Targeting TGF-beta signaling for the treatment of fibrosis - Györfi, Andrea-Hermina; Matei, Alexandru-Emil; Distler, Jörg (Matrix Biology, 2018)
Transforming growth factor-alpha (TGF-beta) is widely recognized as a core pathway of fibrosis. Inhibition of TGF-beta signaling may thus offer potential for antifibrotic therapies. Long-term inhibition of TGF-beta signaling at the level of its isoforms and receptors can be associated with unacceptable adverse effects. However, TGF-beta regulates a myriad of intracellular signaling cascades to transmit its profibrotic effects and several of those pathways offer potential for pharmacologic intervention. Moreover, the multiple interactions of TGF-beta with other profibrotic pathways also yielded candidates for therapeutic intervention. In this review, we discuss selected targets within the TGF-beta pathway with high translational potential. (C) 2018 Elsevier B.V. All rights reserved.
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Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs - Zhang, Mingjun; Haughey, Michael; Wang, Nai Yu; Blease, Kate; Kapoun, Ann M.; Couto, Suzana; Belka, Igor; Hoey, Timothy; Groza, Matthew; Hartke, James; Bennett, Brydon; Cain, Jennifer; et al. (PLoS ONE, 2020)
The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl4)-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis.
CRIS-Team Scopus Importer:2020-03-20

Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis - Tajik, Narges; Frech, Michael; Schulz, Oscar; Schälter, Fabian; Lucas, Sébastien; Azizov, Vugar; Dürholz, Kerstin; Steffen, Franziska; Omata, Yasunori; Rings, Andreas; Bertog, Marko; Rizzo, Aroldo; et al. (Nature Communications, 2020)
Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.
CRIS-Team Scopus Importer:2020-05-05

TARGET OUTCOMES IN PSA: SIMULTANEOUS ACHIEVEMENT OF ACR50-PASI100 AND BEYOND: INSIGHTS FROM SPIRIT-H2H AT WEEK 24 - Smolen, J. S.; Behrens, F.; Leage, S. Liu; Sapin, C.; De La Torre, I.; Meszaros, G.; Schett, Georg; Gossec, L.; Ostor, A.; Combe, B.; Van Den Bosch, F. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Target Outcomes in Psoriatic Arthritis: Simultaneous Achievement of ACR50-Psoriasis Area and Severity Index 100 and Beyond: Insights from Open-Label, Assessor-Blinded Study at Week 24 - Smolen, Josef; Behrens, Frank; Liu-Leage, Soyi; Sapin, Christophe; De La Torre, Inmaculada; Meszaros, Gabriella; Schett, Georg; Gossec, Laure; Ostor, Andrew; Combe, Bernard; Van Den Bosch, Filip (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway - Bozec, Aline; Zaiss, Mario; Kagwiria, Rosebeth; Voll, Reinhard; Rauh, Manfred; Chen, Zhu; Müller-Schmucker, Sandra; Kroczek, Richard A.; Heinzerling, Lucie; Moser, Muriel; Mellor, Andrew L.; David, Jean-Pierre; et al. (Science Translational Medicine, 2014)
Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
EVALuna2:12912

T-cell receptor transfer for boosting HIV-1-specific T-cell immunity in HIV-1-infected patients - Mummert, Christiane; Hofmann, Christian; Hueckelhoven, Angela G.; Bergmann, Silke; Mueller-Schmucker, Sandra M.; Harrer, Ellen G.; Dörrie, Jan; Schaft, Niels; Harrer, Thomas (Aids, 2016)
Strategies to cure HIV-1 infection require the eradication of viral reservoirs. An innovative approach for boosting the cytotoxic T-lymphocyte response is the transfer of T-cell receptors (TCRs). Previously, we have shown that electroporation of TCR-encoding mRNA is able to reprogram CD8 T cells derived from healthy donors. So far, it is unknown whether the transfer of HIV-1-specific TCRs is capable to reprogram CD8 T cells of HIV-1-infected patients. To assess the efficiency of TCR-transfer by mRNA electroporation and the functionality of reprogramed T cells in HIV-1-infected patients, we performed an in-vitro analysis of TCR-transfer into T cells from HIV-1-infected patients in various stages of disease and from healthy controls.Peripheral blood mononuclear cells from 16 HIV-1-infected patients (nine HLA-A02-positive, seven HLA-A02-negative) and from five healthy controls were electroporated with mRNA-constructs encoding TCRs specific for the HLA-A02/HIV-1-gag p17 epitope SLYNTVATL (SL9). Functionality of the TCRs was measured by ?IFN-ELISpot assays.SL9/TCR transfection into peripheral blood mononuclear cells from both HLA-A02-positive and HLA-A02-negative HIV-1-infected patients and from healthy blood donors reprogramed T cells for recognition of SL9-presenting HLA-A02-positive cells in ?IFN-ELISpot assays. SL9/TCR-transfer into T cells from an immunodeficient AIDS patient could induce recognition of SL9-expressing target cells only after reversion of T-cell dysfunction by antiretroviral therapy.The transfer of HIV-1-p17-specific TCRs into T cells is functional both in HIV-1-infected patients as well as in healthy blood donors. TCR-transfer is a promising method to boost the immune system against HIV-1.
EVALuna2:13288

T cells as key players for bone destruction in gouty arthritis? - Harre, Ulrike; Derer, Anja; Schorn, Christine; Schett, Georg; Herrmann, Martin (Arthritis Research & Therapy, 2011)
The deposition of monosodium urate (MSU) crystals in synovial fluid and tissue leads to gouty arthritis frequently associated with synovial inflammation and bone erosions. The cellular mechanism that links MSU crystals to an increased number of osteoclasts has not yet been fully understood. In a recent issue of Arthritis Research & Therapy Lee and colleagues proposed that bone destruction in chronic gouty arthritis is at least in part dependent on expression by T cells of receptor activator of NF-κB ligand (RANKL). The authors showed that pro-resorptive cytokines such as IL-1β, IL-6, and TNFα are expressed within tophi and stromal infiltrates. In vitro stimulation with MSU crystals revealed monocytes as a source for these cytokines, whereas T cells produce RANKL, the major trigger of osteoclastogenesis. © 2011 BioMed Central Ltd.
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TELEMEDICINE IN RHEUMATOLOGY: ACCEPTANCE BY PATIENTS AND MEDICAL PRACTITIONERS IN GERMANY (TELERHEUMABB) - INTERIM ANALYSIS - Muehlensiepen, F.; Marquardt, W.; Knitza, Johannes; Hueber, A.; Welcker, M. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Telemedizin in der Rheumatologie - Krusche, M.; Mühlensiepen, F.; Aries, P.; Welcker, M.; Knitza, Johannes (Zeitschrift für Rheumatologie, 2020)
Due to the outbreak of the COVID-19 pandemic, in recent months we have experienced deep changes in our daily and professional lives. In the context of pandemic containment, routine rheumatological procedures have changed in many areas. To guarantee sufficient protection against the infection for patients and staff, telemedicine (especially telephone and video consultation) has increasingly been used. Due to the Digital Healthcare Act (DiGAV), whereby patients will have a legal claim to specific digital health applications in Germany, medical apps and wearables will offer new opportunities for telemedical monitoring. This article provides an overview of telemedical care options in the field of rheumatology. Furthermore, opportunities and limitations of telemedicine in rheumatology are reviewed.
CRIS-Team Scopus Importer:2020-10-23
Keywords: Apps; Digitalization; Telephone consultation; Video consultation; Wearables

TELERA-Asynchronous TELEmedicine for Patients With Rheumatoid Arthritis: Study Protocol for a Prospective, Multi-Center, Randomized Controlled Trial - Mucke, Johanna; Knitza, Johannes; Muehlensiepen, Felix; Grahammer, Manuel; Stenzel, Ramona; Simon, David; Kleyer, Arnd; Krönke, Gerhard; Sharp, Charlotte; Bendzuck, Gerlinde; Korinth, Marianne; Elling-Audersch, Corinna; et al. (Frontiers in Medicine, 2021)
Innovative strategies are needed to adequately assess and monitor disease activity of patients with rheumatoid arthritis (RA) in times of scarce appointments. The aim of the TELERA study is to evaluate the feasibility and performance of asynchronous telemedicine visits based on patient-generated data and patient's drug history. RA patients use a medical app, ABATON, that captures the results of a self-performed quick CRP-test, joint-count, and electronic patient-reported outcomes in between visits. This is a prospective, multi-center, randomized controlled trial performed in four German university centers. The estimated sample size is 120 patients. The main outcome is the agreement of rheumatologists' treatment decisions based on asynchronous telemedicine patient-generated data with traditional in-person rheumatology clinic-based decisions and with patient suggestions. The TELERA trial will provide evidence regarding the implementation of remote care in rheumatology.
CRIS-Team WoS Importer:2022-01-14

TEMPORAL MIGRATION OF IMMUNE CELLS FROM PSORIATIC SKIN TO JOINTS INITIATING SYNOVIAL INFLAMMATION IN PSORIATIC ARTHRITIS - Raimondo, Maria Gabriella; Rauber, Simon; Xu, Cong; Mohammadian, Hashem; Vogg, Mario; Anchang, Charles Gwellem; Rigau, Aleix; Luber, M.; Labinsky, Hannah; Soare, A.; Distler, Jörg; Fearon, U.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis - Gracey, Eric; Burssens, Arne; Cambre, Isabelle; Schett, Georg; Lories, Rik; Mcinnes, Iain B.; Asahara, Hiroshi; Elewaut, Dirk (Nature Reviews Rheumatology, 2020)
Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in ‘overuse’ injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.
CRIS-Team Scopus Importer:2020-03-06

TFG is required for autophagy flux and to prevent endoplasmic reticulum stress in CH12 B lymphoma cells - Steinmetz, Tobit; Schlötzer-Schrehardt, Ursula; Hearne, Abigail; Schuh, Wolfgang; Wittner, Jens; Schulz, Sebastian; Winkler, Thomas; Jäck, Hans-Martin; Mielenz, Dirk (Autophagy, 2020)
Plasma cells depend on quality control of newly synthesized antibodies in the endoplasmic reticulum (ER) via macroautophagy/autophagy and proteasomal degradation. The cytosolic adaptor protein TFG (Trk-fused gene) regulates ER-Golgi transport, the secretory pathway and proteasome activity in non-immune cells. We show here that TFG is upregulated during lipopolysaccharide- and CpG-induced differentiation of B1 and B2 B cells into plasmablasts, with the highest expression of TFG in mature plasma cells. CRISPR-CAS9-mediated gene disruption of tfg in the B lymphoma cell line CH12 revealed increased apoptosis, which was reverted by BCL2 but even more by ectopic TFG expression. Loss of TFG disrupted ER structure, leading to an expanded ER and increased expression of ER stress genes. When compared to wild-type CH12 cells, tfg KO CH12 cells were more sensitive toward ER stress induced by tunicamycin, monensin and proteasome inhibition or by expression of an ER-bound immunoglobulin (Ig) μ heavy (µH) chain. CH12 tfg KO B cells displayed more total LC3, lower LC3-II turnover and increased numbers and size of autophagosomes. Tandem-fluorescent-LC3 revealed less accumulation of GFP-LC3 in starved and chloroquine-treated CH12 tfg KO B cells. The GFP:RFP ratio of tandem-fluorescent-LC3 was higher in tunicamycin-treated CH12 tfg KO B cells, suggesting less autophagy flux during induced ER stress. Based on these data, we suggest that TFG controls autophagy flux in CH12 B cells and propose that TFG is a survival factor that alleviates ER stress through the support of autophagy flux in activated B cells and mature plasma cells.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Antibody; apoptosis; autophagy; autophagy flux; B cell; B1 B cell; endoplasmic reticulum stress; immunoglobulin; plasma cell; Trk-fused gene

TFG is upregulated during plasma cell differentiation and regulates apoptosis, ER stress and autophagy in a B cell line - Steinmetz, Tobit; Reimer, Dorothea; Urbanczyk, Sophia; Schlötzer-Schrehardt, Ursula; Winkler, Thomas; Jäck, Hans-Martin; Mielenz, Dirk (JOURNAL OF IMMUNOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-08

TGF beta-Dependent Upregulation of XIAP Fosters Fibroblast Activation and Tissue Fibrosis By Promoting Canonical Wnt Signaling - Bergmann, Christina; Hallenberger, Ludwig; Brandt, Adrian; Merlevede, Benita; Dees, Clara; Chen, Chih-Wei; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg (2017)
EVALuna2:33427

TGF-beta-Induced Epigenetic Silencing of SOCS3 Facilitates STAT3 Signaling to Promote Fibroblast Activation and Tissue Fibrosis in Systemic Sclerosis - Dees, Clara; Zhang, Yun; Pötter, Sebastian; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2017)
EVALuna2:33431

TGF beta Promotes Fibrosis By MYST1-Dependent Epigenetic Regulation of Autophagy - Zehender, Ariella; Lin, Neng-Yu; Stefanica, Adrian; Chen, Chih-Wei; Soare, Alina; Wohlfahrt, Thomas; Rauber, Simon; Bergmann, Christina; Distler, Oliver; Schett, Georg; Distler, Jörg; Ramming, Andreas (2017)
EVALuna2:33446

