (OARSI) and Mankin scores and µCT scanning. Collagen X staining was used as a marker of chondrocyte hypertrophy. The role of hairy/enhancer of split 1 (Hes-1) was investigated with knockdown and overexpression experiments.Notch signalling was activated in human and murine OA with increased expression of Jagged1, Notch-1, accumulation of the Notch intracellular domain 1 and increased transcription of Hes-1. Notch1 AS mice showed exacerbated OA with increases in OARSI scores, osteophyte formation, increased subchondral bone plate density, collagen X and osteocalcin expression and elevated levels of Epas1 and ADAM-TS5 mRNA. Inhibition of the Notch pathway induced activation of hedgehog signalling with induction of Gli-1 and Gli-2 and increased transcription of hedgehog target genes. The regulatory effects of Notch signalling on Gli-expression were mimicked by Hes-1.Inhibition of Notch signalling activates hedgehog signalling, enhances chondrocyte hypertrophy and exacerbates experimental OA including osteophyte formation. These data suggest that the activation of the Notch pathway may limit aberrant hedgehog signalling in OA.
EVALuna2:13184

Inhibition of Nuclear Receptor Coactivator 3 Attenuates Fibrosis in Murine Models of Systemic Sclerosis - Pötter, Sebastian; Dees, Clara; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2018)
EVALuna2:34967

Inhibition of Osteoarthritis by Adipose-Derived Stromal Cells Overexpressing Fra-1 in Mice - Schwabe, Kay; Garcia, Mireia; Ubieta, Kenia; Hannemann, Nicole; Herbort, Bettina; Luther, Julia; Noel, Daniele; Jorgensen, Christian; Casteilla, Louis; David, Jean-Pierre; Stock, Michael; Herrmann, Martin; et al. (Arthritis and Rheumatology, 2016)
To determine whether overexpression of the activator protein 1 (AP-1) transcription factor Fra-1 in adipose-derived stromal cells (ADSCs) is an effective treatment of collagenase-induced osteoarthritis (OA).OA was induced by injection of collagenase into the knee joints of male C57BL/6 mice. ADSCs were isolated from the inguinal fat pads of 8-week-old wild-type or Fra-1-transgenic mice and injected into the knee joints of mice with collagenase-induced OA 7 days after OA induction. Histologic analyses of cartilage destruction and chondrocyte cell death were performed. Adipogenic differentiation capacity was evaluated, gene expression was analyzed, and cytokine profiling was performed in stromal vascular fractions (SVFs) and ADSCs.OA-related cartilage destruction and chondrocyte cell death were significantly reduced in mouse knee joints treated with ADSCs from Fra-1-transgenic mice compared to mouse knee joints treated with ADSCs from wild-type mice. This effect did not result from the higher number of adipogenic progenitors observed in SVFs from Fra-1-transgenic compared to wild-type mouse fat pads, since injection of wild-type mouse ADSCs enriched for adipogenic progenitors did not show any additional chondroprotective effects compared to nonsorted ADSCs. However, Fra-1-transgenic mouse ADSCs showed decreased adipogenic differentiation capacity. Moreover, Fra-1 significantly inhibited proinflammatory interleukin-6 and pentraxin 3 expression, while increasing the expression of extracellular matrix proteins, such as periostin and spondin 1. These findings suggest that Fra-1 overexpression leads to an increased chondroprotective effect of ADSCs in OA.ADSCs overexpressing Fra-1 effectively protect against OA. Our data indicate that genetic modifications of ADSCs, such as Fra-1 overexpression, may improve their potential to protect articular cartilage against OA-mediated damage.
EVALuna2:13146