TGF-β-induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis - Dees, Clara; Pötter, Sebastian; Zhang, Yun; Bergmann, Christina; Zhou, Xiang; Luber, Markus; Wohlfahrt, Thomas; Karouzakis, Emmanuel; Ramming, Andreas; Gelse, Kolja; Yoshimura, Akihiko; Jaenisch, Rudolf; et al. (Journal of Clinical Investigation, 2020)
Fibroblasts are key effector cells in tissue remodeling. They remain persistently activated in fibrotic diseases, resulting in progressive deposition of extracellular matrix. Although fibroblast activation may be initiated by external factors, prolonged activation can induce an “autonomous,” self-maintaining profibrotic phenotype in fibroblasts. Accumulating evidence suggests that epigenetic alterations play a central role in establishing this persistently activated pathologic phenotype of fibroblasts. We demonstrated that in fibrotic skin of patients with systemic sclerosis (SSc), a prototypical idiopathic fibrotic disease, TGF-β induced the expression of DNA methyltransferase 3A (DNMT3A) and DNMT1 in fibroblasts in a SMAD-dependent manner to silence the expression of suppressor of cytokine signaling 3 (SOCS3) by promoter hypermethylation. Downregulation of SOCS3 facilitated activation of STAT3 to promote fibroblast-to-myofibroblast transition, collagen release, and fibrosis in vitro and in vivo. Reestablishment of the epigenetic control of STAT3 signaling by genetic or pharmacological inactivation of DNMT3A reversed the activated phenotype of SSc fibroblasts in tissue culture, inhibited TGF-β-dependent fibroblast activation, and ameliorated experimental fibrosis in murine models. These findings identify a pathway of epigenetic imprinting of fibroblasts in fibrotic disease with translational implications for the development of targeted therapies in fibrotic diseases.
CRIS-Team Scopus Importer:2020-05-12

TGFβ PROMOTES FIBROSIS BY MYST1-DEPENDENT EPIGENETIC REGULATION OF AUTOPHAGY - Zehender, A.; Lin, N. -Y.; Stefanica, Adrian; Chen, Chih-Wei; Soarel, A.; Wohlfahrt, T.; Reuber, S.; Bergmann, C.; Ramming, A.; Distler, O.; Distler, Jörg (2018)
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TGFβ promotes fibrosis by MYST1-dependent epigenetic regulation of autophagy - Zehender, Ariella; Li, Yi-Nan; Lin, Neng Yu; Stefanica, Adrian; Nüchel, Julian; Chen, Chih-Wei; Hsu, Hsiao Han; Zhu, Honglin; Ding, Xiao; Huang, Jingang; Shen, Lichong; Györfi, Andrea-Hermina; et al. (Nature Communications, 2021)
Activation of fibroblasts is essential for physiological tissue repair. Uncontrolled activation of fibroblasts, however, may lead to tissue fibrosis with organ dysfunction. Although several pathways capable of promoting fibroblast activation and tissue repair have been identified, their interplay in the context of chronic fibrotic diseases remains incompletely understood. Here, we provide evidence that transforming growth factor-β (TGFβ) activates autophagy by an epigenetic mechanism to amplify its profibrotic effects. TGFβ induces autophagy in fibrotic diseases by SMAD3-dependent downregulation of the H4K16 histone acetyltransferase MYST1, which regulates the expression of core components of the autophagy machinery such as ATG7 and BECLIN1. Activation of autophagy in fibroblasts promotes collagen release and is both, sufficient and required, to induce tissue fibrosis. Forced expression of MYST1 abrogates the stimulatory effects of TGFβ on autophagy and re-establishes the epigenetic control of autophagy in fibrotic conditions. Interference with the aberrant activation of autophagy inhibits TGFβ-induced fibroblast activation and ameliorates experimental dermal and pulmonary fibrosis. These findings link uncontrolled TGFβ signaling to aberrant autophagy and deregulated epigenetics in fibrotic diseases and may contribute to the development of therapeutic interventions in fibrotic diseases.
CRIS-Team Scopus Importer:2021-08-06

Th2 and eosinophil responses ameliorate arthritis and inflammatory bone loss - Andreev, Darja; Chen, Zhu; Oeser, Katharina; Krljanac, B.; Hueber, Axel; Kleyer, Arnd; Weigmann, Benno; Vöhringer, David; Schett, Georg; Bozec, Aline (2017)
EVALuna2:33419

Th2 and eosinophil responses suppress inflammatory arthritis - Chen, Zhu; Andreev, Darja; Oeser, Katharina; Krljanac, Branislav; Hueber, Axel; Kleyer, Arnd; Vöhringer, David; Schett, Georg; Bozec, Aline (Nature Communications, 2016)
Th2-eosinophil immune responses are well known for mediating host defence against helminths. Herein we describe a function of Th2-eosinophil responses in counteracting the development of arthritis. In two independent models of arthritis, Nippostrongylus brasiliensis infection leads to Th2 and eosinophil accumulation in the joints associated with robust inhibition of arthritis and protection from bone loss. Mechanistically, this protective effect is dependent on IL-4/IL-13-induced STAT6 pathway. Furthermore, we show that eosinophils play a central role in the modulation of arthritis probably through the increase of anti-inflammatory macrophages into arthritic joints. The presence of these pathways in human disease is confirmed by detection of GATA3-positive cells and eosinophils in the joints of rheumatoid arthritis patients. Taken together, these results demonstrate that eosinophils and helminth-induced activation of the Th2 pathway axis effectively mitigate the course of inflammatory arthritis.
EVALuna2:13286

The 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis - Krönke, Gerhard; Reich, Nicole; Scholtysek, Carina; Akhmetshina, Alfiya; Uderhardt, Stefan; Zerr, Pawel; Palumbo, Katrin; Lang, Veronika; Dees, Clara; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2012)
Background: Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc. Objectives: To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis. Methods: Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO -/- mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO -/- mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms Results: In both models, 12/15-LO -/- mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO -/- fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects. Conclusions: These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.
CRIS-Team Scopus Importer:2020-11-20

The 12/15-lipoxygenase pathway promotes osteoclast development and differentiation - Krönke, Gerhard; Uderhardt, Stefan; Katzenbeisser, Julia; Schett, Georg (Autoimmunity, 2009)
Although 12/15-lipoxygenase (12/15-LO) has been implicated as negative regulator of systemic bone mass in mice and humans, the underlying mechanisms remain elusive. Here, we show that 12/15-LO is a positive regulator of osteoclast (OC) development. Enzymatic inhibition as well as genetic ablation of 12/15-LO significantly impaired osteoclastogenesis. Conversely, addition of the 12/15-LO-derived eicosanoids 12- and 15-HETE augmented differentiation of precursors into fully matured OCs. Together these data point towards a crucial role of 12/15-LO in the regulation of OC development. Therefore, 12/15-LO and its human homologue 15-LO may display novel targets for the treatment of diseases such as osteoporosis and rheumatoid arthritis. © 2009 Informa UK Ltd All rights reserved.
CRIS-Team Scopus Importer:2020-11-20
Keywords: 12/15-LO; HETE; OC

THE 4-D+ NANOSCOPE: THE RESOLUTION FOR BIOLOGICAL SAMPLES - Kling, L.; Mill, L.; Grüneboom, Anika; Sarau, G.; Herrmann, Martin; Schett, Georg; Maier, Andreas; Christiansen, S. H. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

The adaptor protein Swiprosin-1/EFhd2 is dispensable for platelet function in mice - Morowski, Martina; Brachs, Sebastian; Mielenz, Dirk; Nieswandt, Bernhard; Duetting, Sebastian (PLoS ONE, 2014)
Platelets are anuclear cell fragments derived from bone marrow megakaryocytes that safeguard vascular integrity, but may also cause pathological vessel occlusion. Reorganizations of the platelet cytoskeleton and agonist-induced intracellular Ca2+-mobilization are crucial for platelet hemostatic function. EF-hand domain containing 2 (EFhd2, Swiprosin-1) is a Ca2+-binding cytoskeletal adaptor protein involved in actin remodeling in different cell types, but its function in platelets is unknown.Based on the described functions of EFhd2 in immune cells, we tested the hypothesis that EFhd2 is a crucial adaptor protein for platelet function acting as a regulator of Ca2+-mobilization and cytoskeletal rearrangements.We generated EFhd2-deficient mice and analyzed their platelets in vitro and in vivo. Efhd2-/- mice displayed normal platelet count and size, exhibited an unaltered in vivo life span and showed normal Ca2+-mobilization and activation/aggregation responses to classic agonists. Interestingly, upon stimulation of the immunoreceptor tyrosine-based activation motif-coupled receptor glycoprotein (GP) VI, Efhd2-/- platelets showed a slightly increased coagulant activity. Furthermore, absence of EFhd2 had no significant impact on integrin-mediated clot retraction, actomyosin rearrangements and spreading of activated platelets on fibrinogen. In vivo EFhd2-deficiency resulted in unaltered hemostatic function and unaffected arterial thrombus formation.These results show that EFhd2 is not essential for platelet function in mice indicating that other cytoskeletal adaptors may functionally compensate its loss.
EVALuna2:13623

The ageing joint-standard age- and sex-related values of bone erosions and osteophytes in the hand joints of healthy individuals - Berlin, Andreas; Simon, David; Tascilar, K.; Figueiredo, C.; Bayat, Sara; Finzel, Stephanie; Klaus, E.; Rech, Jürgen; Hueber, Axel; Kleyer, Arnd; Schett, Georg (Osteoarthritis and Cartilage, 2019)
Objective: To analyze the age-related changes of the physiological hand joint architecture. Method: To address this concept, healthy individuals (each 10 women and 10 men in six different age decades spanning from 21 to 80 years) were recruited through a field campaign, investigated for the absence of rheumatic diseases and other comorbidities and received high-resolution quantitative computed tomography (HR-pQCT) examination of the hand joints. Number and extent of erosions and osteophytes were quantified across the ages and different sexes. Results: Bone erosions [median (Q1–Q3), 1 (0–2)] and osteophytes [2 (1–4)] were found in healthy women and men with no significant sex differences. Structural changes however accumulated with age: the overall incidence rate ratio (IRR) for the number of erosions and osteophytes per age were 1.04 (95% CI: erosions 1.03–1.06; osteophytes: 1.03–1.05). This means a 4% increase in the number of erosions and osteophytes per year. Using third decade as reference, healthy individuals in the age decades from 50 years had higher IRR for erosion numbers (sixth, seventh, eigth decade: 4.87 (2.20–11.75), 6.81 (3.08–16.46) and 6.92 (3.11–16.79)) compared to younger subjects (fourth, fifth decade: 1.80 (0.69–4.87), 1.53 (0.59–4.10)). The IRRs of osteophytes also indicate a gradual increase after the fifth decade, with IRRs of 2.32 (1.32–4.17), 4.17 (2.38–7.49) and 6.86 (3.97–12.20) for the sixth, seventh and eigth decades, respectively. Conclusions: Structural changes in the hand joints of healthy individuals are age dependent. While being rare under 50 years of age, erosions and osteophytes accumulate above the age of 50, suggesting that the threshold between “normal” and “pathological” is shifted with the increase of age.
CRIS-Team Scopus Importer:2019-06-07
Keywords: Bone erosions; Computed tomography; Hand joints; Healthy individuals; Osteophytes

THE ANTI-RO52 PREVALENCE IN THE SJOGREN'S SYNDROME PICTURE: A SINGLE CENTER CROSS SECTIONAL STUDY - Valor, Larissa; Schenker, Hannah; Hagen, Melanie; Knitza, Johannes; Rech, Jürgen; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-16

THE AP1 TRANSCRIPTION FACTOR CJUN AMPLIFIES HEDGEHOG-INDUCED FIBROBLAST ACTIVATION AND TISSUE FIBROSIS - Bergmann, C.; Merlevede, B.; Beyer, Christian; Hallenberger, L.; Brandt, Adrian; Dees, Clara; Pötter, Sebastian; Bozec, Aline; Schett, Georg; Distler, Jörg (2018)
EVALuna2:34992

The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages - Hannemann, Nicole; Jordan, Jutta; Paul, Sushmita; Reid, Stephen; Baenkler, Hanns-Wolf; Sonnewald, Sophia; Bäuerle, Tobias; Vera, Julio; Schett, Georg; Bozec, Aline (Journal of Immunology, 2017)
Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-?B and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.
EVALuna2:13412

The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development - Renoux, Florian; Stellato, Mara; Haftmann, Claudia; Vogetseder, Alexander; Huang, Riyun; Subramaniam, Arun; Becker, Mike O.; Blyszczuk, Przemyslaw; Becher, Burkhard; Distler, Jörg; Kania, Gabriela; Boyman, Onur; et al. (Cell Reports, 2020)
Regulatory T cells (Tregs) represent a major population in the control of immune homeostasis and autoimmunity. Here we show that Fos-like 2 (Fosl2), a TCR-induced AP1 transcription factor, represses Treg development and controls autoimmunity. Mice overexpressing Fosl2 (Fosl2tg) indeed show a systemic inflammatory phenotype, with immune infiltrates in multiple organs. This phenotype is absent in Fosl2tg × Rag2−/− mice lacking T and B cells, and Fosl2 induces T cell-intrinsic reduction of Treg development that is responsible for the inflammatory phenotype. Fosl2tg T cells can transfer inflammation, which is suppressed by the co-delivery of Tregs, while Fosl2 deficiency in T cells reduces the severity of autoimmunity in the EAE model. We find that Fosl2 could affect expression of FoxP3 and other Treg development genes. Our data highlight the importance of AP1 transcription factors, in particular Fosl2, during T cell development to determine Treg differentiation and control autoimmunity.
CRIS-Team Scopus Importer:2020-07-03
Keywords: autoimmunity; FoxP3; immunology; inflammation; mouse models; regulatory T cells; T cells

The AP-1 transcription factor Fra1 inhibits follicular B cell differentiation into plasma cells - Groetsch, Bettina; Brachs, Sebastian; Lang, Christiane; Luther, Julia; Derer, Anja; Schlötzer-Schrehardt, Ursula; Bozec, Aline; Fillatreau, Simon; Berberich, Ingolf; Hobeika, Elias; Reth, Michael; Wagner, Erwin F.; et al. (Journal of Experimental Medicine, 2014)
The cornerstone of humoral immunity is the differentiation of B cells into antibody-secreting plasma cells. This process is tightly controlled by a regulatory gene network centered on the transcriptional repressor B lymphocyte-induced maturation protein 1 (Blimp1). Proliferation of activated B cells is required to foster Blimp1 expression but needs to be terminated to avoid overshooting immune reactions. Activator protein 1 (AP-1) transcription factors become quickly up-regulated upon B cell activation. We demonstrate that Fra1, a Fos member of AP-1, enhances activation-induced cell death upon induction in activated B cells. Moreover, mice with B cell-specific deletion of Fra1 show enhanced plasma cell differentiation and exacerbated antibody responses. In contrast, transgenic overexpression of Fra1 blocks plasma cell differentiation and immunoglobulin production, which cannot be rescued by Bcl2. On the molecular level, Fra1 represses Blimp1 expression and interferes with binding of the activating AP-1 member c-Fos to the Blimp1 promoter. Conversely, overexpression of c-Fos in Fra1 transgenic B cells releases Blimp1 repression. As Fra1 lacks transcriptional transactivation domains, we propose that Fra1 inhibits Blimp1 expression and negatively controls plasma cell differentiation through binding to the Blimp1 promoter. In summary, we demonstrate that Fra1 negatively controls plasma cell differentiation by repressing Blimp1 expression.
EVALuna2:13013

The B cell response to citrullinated antigens in the development of rheumatoid arthritis - Scherer, Hans Ulrich; Huizinga, Tom W. J.; Krönke, Gerhard; Schett, Georg; Toes, Rene E. M. (Nature Reviews Rheumatology, 2018)
The immune response to citrullinated antigens is found almost exclusively in patients with rheumatoid arthritis (RA). It is a dynamic response that expands before the onset of disease and generates antibodies (anti-citrullinated protein antibodies (ACPAs)) that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and warrants detailed investigation, as it can offer insights into the earliest immunologic mechanisms that lead up to the development of RA. The acquisition of variable domain glycans, in fact, could enable ACPA-expressing B cells to breach tolerance. Although the underlying mechanisms are still elusive, data to support this concept are emerging, owing to the reliable identification and isolation of citrullinated antigen-directed B cells from patients with RA. This technological proficiency also allows for the generation of an increasing number of well-defined monoclonal ACPAs, and provides the opportunity to test and define the mechanisms by which the citrullinated antigen-directed B cell response contributes to the onset and persistence of inflammation. Together with a revised perception of the HLA-risk effect and novel insights into how T cells can govern antibody effector functions, these developments shape an increasingly clear picture of the B cell response to citrullinated antigens in the development of RA.
EVALuna2:34155

The BCMA:Tomato Mouse - a new reporter to characterize long-lived plasma cells - Schulz, Sebastian; Wittner, Jens; Kueh, Andrew J.; Pal, Martin; Herold, Marko J.; Schuh, Wolfgang; Jäck, Hans-Martin (JOURNAL OF IMMUNOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-08

The bone marrow side of axial spondyloarthritis - Mauro, Daniele; Gandolfo, Saviana; Tirri, Enrico; Schett, Georg; Maksymowych, Walter P.; Ciccia, Francesco (Nature Reviews Rheumatology, 2023)
Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFβ) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.
CRIS-Team Scopus Importer:2023-07-21

The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort - Hernández, Jasmin; Jordan, Suzana; Dobrota, Rucsandra; Iudici, Michele; Hasler, Paul; Ribi, Camillo; Villiger, Peter; Vlachoyiannopoulos, Panayiotis; Vacca, Alessandra; Garzanova, Ludmila; Giollo, Alessandro; Rosato, Edoardo; et al. (Swiss Medical Weekly, 2021)
OBJECTIVES: Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients. METHODS: We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts. RESULTS: We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p <0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1–12) Swiss vs 6.0 years (2–12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed. CONCLUSION: This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis.
CRIS-Team Scopus Importer:2021-09-03

The Ca2+ sensor protein swiprosin-1/EFhd2 is present in neurites and involved in kinesin-mediated transport in neurons - Purohit, Pavitra; Perez-Branguli, Francesc; Prots, Iryna; Borger, Eva; Gunn-Moore, Frank; Welzel, Oliver; Loy, Kristina; Wenzel, Eva Maria; Groemer, Teja W.; Brachs, Sebastian; Holzer, Max; Buslei, Rolf; et al. (PLoS ONE, 2014)
Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2-/-/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with pre- and post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2-/- neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2-/- primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.
EVALuna2:7246

The Canonical Wnt Pathway in the Pathogenesis of Cardiac Allograft Vasculopathy - Kuckhahn, A.; Ramsperger-Gleixner, Martina; Distler, Jörg; Spriewald, B.; Ensminger, S.; Weyand, Michael; Heim, Christian (JOURNAL OF HEART AND LUNG TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2020-04-24

The Canonical Wnt Pathway in the Pathogenesis of Cardiac Allograft Vasculopathy - Kuckhahn, A.; Ramsperger-Gleixner, Martina; Distler, Jörg; Spriewald, B.; Ensminger, S.; Weyand, Michael; Heim, Christian (Journal of Heart and Lung Transplantation, 2020)
PURPOSE: The canonical wnt pathway with its central signaling molecule β-catenin is important for tissue development and homeostasis and its dysregulation leads to many diseases including pathologies of the cardiovascular system. Inhibition of the wnt pathway has the potential to protect against cardiac allograft vasculopathy (CAV), because it reduces the proliferation of smooth muscle cells (SMCs), which is a main pathomechanism of CAV and causes neointima formation and vessel occlusion. METHODS: For in vitro experiments human (hu) and murine (mu) aortic SMCs were grown in the presence of increasing concentrations of wnt inhibitors, such as XAV-939, ICG-001 or PKF118-310. Cell proliferation was measured as the extent of PrestoBlue Cell Viability Reagent metabolism and expression of representative wnt target genes was assessed by Taqman PCR. Additionally, the wnt inhibitors were used in the mouse model of aortic transplantation (n=8 mice/group) and the extent of neointima formation as an indicator for CAV was analyzed. We also measured the expression of β-catenin (immunofluorescence staining), wnt target genes (Taqman PCR) and several inflammatory cytokines (Taqman PCR) in the transplant. RESULTS: In vitro experiments revealed dose-dependent proliferation inhibition in huSMCs and muSMCs after treatment with each wnt inhibitor. PKF118-310 induced cell death in the highest concentrations tested. While XAV-939 had only minor influence on the expression of the wnt target genes cyclin D1, axin2 and p21, ICG-001 and PKF118-310 induced the expression of p21 and cyclin D1 and reduced the expression of axin2. Interestingly, in vivo experiments showed no effect of XAV-939 and ICG-001 on neointima formation, whereas neointimal amounts of β-catenin were significantly reduced. ICG-001 also reduced the expression of inflammatory cytokines (INFγ, TNFα and IL-6) and of p21, but did not influence cyclin D1 expression. XAV-939 had no relevant influence on cytokine expression. Results for PKF118-310 and wnt target gene expression in transplants after XAV-939 treatment are currently assessed. CONCLUSION: Strong anti-proliferative effects were found in vitro for all three wnt inhibitors, but this did not lead to reduced CAV development in a mouse model of vessel transplantation. Effects on SMCs themselves after ICG-001 and PKF118-310 seem indeed mediated via regulation of wnt target genes.
CRIS-Team Scopus Importer:2020-06-09

The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats. - Hoffmann, Markus H.; Bruns, Heiko; Baeckdahl, Liselotte; Neregard, Petra; Niederreiter, Birgit; Herrmann, Martin; Catrina, Anca Irinel; Agerberth, Birgitta; Holmdahl, Rikard (Annals of the Rheumatic Diseases, 2013)
In rheumatoid arthritis (RA), neutrophil granulocytes fuel inflammation and damage tissue in the joint by releasing cytotoxic agents, antimicrobial peptides, proteases and other inflammatory mediators. The human cathelicidin LL-37 has recently been implicated in the development of systemic lupus erythematosus and psoriasis. To elucidate if antimicrobial peptides (AMPs) contribute to the pathogenesis of arthritis. Expression of LL-37 was determined in synovial membranes from patients with arthritis and control subjects. Expression of the rat cathelicidin rCRAMP and defensins was characterised in joints, blood and secondary lymphoid organs during pristane-induced arthritis (PIA) in rats and in a transfer model of PIA induced by CD4 T cells. Serum samples of rats with arthritis were tested for IgG and IgM autoantibodies against rCRAMP by immunoblot and for interferon (IFNα) by ELISA. Cathelicidins are strongly upregulated in RA synovial membranes and in joints from rats with arthritis as compared with healthy joints. Expression was most prominent in neutrophil granulocytes and macrophages/osteoclasts. Cathelicidin expression is also upregulated in the blood and spleen of pristane-injected rats, with strongest expression detected in activated CD62L- cells coexpressing granulocyte and monocyte markers. Pristane injection caused accumulation of low-density granulocytes in the blood. After pristane injection, the increased expression of rCRAMP coincided with higher levels of cell death, raised levels of interferon (IFN)α and development of autoantibodies. Our results show strong upregulation of cathelicidins and β-defensins coinciding with pathological events of arthritis. Higher expression and release of AMPs might contribute to development and/or maintenance of disease by systemic or local mechanisms. BACKGROUND OBJECTIVE METHODS RESULTS CONCLUSIONS

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts - Friščić, Jasna; Böttcher, Martin; Reinwald, Christiane; Bruns, Heiko; Wirth, Benjamin; Popp, Sebastian; Walker, Kellie Irene; Ackermann, Jochen A.; Chen, Xi; Turner, Jason; Zhu, Honglin; Seyler, Lisa; et al. (Immunity, 2021)
Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
CRIS-Team Scopus Importer:2021-04-19
Keywords: arthritis; cell metabolism; cellular senescence; complement system; inflammasome; inflammation; mechanistic target of rapamycin; synovial fibroblasts; tissue priming; trained immunity

The delivery of antigens to dendritic cells is a potent futureoption for anti-tumor therapies - Lehmann, Christian; Heger, Lukas; Neubert, K.; Harzer, Christina; Amon, Lukas; Yamazaki, S.; Heidkamp, Gordon Frederik; Eissing, N.; Krug, A.; Leusen, J.; Ravetch, J.; Nimmerjahn, Falk; et al. (2017)
EVALuna2:34372

The Disruption of Trust in the Digital Transformation Leading to Health 4.0 - Guckert, Michael; Milanovic, Kristina; Hannig, Jennifer; Simon, David; Wettengl, Tamara; Evers, Daniel; Kleyer, Arnd; Keller, Till; Pitt, Jeremy (Frontiers in Digital Health, 2022)
The specification and application of policies and guidelines for public health, medical education and training, and screening programmes for preventative medicine are all predicated on trust relationships between medical authorities, health practitioners and patients. These relationships are in turn predicated on a verbal contract that is over two thousand years old. The impact of information and communication technology (ICT), underpinning Health 4.0, has the potential to disrupt this analog relationship in several dimensions; but it also presents an opportunity to strengthen it, and so to increase the take-up and effectiveness of new policies. This paper develops an analytic framework for the trust relationships in Health 4.0, and through three use cases, assesses a medical policy, the introduction of a new technology, and the implications of that technology for the trust relationships. We integrate this assessment in a set of actionable recommendations, in particular that the trust framework should be part of the design methodology for developing and deploying medical applications. In a concluding discussion, we advocate that, in a post-pandemic world, IT to support policies and programmes to address widespread socio-medical problems with mental health, long Covid, physical inactivity and vaccine misinformation will be essential, and for that, strong trust relationships between all the stakeholders are absolutely critical.
CRIS-Team Scopus Importer:2022-11-04
Keywords: artificial intelligence; Health 4.0; medical education; public health; supervised exercise; trust; virtual reality

The double-edged role of 12/15-lipoxygenase during inflammation and immunity - Ackermann, Jochen A.; Hofheinz, Katharina; Zaiss, Mario; Krönke, Gerhard (BBA - Biochimica et Biophysica Acta, 2016)
12/15-Lipoxygenase (12/15-LOX) mediates the enzymatic oxidation of polyunsaturated fatty acids, thereby contributing to the generation of various bioactive lipid mediators. Although 12/15-LOX has been implicated in the pathogenesis of multiple chronic inflammatory diseases, its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation-associated tissue damage. This review aims to give a comprehensive overview about our current knowledge on the role of this enzyme during the regulation of inflammation and immunity. "This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder".
EVALuna2:13307

The double-edged role of neutrophil extracellular traps in inflammation - Euler, Maximilien; Hoffmann, Markus (Biochemical Society Transactions, 2019)
While there are numerous studies showing that neutrophil extracellular traps (NETs) contribute to autoimmune inflammation and cause bystander tissue injury, human individuals with genetic impairments in NET formation curiously often suffer from exacerbated autoimmune diseases and/or chronic inflammatory conditions. These findings are confirmed in some mouse models of systemic lupus erythematosus (SLE) and gouty arthritis, where an absence of neutrophils or impairment of NET formation leads to exacerbation of autoimmunity and chronic inflammation. Thus, aside from their role as archetypical proinflammatory cells, neutrophils in general, and NETs in particular, can also interrupt the self-amplifying loop of cell activation and cell recruitment that characterizes neutrophilic inflammation. Here, we review the current state-of-the-science regarding anti-inflammatory and immune-regulatory action of NETs. We give an overview about the mechanistic involvement of NET-associated neutrophil serine proteases and suggest how tailored induction of NET formation could be exploited for the treatment of chronic autoinflammatory disorders.
CRIS-Team WoS Importer:2020-02-14