Inhibition of phosphodiesterase 4 (PDE4) reduces dermal fibrosis by interfering with the release of interleukin-6 from M2 macrophages - Maier, Christiane; Bergmann, Christina; Weinkam, Rita; Kittan, Nicolai; Schett, Georg; Distler, Jörg; Beyer, Christian; Ramming, Andreas (Annals of the Rheumatic Diseases, 2017)
To investigate the disease-modifying effects of phosphodiesterase 4 (PDE4) inhibition in preclinical models of systemic sclerosis (SSc).We studied the effects of PDE4 inhibition in a prevention and a treatment model of bleomycin-induced skin fibrosis, in the topoisomerase mouse model as well as in a model of sclerodermatous chronic graft-versus-host disease. To better understand the mode of action of PDE4 blockade in preclinical models of SSc, we investigated fibrosis-relevant mediators in fibroblasts and macrophages from healthy individuals and patients suffering from diffuse-cutaneous SSc on blockade of PDE4.Specific inhibition of PDE4 by rolipram and apremilast had potent antifibrotic effects in bleomycin-induced skin fibrosis models, in the topoisomerase I mouse model and in murine sclerodermatous chronic graft-versus-host disease. Fibroblasts were not the direct targets of the antifibrotic effects of PDE4 blockade. Reduced leucocyte infiltration in lesional skin on PDE4 blockade suggested an immune-mediated mechanism. Further analysis revealed that PDE4 inhibition decreased the differentiation of M2 macrophages and the release of several profibrotic cytokines, resulting in reduced fibroblast activation and collagen release. Within these profibrotic mediators, interleukin-6 appeared to play a central role.PDE4 inhibition reduces inflammatory cell activity and the release of profibrotic cytokines from M2 macrophages, leading to decreased fibroblast activation and collagen release. Importantly, apremilast is already approved for the treatment of psoriasis and psoriatic arthritis. Therefore, PDE4 inhibitors might be further developed as potential antifibrotic therapies for patients with SSc. Our findings suggest that particularly patients with inflammation-driven fibrosis might benefit from PDE4 blockade.
EVALuna2:13394

Inhibition of sumoylation prevents experimental fibrosis - Khodzhigorova, Aisa; Distler, Alfiya; Lang, Veronika; Dees, Clara; Schneider, Holm; Beyer, Christian; Gelse, Kolja; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2012)
Objectives: Fibrosis is a predominant cause of death in systemic sclerosis (SSc). First epigenetic modifications have recently been shown to contribute to activation of SSc fibroblasts. Here, we investigated inhibition of sumoylation as a novel antifibrotic approach. Methods: Sumoylation was inhibited by siRNA-mediated knockdown of the Small Ubiquitin-like MOdifiers (SUMO) E2-conjugating enzyme Ubc9, which is essential for sumoylation. The effects of knockdown of Ubc9 were analysed in bleomycin-induced dermal fibrosis, and in the model of fibrosis induced by overexpression of a constitutively active TGF-beta receptor type I (TBR). SUMO-1 and phosphorylated Smad3 were detected by immunohistochemistry. Results: Increased staining for SUMO-1 was detected in patients with SSc and in experimental fibrosis. Inhibition of sumoylation exerted potent antifibrotic effects and prevented dermal thickening, myofibroblast differentiation and accumulation of collagen induced by bleomycin, or by overexpression of constitutively active TBR. Moreover, knockdown of Ubc9 reduced the accumulation of phosphorylated Smad3 in experimental fibrosis indicating that inhibition of sumoylation may normalise canonical TGF-β signalling in vivo. Conclusions: We demonstrate that inhibition of sumoylation reduces canonical TGF-β signalling and prevents experimental fibrosis in different preclinical models. These data provide first evidence that targeting of aberrant sumoylation may be a novel therapeutic approach for fibrotic diseases.
CRIS-Team Scopus Importer:2020-07-01