The dual role of Reactive Oxygen Species in autoimmune and inflammatory diseases: evidence from preclinical models - Hoffmann, Markus; Griffiths, Helen R. (Free Radical Biology and Medicine, 2018)
Reactive oxygen species (ROS) are created in cells during oxidative phosphorylation by the respiratory chain in the mitochondria or by the family of NADPH oxidase (NOX) complexes. The first discovered and most studied of these complexes, NOX2, mediates the oxidative burst in phagocytes. ROS generated by NOX2 are dreadful weapons: while being essential to kill ingested pathogens they can also cause degenerative changes on tissue if production and release are not balanced by sufficient detoxification. In the last fifteen years evidence has been accumulating that ROS are also integral signaling molecules and are important for regulating autoimmunity and immune-mediated inflammatory diseases. It seems that an accurate redox balance is necessary to sustain an immune state that both prevents the development of overt autoimmunity (the bright side of ROS) and minimizes collateral tissue damage (the dark side of ROS). Herein, we review studies from rodent models of arthritis, lupus, and neurodegenerative diseases that show that low NOX2-derived ROS production is linked to disease and elaborate on the underlying cellular and molecular mechanisms and the translation of these results to disease in humans.
EVALuna2:213255

The effect of ageing on fat infiltration of thigh and paraspinal muscles in men - Engelke, Klaus; Ghasemikaram, Mansour; Chaudry, Oliver; Uder, Michael; Nagel, Armin Michael; Jakob, Franz; Kemmler, Wolfgang (Aging Clinical and Experimental Research, 2022)
Background Myosteatosis, skeletal muscle fat infiltration, is associated with inflammation and fibrosis. The age-related increase of myosteatosis is an important characteristic of sarcopenia and contributes to fragility. Aims To investigate the impact of healthy aging on intermuscular adipose tissue (IMAT) and muscle fat fraction (FF) in the thigh and the paraspinal muscles in males. Methods In 54 healthy males (age 20-70), all active hobby golfers, magnetic resonance imaging was performed to determine volume of IMAT, volume of muscle tissue (MT) and of percentage of FF. Results Between ages 20-70, at the thigh, IMAT/MT volume and MT FF increased annually by 2.9% and 1.3%, respectively. At the psoas IMAT/Psoas volume did not change with age. MT FF increased by 1.5% annually. At the erector spinae IMAT/Erector volume decreased by 0.3% and MT FF increased by 2.8% annually. Discussion With increasing age, in males, thigh muscle atrophied, muscle tissue was partly replaced by adipose tissue and remaining muscle tissue also contained more fat. Similar effects were observed in the erector spinae. The psoas muscle did not atrophy, although MT FF also increased with age. Overall correlations with age were weak to moderate with higher correlations observed in the paraspinal muscles. Conclusions Age-related increases of muscle fat infiltration were observed in the thigh and in the spine. Muscle atrophy did not occur in the psoas. In cross-sectional studies, an adjustment of volumetric parameters by muscle volume is advisable when comparing age-dependent results.
CRIS-Team WoS Importer:2022-06-10
Keywords: MRI; Thigh; Erector spinae; Psoas; IMAT; Muscle fat fraction

The effect of cilgavimab and neutralisation by vaccine-induced antibodies in emerging SARS-CoV-2 BA.4 and BA.5 sublineages - Arora, Prerna; Zhang, Lu; Nehlmeier, Inga; Kempf, Amy; Cossmann, Anne; Dopfer-Jablonka, Alexandra; Schulz, Sebastian R.; Jäck, Hans-Martin; Behrens, Georg M.N.; Pöhlmann, Stefan; Hoffmann, Markus (Lancet Infectious Diseases, 2022)
CRIS-Team Scopus Importer:2022-12-02

The effect of micro-and hypergravity on serum comp levels in healthy adults - Niehoff, A.; Dreiner, M.; Mundermann, A.; Zaucke, F.; Liphardt, Anna-Maria (OSTEOARTHRITIS AND CARTILAGE, 2019)
CRIS-Team WoS Importer:2019-05-21

The effect of nintedanib versus mycophenolate mofetil in the Fra2 mouse model of systemic sclerosis-associated interstitial lung disease. - Wollin, Lutz; Trinh, Minh Thuong; Zhang, Yun; Distler, Jörg (Clinical and Experimental Rheumatology, 2021)
OBJECTIVES: Interstitial lung disease (ILD) is a key driver of mortality in patients with systemic sclerosis (SSc). A lack of approved treatments encompasses a high unmet medical need. Nintedanib has recently been approved for treatment in SSc-associated ILD (SSc-ILD) following SENSCIS®, a Phase III clinical trial showing that nintedanib slows the loss of pulmonary function in patients with SSc-ILD relative to placebo, as measured by annual rate of decline in forced vital capacity over 52 weeks. The aim of this study was to compare the activity of nintedanib and mycophenolate mofetil (MMF) in a transgenic Fra2 mouse model of SSc-ILD. METHODS: Fra2 transgenic mice were treated with MMF or nintedanib. Haematoxylin and Eosin and Sirius Red staining were used to identify pulmonary fibrosis and vascular remodelling in whole lung sections. Fibrosis was quantified by Ashcroft scoring, fold change in fibrotic area, and hydroxyproline. Ki67, SM22a, CD31, and caspase-3 staining was used to quantify proliferating vascular smooth muscle cells and apoptotic endothelial cells. RESULTS: Nintedanib effectively ameliorated pulmonary vascular remodelling and fibrosis in Fra2 transgenic mice. Pulmonary fibrotic and vascular remodelling parameter scores and the apoptosis of dermal endothelial cells were significantly reduced compared with vehicle-treated Fra2 transgenic mice. Treatment with MMF had only mild antifibrotic effects and no effect on pulmonary vascular remodelling. CONCLUSIONS: In this model of SSc-ILD, nintedanib ameliorated pulmonary fibrosis, remodelling of pulmonary vasculature, and the apoptosis of endothelial cells. In contrast, MMF had minor effects on pulmonary fibrosis and no effects on vascular manifestations.
EVALuna2:486833
Keywords: systemic sclerosis; interstitial lung disease; nintedanib; mycophenolate mofetil; fibrosis

The effect of nintedanib versus mycophenolate mofetil in the Fra2 mouse model of systemic sclerosis-associated interstitial lung disease - Wollin, Lutz; Trinh, Minh Thuong; Zhang, Yun; Distler, Jörg (Clinical and Experimental Rheumatology, 2021)
Objective. Interstitial lung disease (ILD) is a key driver of mortality in patients with systemic sclerosis (SSc). A lack of approved treatments encompasses a high unmet medical need. Nintedanib has recently been approved for treatment in SSc-associated ILD (SSc-ILD) following SENSCIS (R), a Phase III clinical trial showing that nintedanib slows the loss of pulmonary function in patients with SSc-ILD relative to placebo, as measured by annual rate of decline in forced vital capacity over 52 weeks. The aim of this study was to compare the activity of nintedanib and mycophenolate mofetil (MMF) in a transgenic Fra2 mouse model of SSc-ILD.
CRIS-Team WoS Importer:2021-08-13

The Effect of Nintedanib versus Mycopheolate Mofetil in the FRA2 Mouse Model of Systemic Sclerosis Associated Interstitial Lung Disease - Thuong Trin-Minh,; Zhang, Yun; Distler, Jörg; Wollin, Lutz (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

The effects of Kv1.3 and IKCa1 channel inhibition on cytokine production and calcium influx of T lymphocytes in rheumatoid arthritis and ankylosing spondylitis - Toldi, Gergely; Munoz, Luis Enrique; Herrmann, Martin; Schett, Georg; Balog, Attila; Munoz Becerra, Luis (Immunologic Research, 2016)
Kv1.3 and IKCa1 lymphocyte potassium channels have been implicated as important targets of selective immunomodulation. We compared the alterations in cytokine production upon selective inhibition of Kv1.3 or IKCa1 channels (by MGTX and TRAM, respectively) in healthy donors (HD), RA and AS patients. We also determined calcium influx kinetics and its sensitivity to Kv1.3 and IKCa1 channel inhibition following PHA activation in CD4, Th1, Th2 and CD8 cells as well as monocytes. The application of TRAM resulted in a lower production of TNF-a and IL1-RA in all three study groups. Inhibition by TRAM had contrary effects on the production of IL-1b and IL-5: While their production was increased by PBMCs of RA patients, this effect was not observed in HD and AS PBMCs. While treatment with MGTX resulted in a similar decrease in calcium influx in the CD4 and Th2 subsets across all study groups, TRAM treatment had opposite effects on RA and HD samples: It decreased calcium influx in the Th2 and CD8 subsets in RA, while only Th1 cells were affected in HDs. The effects of IKCa1 channel inhibition are controversial in samples of RA and AS patients, since it shifts the inflammatory balance into the pro-inflammatory direction.
EVALuna2:13123
Keywords: AS; Calcium influx; Cytokine; IKCa1; Kv1.3; RA

The Exciting Future for Scleroderma: What Therapeutic Pathways Are on the Horizon? - Distler, Jörg; Riemekasten, Gabriela; Denton, Christopher P. (Rheumatic Disease Clinics of North America, 2023)
CRIS-Team Scopus Importer:2023-03-24
Keywords: Antibody; Clinical trial; Cytokine; Extracellular matrix; Scleroderma

The F4/AS01B HIV-1 Vaccine Candidate Is Safe and Immunogenic, But Does Not Show Viral Efficacy in Antiretroviral Therapy-Naive, HIV-1-Infected Adults: A Randomized Controlled Trial - Dinges, Warren; Girard, Pierre-Marie; Podzamczer, Daniel; Brockmeyer, Norbert H.; Garcia, Felipe; Harrer, Thomas; Lelievre, Jean-Daniel; Frank, Ian; De Verdiere, Nathalie Colin; Yeni, Guy-Patrick; Ortega Gonzalez, Enrique; Rubio, Rafael; et al. (Medicine, 2016)
The impact of the investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01B vaccine on HIV-1 viral load (VL) was evaluated in antiretroviral therapy (ART)-naive HIV-1 infected adults.This phase IIb, observer-blind study (NCT01218113), included ART-naive HIV-1 infected adults aged 18 to 55 years. Participants were randomized to receive 2 (F4/AS01B_2 group, N = 64) or 3 (F4/AS01B_3 group, N = 62) doses of F4/AS01B or placebo (control group, N = 64) at weeks 0, 4, and 28. Efficacy (HIV-1 VL, CD4 T-cell count, ART initiation, and HIV-related clinical events), safety, and immunogenicity (antibody and T-cell responses) were evaluated during 48 weeks.At week 48, based on a mixed model, no statistically significant difference in HIV-1 VL change from baseline was demonstrated between F4/AS01B_2 and control group (0.073 log10 copies/mL [97.5% confidence interval (CI): -0.088; 0.235]), or F4/AS01B_3 and control group (-0.096 log10 copies/mL [97.5% CI: -0.257; 0.065]). No differences between groups were observed in HIV-1 VL change, CD4 T-cell count, ART initiation, or HIV-related clinical events at intermediate timepoints. Among F4/AS01B recipients, the most frequent solicited symptoms were pain at injection site (252/300 doses), fatigue (137/300 doses), myalgia (105/300 doses), and headache (90/300 doses). Twelve serious adverse events were reported in 6 participants; 1 was considered vaccine-related (F4/AS01B_2 group: angioedema). F4/AS01B induced polyfunctional F4-specific CD4 T-cells, but had no significant impact on F4-specific CD8 T-cell and anti-F4 antibody levels.F4/AS01B had a clinically acceptable safety profile, induced F4-specific CD4 T-cell responses, but did not reduce HIV-1 VL, impact CD4 T-cells count, delay ART initiation, or prevent HIV-1 related clinical events.
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The first biologic for rheumatoid arthritis: factors influencing the therapeutic decision - Pattloch, D.; Richter, A.; Manger, Bernhard; Dockhorn, R.; Meier, L.; Tony, H. -P.; Zink, A.; Strangfeld, A. (Zeitschrift für Rheumatologie, 2016)
Biologics (disease modifying antirheumatic drugs, bDMARD) have been in use in Germany for the treatment of rheumatoid arthritis (RA) since 2001, usually after failure of at least one conventional synthetic (cs)DMARD. We analyzed temporal changes in factors that influence the decision for either a first bDMARD or a further csDMARD.We analyzed data from 9513 bDMARD-naive RA patients in the German biologics register RABBIT who switched to a new therapy. For three recruitment periods (2001-2003, 2004-2006 and 2009-2015) factors influencing the therapeutic decision were analyzed by means of machine learning methods and logistic regression analysis.In all recruitment periods the number of previous csDMARDs, high dosages of glucocorticoids (>7.5 mg/day) and a higher DAS28 (>5.1) were significantly associated with the decision for a first bDMARD. Over time, the chance of receiving a bDMARD increased in patients with moderate disease activity, moderate glucocorticoid dosages (5-7.5 mg/day) and those with comorbidities, such as congestive heart failure or prior malignancy. Men had a higher chance of receiving a bDMARD than women only in the first recruitment period. Private health insurance, high education and gainful employment were significantly associated with more frequent prescription of bDMARDs in all recruitment periods.The time-dependent changes in the impact of disease activity, concomitant drugs, gender and comorbidity on the prescription of bDMARDs mirror the increasing therapeutic options and the growing experience in the application of the new substances in patients at higher risk. The influence of demographic and social factors may reflect safety concerns in patients at increased risk of adverse events but also the need to economize drug costs..
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THE FMF&AID SURVEY - A PATIENT ORGANIZATION DRIVEN SURVEY FOR AUTOINFLAMMATORY DISEASES - Rech, Jürgen; Tascilar, Koray; Tufan, A.; Gattorno, M.; Kuemmerle-Deschner, J. B.; Ozen, S.; Krickau, Tobias; Cohen, E.; Mendonca, L. Oliveira; Kontzias, A.; Vetterli, M. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

The genetic basis for most patients with pustular skin disease remains elusive - Mössner, R.; Wilsmann-Theis, D.; Oji, V.; Gkogkolou, P.; Löhr, S.; Schulz, P.; Körber, A.; Prinz, J. C.; Renner, R.; Schäkel, K.; Vogelsang, L.; Peters, K. P.; et al. (British Journal of Dermatology, 2017)
Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause/ contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP).To better understand the disease-relevance of these genes, we screened our cohorts of patients with pustular skin diseases (primarily GPP and palmoplantar pustular psoriasis [PPP]) for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN.Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, 2 with acute generalized exanthematous pustulosis and 4 with acrodermatitis continua suppurativa Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number-variants, 258 PPP patients for coding changes in AP1S3. 11 heterozygous IL36RN mutations carriers were analyzed for a 2(nd) non-coding IL36RN mutation. Genotype-phenotype-correlations in carriers/ non-carriers of IL36RN mutations were assessed within the GPP cohort.The majority of patients (GPP:64%) did not carry rare variants in any of the three genes. Bi-allelic and mono-allelic IL36RN mutations were identified in 15 and 5 GPP patients, respectively. Non-coding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype-correlation observed for IL36RN mutation carriers was early age of disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutations carriers.The identification of IL36RN mutation carriers harboring additional rare variants in CARD14 or AP1S3, indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest additional disease-causing genetic factors in heterozygous IL36RN mutation carriers outside IL36RN. This article is protected by copyright. All rights reserved.
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The gut-bone axis: how bacterial metabolites bridge the distance - Zaiss, Mario; Jones, Rheinallt M.; Schett, Georg; Pacifici, Roberto (Journal of Clinical Investigation, 2019)
The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.
CRIS-Team Scopus Importer:2019-08-06

The gut-joint axis in rheumatoid arthritis - Zaiss, Mario; Joyce Wu, Hsin-Jung; Mauro, Daniele; Schett, Georg; Ciccia, Francesco (Nature Reviews Rheumatology, 2021)
Intestinal dysbiosis is thought to be involved in the early stages of rheumatoid arthritis (RA). In this Review, the authors discuss the gut-joint axis in RA and the potentially pathogenic role of gut-derived immune cells in the joints.
CRIS-Team WoS Importer:2021-04-09

The Histone Demethylase Jumonji Domain-Containing Protein 3 (JMJD3) As Central Mediator of Fibroblast Activation - Bergmann, Christina; Brandt, Adrian; Dees, Clara; Zhang, Yun; Chen, Chih-Wei; Mallano, Tatjana; Wohlfahrt, Thomas; Liang, Ruifang; Kagwiria, Rosebeth; Bozec, Aline; Rieker, Ralf; Abraham, David; et al. (2017)
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The histone demethylase Jumonji domain-containing protein 3 (JMJD3) regulates fibroblast activation in systemic sclerosis - Bergmann, Christina; Brandt, Adrian; Merlevede, Benita; Hallenberger, Ludwig; Dees, Clara; Wohlfahrt, Thomas; Pötter, Sebastian; Zhang, Yun; Chen, Chih-Wei; Mallano, Tatjana; Liang, Ruifang; Kagwiria, Rosebeth; et al. (Annals of the Rheumatic Diseases, 2017)
Systemic sclerosis (SSc) fibroblasts remain activated even in the absence of exogenous stimuli. Epigenetic alterations are thought to play a role for this endogenous activation. Trimethylation of histone H3 on lysine 27 (H3K27me3) is regulated by Jumonji domain-containing protein 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in a therapeutically targetable manner. The aim of this study was to explore H3K27me3 demethylases as potential targets for the treatment of fibrosis.JMJD3 was inactivated by small interfering RNA-mediated knockdown and by pharmacological inhibition with GSKJ4. The effects of targeted inactivation of JMJD3 were analysed in cultured fibroblasts and in the murine models of bleomycin-induced and topoisomerase-I (topoI)-induced fibrosis. H3K27me3 at the FRA2 promoter was analysed by ChIP.The expression of JMJD3, but not of UTX, was increased in fibroblasts in SSc skin and in experimental fibrosis in a transforming growth factor beta (TGF?)-dependent manner. Inactivation of JMJD3 reversed the activated fibroblast phenotype in SSc fibroblasts and prevented the activation of healthy dermal fibroblasts by TGF?. Pharmacological inhibition of JMJD3 ameliorated bleomycin-induced and topoI-induced fibrosis in well-tolerated doses. JMJD3 regulated fibroblast activation in a FRA2-dependent manner: Inactivation of JMJD3 reduced the expression of FRA2 by inducing accumulation of H3K27me3 at the FRA2 promoter. Moreover, the antifibrotic effects of JMJD3 inhibition were reduced on knockdown of FRA2.We present first evidence for a deregulation of JMJD3 in SSc. JMJD3 modulates fibroblast activation by regulating the levels of H3K27me3 at the promoter of FRA2. Targeted inhibition of JMJD3 limits the aberrant activation of SSc fibroblasts and exerts antifibrotic effects in two murine models.
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THE HOMEOPROTEIN ENGRAILED-1 REGULATES CANONICAL TGF-beta SIGNALING VIA FIBROBLAST DIFFERENTIATION AND TISSUE FIBROSIS - Mallano, Tatjana; Palumbo-Zerr, K.; Beyer, Christian; Dees, Clara; Huang, J.; Wohlfahrt, T.; Distler, O.; Schett, Georg; Distler, Jörg (2016)
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The human sialic acid-binding immunoglobulin-like lectin Siglec-9 and its murine homolog Siglec-E control osteoclast activity and bone resorption - Andes, F. T.; Adam, Susanne; Hahn, Madelaine; Aust, O.; Frey, Silke; Grüneboom, Anika; Nitschke, Lars; Schett, Georg; Steffen, Ulrike (Bone, 2020)
Regulation of osteoclast differentiation and function is a central element in bone homeostasis. While the role of soluble factors, such as cytokines, hormones and growth factors, in controlling osteoclast differentiation has been intensively characterized, the function of surface receptors is less well understood. Sialic acid-binding immunoglobulin-like lectin (Siglec)-9 and its murine homolog Siglec-E are sialic acid-recognizing inhibitory receptors from the CD33-related Siglec-family and mainly expressed on myeloid cells. We found Siglec-9 and Siglec-E to be expressed at all stages of human and murine osteoclastogenesis, respectively. Siglec-E knockout mice displayed lower bone mass despite unchanged osteoclast numbers and an increased bone formation rate. Ex vivo osteoclast assays using Siglec-E knockout cells or a blocking antibody against human Siglec-9 confirmed the suppressive effect of Siglec-9/Siglec-E on osteoclast function. Although osteoclast numbers were unchanged or even slightly decreased, the blockade/absence of Siglec-9/Siglec-E resulted in an augmented resorption activity of mature osteoclasts. This increased resorption activity was associated with enlarged actin rings. Together, our results suggest Siglec-9/Siglec-E to inhibit osteoclast activation independently from osteoclast differentiation and thereby propose a new mechanism for the control of local bone resorption.
CRIS-Team Scopus Importer:2020-10-16
Keywords: Bone; Osteoclasts; Resorption; Siglec-9; Siglec-E

The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements - Hoffmann-Vold, Anna Maria; Maher, Toby M.; Philpot, Edward E.; Ashrafzadeh, Ali; Barake, Rafic; Barsotti, Simone; Bruni, Cosimo; Carducci, Paolo; Carreira, Patricia E.; Castellví, Ivan; Del Galdo, Francesco; Distler, Jörg; et al. (The Lancet Rheumatology, 2020)
Background: Systemic sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods. Methods: Evidence-based consensus statements for systemic sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in systemic sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement. Findings: Between July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with systemic sclerosis should be screened for systemic sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in systemic sclerosis; pulmonary function tests support screening and diagnosis; systemic sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to escalate treatment. Interpretation: Through a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of systemic sclerosis-associated ILD. Funding: An unrestricted grant from Boehringer Ingelheim International.
CRIS-Team Scopus Importer:2020-02-04

The immune reaction against allogeneic necrotic cells is reduced in Annexin A5 knock out mice whose macrophages display an anti-inflammatory phenotype - Frey, Benjamin; Munoz, Luis Enrique; Pausch, Friederike; Sieber, Renate; Franz, Sandra; Brachvogel, Bent; Poschl, Ernst; Schneider, Holm; Roedel, Franz; Sauer, Rolf; Fietkau, Rainer; Herrmann, Martin; et al. (Journal of Cellular and Molecular Medicine, 2009)
Proteins of the annexin family bind to phospholipids in a Ca2+ dependent manner. The exposure of phosphatidylserine (PS) by apoptotic as well as necrotic cells is one major eat-me-signal for macrophages. Annexin A5 (Anx A5) preferentially binds to PS. The availability of Anx A5 knock out (KO) mice allowed us to investigate for the first time if endogenous Anx A5 modulates the immune response towards allogeneic cells. Furthermore, the effect of Anx A5 gene deletion on the phagocytic process as well as on the inflammatory reaction of macrophages was explored. We found that Anx A5 KO mice have a strongly reduced allogeneic cellular immune reaction against primary as well as secondary necrotic cells. In vivo phagocytosis experiments revealed that macrophages of Anx A5 KO mice displayed an increased uptake of necrotic cells. Additionally, an increased secretion of the anti-inflammatory cytokine IL-10 of isolated macrophages of Anx A5 KO mice after contact with necrotic cells was observed. Furthermore, the promoter activity of the Anx A5 gene was enhanced after stimulation of macrophages. The tumour size of an allogeneic tumour regressed faster when endogenous Anx A5 was present. These data demonstrate that endogenous Anx A5 influences the phagocytosis of necrotic cells, modulates the immune response towards allogeneic cells and acts as an inflammatory protein. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Allogeneic cells; Annexin A5; Immune modulation; Inflammation; Macrophages; Phagocytosis; Primary necrosis; Secondary necrosis

The Impact of Hyperosmolality on Activation and Differentiation of B Lymphoid Cells - Cvetkovic, Ljiljana; Perisic, Stojan; Titze, Jens; Jäck, Hans-Martin; Schuh, Wolfgang (Frontiers in Immunology, 2019)
B lymphocytes, as a central part of adaptive immune responses, have the ability to fight against an almost unlimited numbers of pathogens. Impairment of B cell development, activation and differentiation to antibody secreting plasma cells can lead to malignancy, allergy, autoimmunity and immunodeficiency. However, the impact of environmental factors, such as hyperosmolality or osmotic stress caused by varying salt concentrations in different lymphoid organs, on these processes is not well-understood. Here, we report that B cells respond to osmotic stress in a biphasic manner. Initially, increased osmolality boosted B cell activation and differentiation as shown by an untimely downregulation of Pax5 as well as upregulation of CD138. However, in the second phase, we observed an increase in cell death and impaired plasmablast differentiation. Osmotic stress resulted in impaired class switch to IgG1, inhibition of phosphorylation of p38 mitogen-activated kinase and a delayed NFAT5 response. Overall, these findings demonstrate the importance of microenvironmental hyperosmolality and osmotic stress caused by NaCl for B cell activation and differentiation.
CRIS-Team WoS Importer:2019-04-30

THE IMPACT OF IL-17A THERAPY ON IGG SIALYLATION IN HUMANS - Pfeifle, René; Kittler, Julia; Wuhrer, M.; Schett, Georg; Krönke, Gerhard (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-09-24

THE IMPACT OF LOW-DOSE RADIATION ON INFLAMMATORY DISEASES - Deloch, Lisa; Derer, Anja; Hueber, Axel; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2016)
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The impact of rheumatoid factor and ACPA on bone erosion in rheumatoid arthritis - Hecht, Carolin; Schett, Georg; Finzel, Stephanie (Annals of the Rheumatic Diseases, 2015)
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The importance of the NFAT5/TonEBP-Inediated osmotic stress response in B cells - Rokvic, Ljiljana; Titze, Jens; Schuh, Wolfgang; Jäck, Hans-Martin (2017)
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The INBUILD Trial of Nintedanib in Patients with Progressive Fibrosing Interstitial Lung Diseases: Subgroup with Autoimmune Diseases - Matteson, Eric; Kelly, Clive; Distler, Jörg; Mann-Vold, Anna Maria Hoff; Seibold, James; Mittoo, Shikha; Distler, Oliver; Goeldner, Rainer-Georg; Schlenker-Herceg, Rozsa; Stowasser, Susanne; Quaresma, Manuel; Flaherty, Kevin (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