INNATE LYMPHOID CELLS AND FIBROTIC REGULATION - Horsburgh, Steven; Todryk, Stephen; Distler, Jörg; O'Reilly, Steven; Ramming, Andreas (Immunology Letters, 2017)
Innate lymphoid cells (ILCs) are innate immune cells that do not possess B or T cell receptors but belong to the lymphoid lineage. While these cells have not yet been extensively investigated since their classification as a homogenous group, emerging evidence suggests that they exert significant regulatory roles in both tissue remodelling and inflammation, and are therefore, also involved in fibrotic regulation. The following review will serve to outline the transcription factors, surface markers, and cytokines that define each subgroup, and the process by which these cells differentiate. Furthermore, the diverse functions of these cells in non-pathogenic states will be discussed, in addition to the interactions between ILCs and other cells of the immune system, both innate and adaptive, and how these pathways can elicit both pro- and anti-inflammatory and -fibrotic effects in varying tissues.
EVALuna2:13445

INNATE LYMPHOID CELLS ARE PREDICTORS OF DISEASE PROGRESSION IN SYSTEMIC SCLEROSIS: A 3-YEARS FOLLOW-UP STUDY - Soare, A.; Weber, Stefanie; Schett, Georg; Distler, Jörg; Ramming, Andreas (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

INNATE LYMPHOID CELLS CORRELATE WITH DISEASE ACTIVITY AND BONE REMODELLING IN PSORIATIC ARTHRITIS - Soare, A.; Weber, Stefanie; Maul, L.; Rauber, Simon; Gheorghiu, A. M.; Houssni, I.; Kleyer, Arnd; Luber, M.; Rech, Jürgen; Schett, Georg; Distler, Jörg; Ramming, A. (2018)
EVALuna2:34985

INNATE LYMPHOID CELLS INDUCE A FIBROTIC PHENOTYPE OF FIBROBLASTS - Weber, Stefanie; Anchang, Charles Gwellem; Rauber, S.; Luber, M.; Raimondo, M. G.; Ariza, Y.; Rigau, A. Rius; Kreuter, A.; Schett, Georg; Distler, Jörg; Ramming, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Innate Lymphoid Cells - New Players in Psoriatic Arthritis - Soare, Alina; Weber, Stefanie; Maul, Lisa; Gheorghiu, Ana Maria; Housni, Ismail; Kleyer, Arnd; Luber, Markus; Rauber, Simon; Simon, David; Rech, Jürgen; Schett, Georg; Distler, Jörg; et al. (2017)
EVALuna2:33444

Innovative cellular therapies for autoimmune diseases: expert-based position statement and clinical practice recommendations from the EBMT practice harmonization and guidelines committee. - Greco, Raffaella; Alexander, Tobias; Del Papa, Nicoletta; Müller, Fabian; Saccardi, Riccardo; Sanchez-Guijo, Fermin; Schett, Georg; Sharrack, Basil; Snowden, John A.; Tarte, Karin; Onida, Francesco; Sánchez-Ortega, Isabel; et al. (EClinicalMedicine, 2024)
Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated.
EVALuna2:554515

Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study. - Simon, David; Tascilar, Koray; Fagni, Filippo; Kleyer, Arnd; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Mößner, Johanna; Taubmann, Jule; Mutlu, Melek Yalcin; Knitza, Johannes; et al. (The Lancet Rheumatology, 2022)
Background: Concerns have been raised about the reduced immunogenicity of vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory diseases and the higher risk of breakthrough infections. The objective of our study was to investigate the intensity and longevity of SARS-CoV-2 vaccination responses in patients with immune-mediated inflammatory diseases, and to assess the effects of diagnosis, treatment, and adapted vaccination schedules. Methods: SARS-CoV-2 IgG antibody response after SARS-CoV-2 vaccination was measured over time in a large prospective cohort of healthy controls and participants with immune-mediated inflammatory diseases (attending or admitted to affiliated centres) between Dec 15, 2020, and Dec 1, 2021. Cohort participants with immune-mediated inflammatory diseases and control participants with no diagnosis of immune-mediated inflammatory diseases, were eligible for this analysis. Demographic data and disease-specific data were collected using a questionnaire. Humoral response was compared across treatment and disease groups, and with respect to the receipt of additional vaccinations. SARS-CoV-2 antibody response was measured by ELISA using optical density ratio units and modelled over time with age and sex adjustment using mixed-effects models. Using these models, marginal mean antibody titres and marginal risks of a poor response (optical density ratio <1·1) were calculated for each week starting from week 8 after the first vaccination to week 40. Findings: Among 5076 individuals registered, 2535 participants with immune-mediated inflammatory diseases (mean age 55·0 [15·2] years; 1494 [58·9%] women and 1041 [41·1%] men) and 1198 healthy controls (mean age 40·7 [13·5] years; 554 [46·2%] women and 644 [53·8%] men) were included in this analysis. Mean antibody titres were higher in healthy controls compared with people with immune-mediated inflammatory diseases at all timepoints, with a peak antibody response in healthy controls (mean optical density ratio 12·48; 95% CI 11·50-13·53) of more than twice that in participants with immune-mediated inflammatory diseases (5·50; 5·23-5·77; mean difference 6·98; 5·92-8·04). A poor response to vaccination was observed in participants with immune-mediated inflammatory diseases who were taking B-cell inhibitors (peak mean difference from healthy controls 11·68; 10·07-13·29) and T-cell inhibitors (peakmean difference from healthy controls 10·43; 8·33-12·53). Mean differences in antibody responses between different immune-mediated inflammatory diseases were small. Participants with immune-mediated inflammatory diseases who were given a third vaccine dose had higher mean antibody titres than did healthy controls vaccinated with two vaccine doses at 40 weeks after the initial vaccination (mean difference 1·34; 0·01-2·69). Interpretation: People with immune-mediated inflammatory diseases show a lower and less durable SARS-CoV-2 vaccination response and are at risk of losing humoral immune protection. Adjusted vaccination schedules with earlier booster doses or more frequent re-doses, or both, could better protect people with immune-mediated inflammatory diseases. Funding: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, European Research Council, Innovative Medicine Initiative, Friedrich-Alexander-Universität Erlangen-Nürnberg, Else Kröner-Memorial Foundation.
EVALuna2:506737

Interleukin 17 Blockade in Psoriasis Patients with Subclinical Joint Inflammation- Prospective Open Study to Influence the Course of the Disease by means of Secukinumab - Kampylafka, E.; Oliveira, I.; Linz, C.; Lerchen, V.; Englbrecht, Matthias; Simon, David; Rech, Jürgen; Kleyer, Arnd; Schett, Georg; Sticherling, Michael; Hueber, Axel (JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT, 2019)
CRIS-Team WoS Importer:2019-05-17

Interleukin-17 Blockade Leads to Shifts from Stage-based Towards Response-based Disease Clusters- Comparative Data from Very Early and Established Psoriatic Arthritis - Kampylafka, Eleni; Tascilar, Koray; Lerchen, Veronika; Linz, Christina; Sokolova, Maria; Zekovic, Ana; Kleyer, Arnd; Simon, David; Rech, Jürgen; Sticherling, Michael; Schett, Georg; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Interleukin-1 function and role in rheumatic disease - Schett, Georg; Dayer, Jean-Michel; Manger, Bernhard (Nature Reviews Rheumatology, 2016)
Interleukin (IL)-1, first described 35 years ago as a secreted product of monocytes and neutrophils, refers to IL-1? and IL-1?, two key cytokines in the activation of innate immunity. These cytokines were among the first proteins identified as orchestrators of leukocyte communication, creating the class of secreted products now known as interleukins. The IL-1 family comprises a total of 11 members, including the two activating cytokines IL-1? and IL-1? as well as an inhibitory mediator, the IL-1 receptor antagonist. IL-1 is processed and activated by a caspase-1 dependent mechanism in conjunction with inflammasome assembly, as well as by caspase-1 independent processes that involve neutrophil proteases. Once activated, IL-1? and IL-1? act as potent proinflammatory cytokines at the local level, triggering vasodilatation and attracting monocytes and neutrophils to sites of tissue damage and stress. Importantly, these cytokines are crucial for the induction of matrix enzymes and serve as potent mediators of tissue damage by altering cartilage and bone homeostasis. Systemically, IL-1 cytokines foster the hypothalamic fever response and promote hyperalgesia. Uncontrolled IL-1 activation is a central component of some inflammatory diseases, including rare hereditary syndromes with mutations in inflammasome-associated genes or more frequent diseases such as gout, characterized by neutrophil infiltration and IL-1 activation. Apart from these connections to inflammatory diseases, an important role for IL-1 in inflammatory atherogenesis is also predicted. To date, four potent inhibitors of IL-1 are available for clinical use or in late-stage clinical development, which not only constitute efficacious therapies, but also helped improve our understanding of the role of IL-1 in human disease.
EVALuna2:13192