The Influence of Hand Osteoarthritis on Bone Microstructure and Biomechanical Properties of Radial Bone - Simon, David; Unbehend, Sara; Bayat, Sara; Rech, Jürgen; Hueber, Axel; Schett, Georg; Kleyer, Arnd (2018)
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The influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome - Lenk, Christian; Meßbacher, Maria-Elena; Abel, Judith; Müller, Sarina Katrin; Mantsopoulos, Konstantinos; Gostian, Antoniu-Oreste; Sievert, Matti; Wirtz, Stefan; Marxreiter, Franz; Winkler, Jürgen; Iro, Heinrich; Traxdorf, Maximilian (European Review for Medical and Pharmacological Sciences, 2023)
OBJECTIVE: The aim of this study was to investigate the influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome. PATIENTS AND METHODS: Endonasal swabs from the olfactory groove of 22 patients with moderate and severe obstructive sleep apnea (OSA) and a control group of 17 healthy controls were obtained at the Department of Otorhinolaryngology of the Friedrich-Alexander-Universität Erlangen-Nürnberg. 16S rRNA gene sequencing was performed to further evaluate the endonasal microbiome. In a second step, the longitudinal influence of continuous positive airway pressure (CPAP) therapy on the nasal microbiome was investigated (3-6 and 6-9 months). RESULTS: Analysis of the bacterial load and β-diversity showed no significant differences between the groups, although patients with severe OSA showed increased α-diversity compared to the control group, while those with moderate OSA showed decreased α-diversity. The evaluation of longitudinal changes in the nasal microbiota during CPAP treatment showed no significant difference in α- or β-diversity. However, the number of bacteria for which a significant difference between moderate and severe OSA was found in the linear discriminant analysis decreased during CPAP treatment. CONCLUSIONS: Long-term CPAP treatment showed an alignment of the composition of the nasal microbiome in patients with moderate and severe OSA as well as an alignment of biodiversity with that of the healthy control group. This change in the composition of the microbiome could be both part of the therapeutic effect in CPAP therapy and a promoting factor of the adverse side effects of the therapy. Further studies are needed to investigate whether the endonasal microbiome is related to CPAP compliance and whether CPAP compliance can be positively influenced in the future by therapeutic modification of the microbiome.
CRIS-Team WoS Importer:2023-05-26

The Interaction of Physical Function and Emotional Well-being in Rheumatoid Arthritis-What is the Impact on Disease Activity and Coping? - Englbrecht, Matthias; Araujo, Madeleine Kruckow Elizabeth; Rech, Jürgen; Schett, Georg; et al. (Seminars in Arthritis and Rheumatism, 2013)
Objective: To evaluate the impact of the interaction of physical function and emotional well-being on disease-related parameters and coping with rheumatoid arthritis. Methods: A cross-sectional survey among 177 RA patients included demographic and disease-related variables as well as the following patient-reported outcome measures: Health Assessment Questionnaire-Disability Index (HAQ-DI) (physical function), Mental Component Summary Scale of the SF-36 (MCSS) for emotional well-being, Rheumatoid Arthritis Disease Activity Index (RADAI), and Coping with Rheumatoid Arthritis Questionnaire (C-RAQ). Based on HAQ-DI and MCSS, six categories representing various levels of physical and emotional impairment were formed. Multivariate analysis of variance and a subsequent discriminant analysis were used to evaluate whether demographic and disease-related variables and coping strategies differed between these categories. Results: Patients with moderate to high impairment of physical function and emotional well-being reported significantly higher disease activity and a more frequent use of distancing and active problem solving coping strategies than patients with low-level impairment (. p<0.001-0.043). Furthermore, these patients reported experiencing significantly higher levels of helplessness (. p<0.001-0.032). Results from the discriminant analysis highlighted a combination of disease activity and helplessness to differentiate best between patients with either low or high impairment of physical function and emotional well-being (. p<0.001). Conclusion: Aside from perceived disease activity, helplessness, and distancing as well as active problem solving allowed for a good discrimination between the different levels of impairment of physical function and emotional well-being. Encouraging and educating patients on how to cognitively reframe their current situation might play a key role in reducing the level of helplessness resulting from impairments of physical function and emotional well-being. © 2013 Elsevier Inc.
CRIS-Team Scopus Importer:2021-02-03
Keywords: Coping; Disease activity; Emotional well-being; Health-related quality of life; Patient-reported outcomes; Physical function; Rheumatoid arthritis

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation - Zaiss, Mario; Rapin, Alexis; Lebon, Luc; Dubey, Lalit Kumar; Mosconi, Ilaria; Sarter, Kerstin; Piersigilli, Alessandra; Menin, Laure; Walker, Alan W.; Rougemont, Jacques; Paerewijck, Oonagh; Geldhof, Peter; et al. (Immunity, 2015)
Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.
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The intestine: A highly dynamic microenvironment for IgA plasma cells - Pracht, Katharina; Wittner, Jens; Kagerer, Fritz; Jäck, Hans-Martin; Schuh, Wolfgang (Frontiers in Immunology, 2023)
To achieve longevity, IgA plasma cells require a sophisticated anatomical microenvironment that provides cytokines, cell-cell contacts, and nutrients as well as metabolites. The intestinal epithelium harbors cells with distinct functions and represents an important defense line. Anti-microbial peptide-producing paneth cells, mucus-secreting goblet cells and antigen-transporting microfold (M) cells cooperate to build a protective barrier against pathogens. In addition, intestinal epithelial cells are instrumental in the transcytosis of IgA to the gut lumen, and support plasma cell survival by producing the cytokines APRIL and BAFF. Moreover, nutrients are sensed through specialized receptors such as the aryl hydrocarbon receptor (AhR) by both, intestinal epithelial cells and immune cells. However, the intestinal epithelium is highly dynamic with a high cellular turn-over rate and exposure to changing microbiota and nutritional factors. In this review, we discuss the spatial interplay of the intestinal epithelium with plasma cells and its potential contribution to IgA plasma cell generation, homing, and longevity. Moreover, we describe the impact of nutritional AhR ligands on intestinal epithelial cell-IgA plasma cell interaction. Finally, we introduce spatial transcriptomics as a new technology to address open questions in intestinal IgA plasma cell biology.
CRIS-Team Scopus Importer:2023-03-24
Keywords: Aryl hydrocarbon (Ah) receptor; IgA; IgA plasma cells; intestinal epithelial barrier; intestinal epithelial cell; plasma cell; survival niche

THE INVOLVEMENT OF THE LONG NONCODING H19X IN TGF beta SIGNALING AND ITS PROFIBROTIC EFFECTS IN SYSTEMIC SCLEROSIS AND OTHER FIBROTIC DISEASES - Pachera, E.; Assassi, S.; Salazar, G.; Frank-Bertoncelj, M.; Dobrota, R.; Brock, M.; Kurreeman, F.; De Vries-Bouwstra, J.; Messemaker, T.; Feghali-Bostwick, C.; Distler, Jörg; Kania, G.; et al. (2016)
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The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis - Fischer, Anita; Abdollahi-Roodsaz, Shahla; Boehm, Christina; Niederreiter, Birgit; Meyer, Brigitte; Yau, Anthony C. Y.; Lonnblom, Erik; Joosten, Leo A. B.; Koenders, Marije; Lehmann, Christian; Dudziak, Diana; Krönke, Gerhard; et al. (Journal of Cellular and Molecular Medicine, 2018)
Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, α-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW)-induced arthritis was reduced in the T cell-dependent phase, whereas T cell-independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis.
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The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain - Süß, Patrick; Rothe, Tobias; Hoffmann, Alana; Schlachetzki, Johannes C. M.; Winkler, Jürgen (Frontiers in Immunology, 2020)
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses. This mini review summarizes the current knowledge of CNS comorbidity in RA patients and known underlying cellular mechanisms. We focus on the differential regulation of CNS myeloid and glial cells in different mouse models of RA reflecting different patterns of peripheral immune activation. Moreover, we address CNS responses to anti-inflammatory treatment in human RA patients and mice. Finally, to illustrate the bidirectional communication between the CNS and chronic peripheral inflammation, we present the current knowledge about the impact of the CNS on arthritis. A comprehensive understanding of the crosstalk between the CNS and chronic peripheral inflammation will help to identify RA patients at risk of developing CNS comorbidity, setting the path for future therapeutic approaches in both RA and neuropsychiatric diseases.
CRIS-Team WoS Importer:2021-01-08

The Joint Vasculitis Registry in German-speaking countries (GeVas) – a prospective, multicenter registry for the follow-up of long-term outcomes in vasculitis - Iking-Konert, Christof; Wallmeier, Pia; Arnold, Sabrina; Adler, Sabine; De Groot, Kirsten; Hellmich, Bernhard; Hoyer, Bimba F.; Holl-Ulrich, Konstanze; Ihorst, Gabriele; Kaufmann, Margit; Koetter, Ina; Mueller-Ladner, Ulf; et al. (BMC Rheumatology, 2021)
Background: Vasculitides comprise a group of rare diseases which affect less than 5 in 10.000 individuals. Most types of vasculitis can become organ- and life-threatening and are characterized by chronicity, high morbidity and relapses, altogether resulting in significant morbidity and mortality. Previous studies have been either monocentric or mainly retrospective – studies with a prospective design mostly consisted of rather small cohorts of 100 to 200 patients. The aim of the Joint Vasculitis Registry in German-speaking countries (GeVas) is to record all patients who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). In GeVas, data are collected prospectively in a multicenter design in Germany, Austria and Switzerland. By this approach, courses of vasculitis and their outcomes can be monitored over an extended period. Methods: GeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term progress and other outcomes of various types of vasculitis. The registry started recruiting in June 2019. As of October 2020, 14 centers have been initiated and started recruiting patients in Germany. Involvement of sites in Austria and the German-speaking counties of Switzerland is scheduled in the near future. Discussion: In June 2019, we successfully established a prospective multicenter vasculitis registry being the first of its kind in German-speaking countries. The participating centers are currently recruiting, and systematic analysis of long-term vasculitis outcomes is expected in the ensuing period. Trial registration: German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866. Registered 10 May 2019.
CRIS-Team Scopus Importer:2021-08-13
Keywords: ANCA; GeVas; Giant cell arteritis; Long term; Outcome; Prospective; Registry; Therapy; Vasculitis

The microprocessor component, DGCR8, is essential for early B-cell development in mice - Brandl, Andreas; Daum, Patrick; Brenner, Sven; Schulz, Sebastian; Yap, Desmond Yat Hin; Boesl, Michael R.; Wittmann, Jürgen; Schuh, Wolfgang; Jäck, Hans-Martin (European Journal of Immunology, 2016)
microRNAs (miRNAs) are important posttranscriptional regulators during hematopoietic lineage commitment and lymphocyte development. Mature miRNAs are processed from primary miRNA transcripts in two steps by the microprocessor complex, consisting of Drosha and its partner DiGeorge Critical Region 8 (DGCR8), and the RNAse III enzyme, Dicer. Conditional ablations of Drosha and Dicer have established the importance of both RNAses in B- and T-cell development. Here, we show that a cre-mediated B-cell specific deletion of DGCR8 in mice results in a nearly complete maturation block at the transition from the pro-B to the pre-B cell stage, and a failure to upregulate Ig ? heavy chain expression in pro-B cells. Furthermore, we found that the death of freshly isolated DGCR8-deficient pro-B cells could be partially prevented by enforced Bcl2 expression. We conclude from these findings that the microprocessor component DGCR8 is essential for survival and differentiation of early B-cell progenitors.
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The microRNA processing subunit DGCR8 is required for a T cell-dependent germinal center response - Daum, Patrick; Ottmann, Shannon; Meinzinger, Julia; Schulz, Sebastian; Corte-Real, Joana; Hauke, Manuela; Roth, Edith; Schuh, Wolfgang; Mielenz, Dirk; Jäck, Hans-Martin; Pracht, Katharina (Frontiers in Immunology, 2022)
We have previously shown that the microRNA (miRNA) processor complex consisting of the RNAse Drosha and the DiGeorge Critical Region (DGCR) 8 protein is essential for B cell maturation. To determine whether miRNA processing is required to initiate T cell-mediated antibody responses, we deleted DGCR8 in maturing B2 cells by crossing a mouse with loxP-flanked DGCR8 alleles with a CD23-Cre mouse. As expected, non-immunized mice showed reduced numbers of mature B2 cells and IgG-secreting cells and diminished serum IgG titers. In accordance, germinal centers and antigen-specific IgG-secreting cells were absent in mice immunized with T-dependent antigens. Therefore, DGCR8 is required to mount an efficient T-dependent antibody response. However, DGCR8 deletion in B1 cells was incomplete, resulting in unaltered B1 cell numbers and normal IgM and IgA titers in DGCR8-knock-out mice. Therefore, this mouse model could be used to analyze B1 responses in the absence of functional B2 cells.
CRIS-Team WoS Importer:2023-01-27

The microRNA processing subunit DGCR8 is required for immune response and germinal center formation - Daum, Patrick; Meinzinger, Julia; Pracht, Katharina; Corte-Real, Joana; Wittmann, Jürgen; Jäck, Hans-Martin (2017)
EVALuna2:13656

The need for comparative data in spondyloarthritis - Choy, Ernest; Baraliakos, Xenofon; Behrens, Frank; D'Angelo, Salvatore; De Vlam, Kurt; Kirkham, Bruce W.; Ostergaard, Mikkel; Schett, Georg; Rissler, Michael; Chaouche-Teyara, Kamel; Perella, Chiara (Arthritis Research & Therapy, 2019)
Spondyloarthritis comprises a group of inflammatory diseases, characterised by inflammation within axial joints and/or peripheral arthritis, enthesitis and dactylitis. An increasing number of biologic treatments, including biosimilars, are available for the treatment of spondyloarthritis. Although there are a growing number of randomised controlled trials assessing treatments in spondyloarthritis, there is a paucity of data from head-to-head studies. Comparative data are required so that clinicians and payers have the level of evidence required to inform clinical decision-making and health economic assessments. In the absence of head-to-head studies, statistical methods such as network meta-analyses and matching-adjusted indirect comparisons (MAICs) are used for assessing comparative effectiveness. Network meta-analysis can be used to compare treatments for trials using a common comparator (e.g. placebo); however, for those without a common comparator or where considerable heterogeneity exists between the study populations, a MAIC that controls for differences in study design and baseline patient characteristics may be used. MAICs, unlike network meta-analyses, are of value for longer-term comparisons beyond the placebo-controlled phase of clinical trials, which is important for chronic diseases requiring long-term treatment, like spondyloarthritis. At present, there are a number of limitations that restrict the effectiveness of MAIC, such as the poor availability of individual patient-level data from trials, which results in patient-level data from one trial being compared with published whole-population data from another. Despite these limitations, drug reimbursement agencies are increasingly accepting MAIC as a means of comparative effectiveness and greater methodological guidance is needed. This report highlights a number of challenges that are specific to conducting comparative studies like MAIC in spondyloarthritis, including disease heterogeneity, the paucity of biomarkers and the duration of studies required for radiographic endpoints in this slow-progressing disease.
CRIS-Team Scopus Importer:2019-05-07
Keywords: Biological therapy; Clinical trials; Psoriatic arthritis; Radiography; Spondyloarthropathy

The non-neuronal cyclin-dependent kinase 5 is a fibrotic mediator potentially implicated in systemic sclerosis and a novel therapeutic target - Wei, Jun; Marangoni, Roberta G.; Fang, Feng; Wang, Wenxia; Huang, Jingang; Distler, Jörg; Varga, John (Oncotarget, 2018)
The mechanisms underlying persistent fibroblast activation and myofibroblast phenoconversion in underlying multi-organ fibrosis in systemic sclerosis (SSc) remain incompletely understood, hindering effective therapies to slow or reverse the process. Cyclin-dependent kinase 5 (CDK5) is a pleiotropic member of the CDK family originally identified in neuronal cells. In contrast to other CDKs, CDK5 activity depends on its CDK5R1 subunit p35. Here we demonstrate that expression of p35 and CDK5 activity are induced by TGF-ß in fibroblasts and adipocytic cell types. Levels of p35 are markedly elevated in both SSc skin biopsies and explanted SSc fibroblasts, as well as in fibrotic skin in mice. Ectopic p35 and CDK5 suppressed adipogenic markers while stimulating collagen production and myofibroblast markers, whereas RNAi-mediated CDK5 knockdown abrogated TGF-β fibrotic responses in a Smad-independent manner. Pharmacological inhibitors of CDK5 likewise prevented and reversed TGF-β responses in fibroblast monolayers and in ex vivo human skin organ cultures, ameliorated collagen overproduction in SSc fibroblasts, and prevented and reversed skin fibrosis in two distinct mouse models of SSc. Together, these results reveal a previously unrecognized key function for p35/CDK5 as a mediator of mesenchymal cell fibrotic responses. The results suggest a potential pathogenic role for elevated p35 expression and CDK5 activity in SSc, and raise the possibility that their selective pharmacological targeting might represent a novel treatment approach in fibrosis.
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The novel interleukin-1 cytokine family members in inflammatory diseases - Hahn, Madelaine; Frey, Silke; Hueber, Axel (Current Opinion in Rheumatology, 2016)
This review provides an update on the new interleukin-1 (IL-1) cytokine family members in inflammatory diseases with focus on recent findings concerning the family members IL-36, IL-37, and IL-38 and their different expression patterns.The IL-1 cytokines are known to be involved in many different inflammatory and autoimmune diseases. The latest IL-1 family members, IL-36, IL-37, and IL-38 have been shown to be differently regulated during course of disease. Studies of patients suffering from inflammatory diseases revealed that those cytokines are upregulated in the serum as well as in inflamed tissue. Both, epithelial cells and infiltrating peripheral mononuclear blood cells serve as source of the cytokines IL-36, IL-37, and IL-38 triggering different outcomes. These results could be confirmed in different mouse models and in-vitro and ex-vivo studies.IL-36, IL-37, and IL-38 are involved in the pathogenesis of the inflammatory diseases psoriasis, rheumatoid arthritis, gout, systemic lupus erythematosus as well as Crohn's disease. Thereby IL-36 acts proinflammatory triggering further inflammatory mediators. In contrast, IL-37 and IL-38 are upregulated to counteract. Understanding the imbalance of the IL-1 family is crucial for future therapeutics.
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The novel molecular mechanism of pulmonary fibrosis: insight into lipid metabolism from reanalysis of single-cell RNA-seq databases - Shi, Xiangguang; Chen, Yahui; Shi, Mengkun; Gao, Fei; Huang, Lihao; Wang, Wei; Wei, Dong; Shi, Chenyi; Yu, Yuexin; Xia, Xueyi; Song, Nana; Chen, Xiaofeng; et al. (Lipids in Health and Disease, 2024)
Pulmonary fibrosis (PF) is a severe pulmonary disease with limited available therapeutic choices. Recent evidence increasingly points to abnormal lipid metabolism as a critical factor in PF pathogenesis. Our latest research identifies the dysregulation of low-density lipoprotein (LDL) is a new risk factor for PF, contributing to alveolar epithelial and endothelial cell damage, and fibroblast activation. In this study, we first integrative summarize the published literature about lipid metabolite changes found in PF, including phospholipids, glycolipids, steroids, fatty acids, triglycerides, and lipoproteins. We then reanalyze two single-cell RNA-sequencing (scRNA-seq) datasets of PF, and the corresponding lipid metabolomic genes responsible for these lipids’ biosynthesis, catabolism, transport, and modification processes are uncovered. Intriguingly, we found that macrophage is the most active cell type in lipid metabolism, with almost all lipid metabolic genes being altered in macrophages of PF. In type 2 alveolar epithelial cells, lipid metabolic differentially expressed genes (DEGs) are primarily associated with the cytidine diphosphate diacylglycerol pathway, cholesterol metabolism, and triglyceride synthesis. Endothelial cells are partly responsible for sphingomyelin, phosphatidylcholine, and phosphatidylethanolamines reprogramming as their metabolic genes are dysregulated in PF. Fibroblasts may contribute to abnormal cholesterol, phosphatidylcholine, and phosphatidylethanolamine metabolism in PF. Therefore, the reprogrammed lipid profiles in PF may be attributed to the aberrant expression of lipid metabolic genes in different cell types. Taken together, these insights underscore the potential of targeting lipid metabolism in developing innovative therapeutic strategies, potentially leading to extended overall survival in individuals affected by PF.
CRIS-Team Scopus Importer:2024-04-12
Keywords: Lipid metabolism; Lipid metabolomic gene; Single-cell RNA-sequencing reanalysis; Pulmonary fibrosis

The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor β and contributes to the development of experimental dermal fibrosis - Avouac, Jerome; Palumbo-Zerr, Katrin; Ruzehaji, Nadira; Tomcik, Michal; Zerr, Pawel; Dees, Clara; Distler, Alfiya; Beyer, Christian; Schneider, Holm; Distler, Oliver; Schett, Georg; Allanore, Yannick; et al. (Arthritis and Rheumatology, 2014)
Objective Nuclear receptors regulate cell growth, differentiation, and homeostasis. Selective nuclear receptors promote fibroblast activation, which leads to tissue fibrosis, the hallmark of systemic sclerosis (SSc). This study was undertaken to investigate the effects of constitutive androstane receptor (CAR)/NR1I3, an orphan nuclear receptor, on fibroblast activation and experimental dermal fibrosis. Methods CAR expression was quantified by quantitative polymerase chain reaction, Western blotting, immunohistochemistry, and immunofluorescence. CAR expression was modulated by small molecules, small interfering RNA, forced overexpression, and site-directed mutagenesis. The effects of CAR activation were analyzed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor type I (TβRI-CA). Results Up-regulation of CAR was detected in the skin and in dermal fibroblasts in SSc patients. Stimulation of healthy fibroblasts with TGFβ induced the expression of CAR messenger RNA and protein in a Smad-dependent manner. Pharmacologic activation or overexpression of CAR in healthy fibroblasts significantly increased the stimulatory effects of TGFβ on collagen synthesis and myofibroblast differentiation, and amplified the stimulatory effects of TGFβ on COL1A2 transcription activity. Treatment with CAR agonist increased the activation of canonical TGFβ signaling in murine models of SSc and exacerbated bleomycin-induced and TβRI-CA-induced fibrosis with increased dermal thickening, myofibroblast counts, and collagen accumulation. Conclusion Our findings indicate that CAR is up-regulated in SSc and regulates TGFβ signaling. Activation of CAR increases the profibrotic effects of TGFβ in cultured fibroblasts and in different preclinical models of SSc. Thus, inactivation of CAR might be a novel approach to target aberrant TGFβ signaling in SSc and in other fibrotic diseases.
CRIS-Team Scopus Importer:2020-07-01

The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation - Rothe, Tobias; Ipseiz, Natacha; Faas, Maria; Lang, Stefanie; Perez-Branguli, Francesc; Metzger, Daniel; Ichinose, Hiroshi; Winner, Beate; Schett, Georg; Krönke, Gerhard (Journal of Immunology, 2017)
Microglia cells fulfill key homeostatic functions and essentially contribute to host defense within the CNS. Altered activation of microglia, in turn, has been implicated in neuroinflammatory and neurodegenerative diseases. In this study, we identify the nuclear receptor (NR) Nr4a1 as key rheostat controlling the activation threshold and polarization of microglia. In steady-state microglia, ubiquitous neuronal-derived stress signals such as ATP induced expression of this NR, which contributed to the maintenance of a resting and noninflammatory microglia phenotype. Global and microglia-specific deletion of Nr4a1 triggered the spontaneous and overwhelming activation of microglia and resulted in increased cytokine and NO production as well as in an accelerated and exacerbated form of experimental autoimmune encephalomyelitis. Ligand-induced activation of Nr4a1 accordingly ameliorated the course of this disease. Our current data thus identify Nr4a1 as regulator of microglia activation and potentially new target for the treatment of inflammatory CNS diseases such as multiple sclerosis.
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The nuclear receptor Nr4a1 mediates anti-inflammatory effects of apoptotic cells - Ipseiz, Natacha; Uderhardt, Stefan; Scholtysek, Carina; Steffen, Martin; Schabbauer, Gernot; Bozec, Aline; Schett, Georg; Krönke, Gerhard (Journal of Immunology, 2014)
Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-?B signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-?B signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to "dying self."
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The Nuclear Receptor ROR-Alpha As a Key Checkpoint of Tissue Repair - Kagwiria, Rosebeth; Liang, Ruifang; Chen, Chih-Wei; Burris, Thomas; Schett, Georg; Distler, Jörg (2017)
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THE NUCLEAR RECEPTOR TR4 ORCHESTRATES CYTOSKELETAL ORGANIZATION IN A G alpha 12/ROCK-DEPENDENT MANNER TO PROMOTE MYOFIBROBLAST DIFFERENTIATION AND TISSUE FIBROSIS IN SYSTEMIC SCLEROSIS - Shen, Lichong; Zhang, Yun; Honglin, Z.; Distler, Jörg (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

The OMERACT Ultrasound Group: A Report from the OMERACT 2016 Meeting and Perspectives - Terslev, Lene; Iagnocco, Annamaria; Bruyn, George A. W.; Naredo, Esperanza; Vojinovic, Jelena; Collado, Paz; Damjanov, Nemanja; Filer, Andrew; Filippou, Georgios; Finzel, Stephanie; Gandjbakhch, Frederique; Ikeda, Kei; et al. (Journal of Rheumatology, 2017)
To provide an update from the Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group on the progress for defining ultrasound (US) minimal disease activity threshold at joint level in rheumatoid arthritis (RA) and for standardization of US application in juvenile idiopathic arthritis (JIA).For minimal disease activity, healthy controls (HC) and patients with early arthritis (EA) who were naive to disease-modifying antirheumatic drugs were recruited from 2 centers. US was performed of the hands and feet, and scored semiquantitatively (0-3) for synovial hypertrophy (SH) and power Doppler (PD). Synovial effusion (SE) was scored a binary variable. For JIA, a Delphi approach and subsequent validation in static images and patient-based exercises were used to developed preliminary definitions for synovitis and a scoring system.For minimal disease activity, 7% HC had at least 1 joint abnormality versus 30% in the EA group. In HC, the findings of SH and PD were predominantly grade 1 whereas all grades were seen in the EA cohort, but SE was rare. In JIA, synovitis can be diagnosed based on B-mode findings alone because of the presence of physiological vascularization. A semiquantitative scoring system (0-3) for synovitis for both B-mode and Doppler were developed in which the cutoff between Doppler grade 2 and grade 3 was 30%.The first step has been taken to define the threshold for minimal disease activity in RA by US and to define and develop a scoring system for synovitis in JIA. Further steps are planned for the continuous validation of US in these areas.
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The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic - Hoffmann, Markus; Krüger, Nadine; Schulz, Sebastian; Cossmann, Anne; Rocha, Cheila; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Moldenhauer, Anna Sophie; Winkler, Martin S.; Lier, Martin; Dopfer-Jablonka, Alexandra; et al. (Cell, 2022)
The rapid spread of the SARS-CoV-2 Omicron variant suggests that the virus might become globally dominant. Further, the high number of mutations in the viral spike protein raised concerns that the virus might evade antibodies induced by infection or vaccination. Here, we report that the Omicron spike was resistant against most therapeutic antibodies but remained susceptible to inhibition by sotrovimab. Similarly, the Omicron spike evaded neutralization by antibodies from convalescent patients or individuals vaccinated with the BioNTech-Pfizer vaccine (BNT162b2) with 12- to 44-fold higher efficiency than the spike of the Delta variant. Neutralization of the Omicron spike by antibodies induced upon heterologous ChAdOx1 (Astra Zeneca-Oxford)/BNT162b2 vaccination or vaccination with three doses of BNT162b2 was more efficient, but the Omicron spike still evaded neutralization more efficiently than the Delta spike. These findings indicate that most therapeutic antibodies will be ineffective against the Omicron variant and that double immunization with BNT162b2 might not adequately protect against severe disease induced by this variant.
CRIS-Team Scopus Importer:2022-01-28
Keywords: antibody; immune evasion; neutralization; Omicron; SARS-CoV-2; spike; vaccine

The Pathogenicity of Anti-β2GP1-IgG Autoantibodies Depends on Fc Glycosylation. - Fickentscher, Christoph; Magorivska, Iryna; Janko, Christina; Biermann, Mona; Bilyy, Rostyslav; Nalli, Cecilia; Tincani, Angela; Medeghini, Veronica; Meini, Antonella; Nimmerjahn, Falk; Schett, Georg; Munoz, Luis E.; et al. (Journal of immunology research, 2015)
To analyze the glycosylation of anti-β2GP1, we investigated purified IgG from healthy children, patients with APS, and asymptomatic adult carriers of antiphospholipid antibodies. We observed that in the sera of healthy children and of patients with APS, IgG3 and IgG2 were predominant, respectively. The potentially protective anti-β2GP1-IgM was lower in the sera of healthy children. Although anti-β2GP1-associated C1q did not differ between children and patients with antiphospholipid syndrome, the associated C3c was significantly higher in the sera of healthy children. This indicates a more efficient clearance of anti-β2GP1 immune complexes in the healthy children. This clearance is not accompanied by inflammation or coagulatory events. It is likely that the most important pathogenic factor of the anti-β2GP1-IgG is related to the different glycosylation observed in healthy and diseased individuals. We detected a significantly higher sialylation of anti-β2GP1-IgG isolated from the sera of healthy children and asymptomatic adults when compared with that of patients with clinically apparent antiphospholipid syndrome. Low sialylated IgG reportedly ameliorates inflammation and inflammation promotes hyposialylation. Thus, both reactions create a vicious circle that precipitates the pathology of the antiphospholipid syndrome including thrombus-formation. We conclude that the increased sialylation of anti-β2GP1-IgG of sera of healthy individuals limits their pathogenicity.