Interleukin-35 is upregulated in systemic sclerosis and its serum levels are associated with early disease - Tomcik, Michal; Zerr, Pawel; Palumbo-Zerr, Katrin; Storkanova, Hana; Hulejova, Hana; Spiritovic, Maja; Kodet, Ondrej; Stork, Jiri; Becvar, Radim; Vencovsky, Jiri; Pavelka, Karel; Filkova, Maria; et al. (Rheumatology, 2015)
IL-35 is a member of the IL-12 family consisting of p35/IL-12a and EBI3/IL-27b subunits. IL-35 exerts immunomodulatory activities in experimental and human autoimmune inflammatory conditions. Our aim was to assess IL-35 expression in the skin and circulation of SSc patients and to characterize its potential association with SSc-related features.Expression of IL-35 in skin and dermal fibroblasts was quantified by quantitative PCR, immunohistochemistry and immunofluorescence. Serum levels of IL-35 (by ELISA), CRP (by turbidimetry), ANA (by immunofluorescence) and autoantibodies of the ENA complex (by immunoblot) were measured in 40 SSc patients. Serum IL-35 was determined in 40 age- and sex-matched healthy controls.IL-35 expression was increased in SSc skin and dermal fibroblasts in a TGF-?-dependent manner. IL-35 induced an activated phenotype in resting fibroblasts and enhanced the release of collagen. IL-35 serum levels were increased in patients with SSc compared with healthy controls [median 83.9 (interquartile range 45.1-146.1) vs 36.2 (interquartile range 17.2-49.4) pg/ml, P < 0.0001]. Serum IL-35 was negatively correlated with disease duration (r = -0.4339, P = 0.0052). In line with this finding, serum IL-35 was increased in patients with an early SSc pattern on capillaroscopy assessment compared with those with active and late SSc patterns.The present study demonstrates overexpression of IL-35 in SSc skin, dermal fibroblasts and serum. TGF-? induces IL-35, which in turn activates resting fibroblasts and enhances the release of collagen, thereby contributing to aberrant TGF-? signalling in SSc. Increased serum IL-35 is associated with early, inflammatory stages of SSc.
EVALuna2:13159

Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts - Schmitt, Verena; Hahn, Madelaine; Kästele, Verena; Wagner, Olga; Wiendl, Maximilian; Derer, Anja; Taddeo, Adriano; Hahne, Stefanie; Radbruch, Andreas; Jäck, Hans-Martin; Schuh, Wolfgang; Mielenz, Dirk; et al. (European Journal of Immunology, 2017)
The IL-1 family member IL-36? has proinflammatory and pathogenic properties in psoriasis. IL-36? binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36?. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL-36?-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36? and stimulation increased IL-36? in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36? by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R-deficiency abrogated IL-36?-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints. This article is protected by copyright. All rights reserved.
EVALuna2:13406

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections - Bénard, Alan; Jacobsen, Anne; Brunner, Maximilian; Krautz, Christian; Klösch, Bettina; Swierzy, Izabela; Naschberger, Elisabeth; Podolska, Malgorzata; Kouhestani, Dina; David, Paul; Birkholz, Torsten; Castellanos, Ixchel; et al. (Nature Communications, 2021)
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
CRIS-Team Scopus Importer:2021-03-05

Interleukin-6 receptor blockade induces limited repair of bone erosions in rheumatoid arthritis: A micro CT study - Finzel, Stephanie; Rech, Jürgen; Schmidt, Sarah; Engelke, Klaus; Englbrecht, Matthias; Schett, Georg (Annals of the Rheumatic Diseases, 2013)
Introduction: Interleukin-6 receptor (IL-6R) blockade improves the signs and symptoms of rheumatoid arthritis (RA) and retards bone damage. Whether IL-6R blockade allows repair of existing bone erosions is so far unclear. Methods: This study examined bone erosions in the metacarpophalangeal joints of 20 patients receiving treatment with the IL-6R blocker tocilizumab using micro CT (μCT). The maximal width and depth of individual bone erosions was measured at baseline and after 1 year of treatment. Results: 133 bone erosions were identified at baseline with a mean (±SD) size of 2.23±1.26 mm and depth of 2.16±1.50 mm. Distribution analysis showed predominant involvement of the second compared with the third and fourth metacarpophalangeal joints, the metacarpal heads compared with the phalangeal bases and the radial quadrants compared with all other surfaces. Repair of bone erosions during tocilizumab treatment was confined to those lesions showing sclerosis at baseline and/or at follow-up and those with a width larger than 1.6 mm. The mean decrease in width of sclerosed erosions was thus 0.14±0.05 mm (p=0.0086) and 0.20±0.08 mm (p=0.019) for sclerosing lesions after 1 year of treatment. Conclusions: Blockade of IL-6R by tocilizumab can induce limited repair in a subset of erosions, particularly in large lesions with sclerosis. Repair of erosions during tocilizumab treatment reflects the favourable impact of IL-6R blockade on local bone remodelling in patients with RA.
CRIS-Team Scopus Importer:2021-02-03

Interspecies Single-Cell RNA-Seq Analysis Reveals the Novel Trajectory of Osteoclast Differentiation and Therapeutic Targets - Omata, Yasunori; Okada, Hiroyuki; Uebe, Steffen; Izawa, Naohiro; Ekici, Arif Bülent; Sarter-Zaiss, Kerstin; Saito, Taku; Schett, Georg; Tanaka, Sakae; Zaiss, Mario (JBMR Plus, 2022)
Bone turnover is finely tuned by cells in the bone milieu, including osteoblasts, osteoclasts, and osteocytes. Osteoclasts are multinucleated giant cells with a bone-resorbing function that play a critical role in regulating skeletal homeostasis. Osteoclast differentiation is characterized by dramatic changes in morphology and gene expression following receptor activator of nuclear factor-kappa-Beta ligand (RANKL) stimulation. We performed single-cell RNA-sequencing analyses of human and murine osteoclast-lineage cells (OLCs) and found that OLCs in the mitotic phase do not differentiate into mature osteoclasts. We also identified a guanosine triphosphatase (GTPase) family member, RAB38, as a highly expressed molecule in both human and murine osteoclast clusters; RAB38 gene expression is associated with dynamic changes in histone modification and transcriptional regulation. Silencing Rab38 expression by using short hairpin RNA (shRNA) inhibited osteoclast differentiation and maturation. In summary, we established an integrated fate map of human and murine osteoclastogenesis; this will help identify therapeutic targets in bone diseases. (c) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
CRIS-Team WoS Importer:2022-05-27

INTESTINAL HIF1 alpha EXPRESSION PROTECTS AGAINST EPITHELIAL CELL DEATH IN ARTHRITIS - Lyu, Pang; Wen, Jinming; Stolzer, Iris; Gießl, Andreas; Song, Rui; Meng, Xiangjun; Cao, Shan; Günther, Claudia; Schett, Georg; Bozec, Aline (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Intra-arterial delivery of neurospheres into isolated perfused porcine colons: a proof of concept - Martel, Richard D.; Hoyos, Nicolas A.; Tapia-Laliena, María Ángeles; Herrmann, Irmgard; Herrmann, Martin; Khasanov, Rasul; Schafer, Karl Herbert (Biology Methods & Protocols, 2024)
Cell replacement in aganglionic intestines is a promising, yet merely experimental tool for the therapy of congenital dysganglionosis of the enteric nervous system like Hirschsprung disease. While the injection of single cells or neurospheres to a defined and very restricted location is trivial, the translation to the clinical application, where large aganglionic or hypoganglionic areas need to be colonized (hundreds of square centimetres), afford a homogeneous distribution of multiple neurospheres all over the affected tissue areas. Reaching the entire aganglionic area in vivo is critical for the restoration of peristaltic function. The latter mainly depends on an intact nervous system that extends throughout the organ. Intra-arterial injection is a common method in cell therapy and may be the key to delivering cells or neurospheres into the capillary bed of the colon with area-wide distribution. We describe an experimental method for monitoring the distribution of a defined number of neurospheres into porcine recta ex vivo, immediately after intra-arterial injection. We designed this method to localize grafting sites of single neurospheres in precise biopsies which can further be examined in explant cultures. The isolated perfused porcine rectum allowed us to continuously monitor the perfusion pressure. A blockage of too many capillaries would lead to an ischaemic situation and an increase of perfusion pressure. Since we could demonstrate that the area-wide delivery of neurospheres did not alter the overall vascular resistance, we showed that the delivery does not significantly impair the local circulation.
CRIS-Team Scopus Importer:2024-05-03
Keywords: cell therapy; enteric nervous system; Hirschsprung disease; intra-arterial; neurosphere

INTRAARTICULAR MICRO CHANNELS OF MCP JOINTS INCREASE DURING DEVELOPMENT OF RHEUMATOID ARTHRITIS - Werner, David; Simon, David; Rech, Jürgen; Haschka, J.; Buder, Thomas; Neuhuber, Winfried; Schett, Georg; Hueber, Axel; Kleyer, Arnd (2015)
EVALuna2:34457

Intratumor Heterogeneity Correlates With Reduced Immune Activity and Worse Survival in Melanoma Patients - Lin, Zhen; Meng, Xianyi; Wen, Jinming; Corral, José María; Andreev, Darja; Kachler, Katerina; Schett, Georg; Chen, Xiaoxiang; Bozec, Aline (Frontiers in Oncology, 2020)
Background: Human malignant melanoma is a highly aggressive, heterogeneous and drug-resistant cancer. Due to a high number of clones, harboring various mutations that affect key pathways, there is an exceptional level of phenotypic variation and intratumor heterogeneity (ITH) in melanoma. This poses a significant challenge to personalized cancer medicine. Hitherto, it remains unclear to what extent the heterogeneity of melanoma affects the immune microenvironment. Herein, we explore the interaction between the tumor heterogeneity and the host immune response in a melanoma cohort utilizing The Cancer Genome Atlas (TCGA). Methods: Clonal Heterogeneity Analysis Tool (CHAT) was used to estimate intratumor heterogeneity, and immune cell composition was estimated using CIBERSORT. The Overall Survival (OS) among groups was analyzed using Kaplan–Meier curves with the log-rank test and multivariate cox regression. RNA-seq data were evaluated to identify differentially expressed immunomodulatory genes. The reverse phase protein array (RPPA) data platform was used to validate immune responses at protein level. Results: Tumors with high heterogeneity were associated with decreased overall survival (p = 0.027). High CHAT tumors were correlated with less infiltration by anti-tumor CD8 T cells (p = 0.0049), T follicular cells (p = 0.00091), and M1 macrophages (p = 0.0028), whereas tumor-promoting M2 macrophages were increased (p = 0.02). High CHAT tumors correlated with a reduced expression of immunomodulatory genes, particularly Programmed Cell Death 1 (PD1) and its ligand PD-L1. In addition, high CHAT tumors exhibited lower immune Cytotoxic T lymphocytes (CTLs)-mediated toxicity pathway score (p = 2.9E−07) and cytotoxic pathway score (p = 2.9E−08). High CHAT tumors were also associated with a lower protein level of immune-regulatory kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) (p = 3.4e−5) and spleen tyrosine kinase (SYK) (p = 0.0011). Conclusions: Highly heterogeneous melanoma tumors are associated with reduced immune cell infiltration and immune response activation as well as decreased survival. Our results reveal that intratumor heterogeneity is an indicative factor for patient survival due to its impact on anti-tumor immune response.
CRIS-Team Scopus Importer:2020-12-25
Keywords: immunomodulator; intratumor heterogeneity; melanoma; The Cancer Genome Atlas; tumor infiltrating lymphocytes

IN VIVO DETECTION OF CORTICAL MICRO CHANNELS IN METACARPOPHALANGEAL JOINTS WITH XTREME-CT - A NEW INSTRUMENT TO VISUALIZE COMMUNICATION BETWEEN THE BONE MARROW AND THE JOINT SPACE - Haschka, J.; Simon, David; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (2014)
EVALuna2:12861

In Vivo Models of Rheumatoid Arthritis - Grötsch, Bettina; Bozec, Aline; Schett, Georg (Methods in Molecular Biology, 2019)
Rheumatoid arthritis (RA) models in mice induced by immunization enable the analyses of molecular mechanism involved in disease development, progression, and resolution of inflammation. Here, we describe three different models mimicking clinic symptoms of human rheumatoid arthritis, which could be transferable to any genetically modified mouse. We will present the protocol for collagen-induced arthritis (CIA), K/BxN serum-induced arthritis (SIA), and the antigen-induced arthritis (AIA) models. To do so, we will detail their way of induction but also how to analyze RA clinical score and pathology characterization. Finally, we will briefly discuss the main characteristics and disadvantages of all three models.
EVALuna2:69396

In-vivo results for rheumatoid arthritis diagnosis with a 360 degrees pulse-echo imaging system - Koch, Andreas; Finzel, Stephanie; Kobler, Andreas; Schett, Georg; Lerch, Reinhard; Ermert, Helmut (IEEE SERVICE CENTER, 445 HOES LANE, PO BOX 1331, PISCATAWAY, NJ 08855-1331 USA, 2012)
Progress in medical ultrasound in recent years makes sonography a valuable method for early rheumatoid arthritis (RA) diagnosis today. However, detecting in ammatory processes in periarticular bones requires expert knowledge and training. 360 degrees compound imaging has already proven to increase ultrasound B-mode image quality significantly, e.g. in breast cancer imaging. Therefore an existing Ultrasound Computed Tomography (USCT) system has been modified for RA diagnosis, with respect to finger joint imaging. Well known concepts in USCT to reconstruct the speed of sound (SOS) distribution can not be applied, as the bone inhibits transmission measurements of fingers. Therefore, an image based local contrast quanti. cation method is proposed to estimate a mean SOS for the soft tissue surrounding the finger joint. Based on this estimation, ultrasound B-mode images can be corrected for refraction and TOF to yield high image quality in 360 degrees compound imaging. This method has been validated by measurements on tissue mimicking phantoms. Healthy volunteers and RA patients have been examined with the USCT system. In-vivo results show a great potential for 360 degrees compound imaging to visualize synovitis as well as bone erosion in RA of finger joints.
Keywords: rheumatoid arthritis; ultrasound computed tomography; full angle spatial compounding; speed of sound estimation; refraction correction; nger joints; in-vivo results