THE PHYSIOLOGICAL FINGER JOINT ARCHITECTURE - AGE-RELATED INCREASE OF EROSIONS AND OSTEOPHYTES IN THE JOINTS OF HEALTHY INDIVIDUALS - Simon, David; Berlin, Andreas; Tascilar, Koray; Bayat, Sara; Engelke, Klaus; Rech, Jürgen; Figuereido, Camille; Hueber, Axel; Schett, Georg; Kleyer, Arnd (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

The potential of omics technologies for the treatment of immune‐mediated inflammatory diseases - Anchang, Charles Gwellem; Xu, Cong; Raimondo, Maria Gabriella; Atreya, Raja; Maier, Andreas; Schett, Georg; Zaburdaev, Vasily; Rauber, Simon; Ramming, Andreas (International Journal of Molecular Sciences, 2021)
Immune‐mediated inflammatory diseases (IMIDs), such as inflammatory bowel diseases and inflammatory arthritis (e.g., rheumatoid arthritis, psoriatic arthritis), are marked by increasing worldwide incidence rates. Apart from irreversible damage of the affected tissue, the systemic nature of these diseases heightens the incidence of cardiovascular insults and colitis‐associated neo-plasia. Only 40–60% of patients respond to currently used standard‐of‐care immunotherapies. In addition to this limited long‐term effectiveness, all current therapies have to be given on a lifelong basis as they are unable to specifically reprogram the inflammatory process and thus achieve a true cure of the disease. On the other hand, the development of various OMICs technologies is consid-ered as “the great hope” for improving the treatment of IMIDs. This review sheds light on the pro-gressive development and the numerous approaches from basic science that gradually lead to the transfer from “bench to bedside” and the implementation into general patient care procedures.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Advanced imaging technologies; Immune‐mediated inflammatory diseases (IMIDs); Single‐cell RNA sequencing; Spatial sequencing

The pro and anti-inflammatory activities of immunoglobulin G - Lux, Anja; Aschermann, Sarah; Biburger, Markus; Nimmerjahn, Falk (Annals of the Rheumatic Diseases, 2010)
Immunoglobulin G (IgG) molecules are a family of glycoproteins essential for defending the body against invading pathogens. The antibody constant domain is very potent in initiating proinflammatory pathways such as the activation of innate immune effector cells via cellular receptors specific for the antibody constant region (Fc receptors) and the activation of the complement pathway. During autoimmune disease the normally protective antimicrobial function of these molecules is targeted to healthy tissues often with disastrous consequences. Interestingly, one successful anti-inflammatory therapy for many autoimmune diseases is the infusion of high doses of IgG molecules, the so-called intravenous IgG therapy. How one class of molecules can have such opposing functions will be the major focus of this review.

THE PROGNOSIS OF HEART FAILURE IN PATIENTS WITH RHEUMATOID ARTHRITIS - Meissner, Y.; Schaefer, M.; Manger, Bernhard; Zaenker, M.; Ochs, W.; Listing, J.; Strangfeld, A. (2018)
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The Progression of Cell Death Affects the Rejection of Allogeneic Tumors in Immune-Competent Mice - Implications for Cancer Therapy - Chaurio Gonzalez, Ricardo Alfredo; Munoz, Luis E.; Maueröder, Christian; Janko, Christina; Harrer, Thomas; Fuernrohr, Barbara G.; Niederweis, Michael; Bilyy, Rostyslav; Schett, Georg; Herrmann, Martin; Berens, Christian (Frontiers in Immunology, 2014)
Large amounts of dead and dying cells are produced during cancer therapy and allograft rejection. Depending on the death pathway and stimuli involved, dying cells exhibit diverse features, resulting in defined physiological consequences for the host. It is not fully understood how dying and dead cells modulate the immune response of the host. To address this problem, different death stimuli were studied in B16F10 melanoma cells by regulated inducible transgene expression of the pro-apoptotic active forms of caspase-3 (revCasp-3), Bid (tBid), and the Mycobacterium tuberculosis-necrosis inducing toxin (CpnTCTD). The immune outcome elicited for each death stimulus was assessed by evaluating the allograft rejection of melanoma tumors implanted subcutaneously in BALB/c mice immunized with dying cells. Expression of all proteins efficiently killed cells in vitro (>90%) and displayed distinctive morphological and physiological features as assessed by multiparametric flow cytometry analysis. BALB/c mice immunized with allogeneic dying melanoma cells expressing revCasp-3 or CpnTCTD showed strong rejection of the allogeneic challenge. In contrast, mice immunized with cells dying either after expression of tBid or irradiation with UVB did not, suggesting an immunologically silent cell death. Surprisingly, immunogenic cell death induced by expression of revCasp-3 or CpnTCTD correlated with elevated intracellular reactive oxygen species (ROS) levels at the time point of immunization. Conversely, early mitochondrial dysfunction induced by tBid expression or UVB irradiation accounted for the absence of intracellular ROS accumulation at the time point of immunization. Although ROS inhibition in vitro was not sufficient to abrogate the immunogenicity in our allo-immunization model, we suggest that the point of ROS generation and its intracellular accumulation may be an important factor for its role as damage associated molecular pattern in the development of allogeneic responses.
EVALuna2:13056

The proinflammatory effect of C-reactive protein on human endothelial cells depends on the Fc?RIIa genotype - Raaz-Schrauder, Dorette; Ekici, Arif Bülent; Klinghammer, Lutz; Stumpf, Christian; Achenbach, Stephan; Herrmann, Martin; Reis, André; Garlichs, Christoph (Thrombosis Research, 2014)
The stimulatory effects of CRP (C-reactive protein) on endothelial cells are mainly mediated via Fc?RIIa. This receptor exists in two different allotypes bearing either arginine (R131) or histidine (H131) at the extracellular amino acid position 131 of the mature protein, but only Fc?RIIa-R131 displays high avidity for CRP. This study investigated the role of the Fc?RIIa genotype in CRP-stimulated endothelial cells.We tested the effects of CRP on expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the endothelial release of pro-inflammatory molecules as a function of the Fc?RIIa-genotype (Fc?RIIa-H/H131, Fc?RIIa-H/R131, Fc?RIIa-R/R131) in HUVEC (Human Umbilical Vein Endothelial Cells). HUVEC were grouped according to their Fc?RIIa status by genotyping with an allele specific nested-PCR. The expression of ICAM-1, VCAM-1, and E-selectin on HUVEC was detected by flow cytometry. The release of soluble markers (sCD40L, IL-6, IL-8, MCP-1, tPA, sP-selectin, and sVCAM-1) was measured using a multiplex assay for flow cytometry.CRP-stimulated expression of ICAM-1 and E-selectin was dependent on the specific Fc?RIIa-genotype, with most pronounced induction in HUVEC with the Fc?RIIa-R/R genotype, followed by H/R and H/H. In accordance with this finding, the supernatants of stimulated HUVEC with the R/R genotype showed significantly higher levels of tPA, MCP-1, and IL-6. Our data show that CRP stimulates the expression of adhesion molecules and the release of soluble markers by HUVEC as a function of the Fc?RIIa-genotype. These findings could be relevant in the context of risk stratification in patients with cardiovascular disease.
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Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases - Chirivi, Renato G. S.; Van Rosmalen, Jos W. G.; Van Der Linden, Maarten; Euler, Maximilien; Schmets, Gonny; Bogatkevich, Galina; Kambas, Konstantinos; Hahn, Jonas; Braster, Quinte; Soehnlein, Oliver; Hoffmann, Markus; Van Es, Helmuth H. G.; et al. (Cellular & Molecular Immunology, 2020)
Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
CRIS-Team WoS Importer:2020-04-07

Therapeutic benefit of apremilast on enthesitis and dactylitis in patients with psoriatic arthritis: a pooled analysis of the PALACE 1-3 studies - Gladman, Dafna D.; Kavanaugh, Arthur; Gómez-Reino, Juan J.; Wollenhaupt, Jürgen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Guerette, Benoit; Delev, Nikolay; Teng, Lichen; Edwards, Christopher J.; Birbara, Charles A.; et al. (RMD Open, 2018)
Objective: The Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) clinical trial programme findings demonstrated that apremilast, an oral phosphodiesterase 4 inhibitor, is effective for treating psoriatic arthritis (PsA). Enthesitis and dactylitis are difficult-to-treat features of PsA leading to disability and affecting quality of life. PALACE 1, 2 and 3 data were pooled to assess the efficacy of apremilast on enthesitis and dactylitis outcomes in patients with these conditions at baseline. Methods: Patients with enthesitis (n=945) or dactylitis (n=633) at baseline were analysed after receiving double-blind treatment with placebo, apremilast 30 mg two times per day or apremilast 20 mg two times per day up to 52 weeks and continuing up to 5 years. Data were analysed through 156 weeks. Enthesitis was evaluated by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and dactylitis via dactylitis count. Results: At week 24, patients receiving apremilast 30 mg two times per day demonstrated a significantly greater mean change in enthesitis (-1.3 vs -0.9; p<0.05) and dactylitis (-1.8 vs -1.3; p<0.01) vs placebo. Patients in the 30 mg dose group showed significantly greater mean (-23.6% vs -7.0%; p<0.05) and median (-50.0% vs -21.1%; p<0.05) per cent changes in MASES; mean and median per cent changes in dactylitis count were numerically, but not significantly, different for either apremilast dose in patients with dactylitis. In the patient population remaining on apremilast, observed mean and median improvements in both conditions were sustained through 156 weeks. Conclusion: Apremilast is effective for the treatment of active PsA, including improvements in enthesitis and dactylitis up to 3 years. Trial registration numbers: NCT01172938, NCT01212757 and NCT01212770.
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Therapeutic molecular targets of SSc-ILD - Zhang, Yun; Distler, Jörg (Journal of Scleroderma and Related Disorders, 2020)
Systemic sclerosis is a fibrosing chronic connective tissue disease of unknown etiology. A major hallmark of systemic sclerosis is the uncontrolled and persistent activation of fibroblasts, which release excessive amounts of extracellular matrix, lead to organ dysfunction, and cause high mobility and motility of patients. Systemic sclerosis–associated interstitial lung disease is one of the most common fibrotic organ manifestations in systemic sclerosis and a major cause of death. Treatment options for systemic sclerosis–associated interstitial lung disease and other fibrotic manifestations, however, remain very limited. Thus, there is a huge medical need for effective therapies that target tissue fibrosis, vascular alterations, inflammation, and autoimmune disease in systemic sclerosis–associated interstitial lung disease. In this review, we discuss data suggesting therapeutic ways to target different genes in distinct tissues/organs that contribute to the development of SSc.
CRIS-Team Scopus Importer:2020-02-04
Keywords: molecular target; pulmonary fibrosis; Systemic sclerosis

Therapie der systemischen Sklerose-assoziierten interstitiellen Lungenerkrankung - Prasse, A.; Bonella, F.; Müller-Ladner, U.; Witte, T.; Hunzelmann, N.; Distler, Jörg (Zeitschrift für Rheumatologie, 2019)
Background: Systemic sclerosis (SSc) is a fibrosing autoimmune disease of the connective tissue. In addition to skin fibrosis, pulmonary involvement and interstitial lung disease (ILD) in particular are the most common and severe manifestations of SSc. The disease is associated with a substantial risk of morbidity and mortality, especially in progressive ILD. In the last 5 years new treatment concepts for SSc-ILD have been investigated in numerous clinical studies. Material and methods: This review is based on a literature search in PubMed, focusing on the most relevant papers published up to the end of 2018 with the keywords “SSc” and “treatment”. Results: The treatment of SSc-ILD has changed over the last few years due to the results of many clinical studies. The updated guidelines of the European League Against Rheumatism (EULAR) recommend the use of cyclophosphamide or hematopoietic stem cell transplantation. Data for a positive influence on SSc-ILD are also available for mycophenolate, tocilizumab and anabasum. Because of the pathophysiological similarities to idiopathic pulmonary fibrosis, the use of the antifibrotic agents nintedanib and pirfenidone is currently being investigated in randomized, multicenter clinical trials and could be a novel and promising therapeutic strategy. Conclusion: Current drug studies may provide innovative therapeutic perspectives for SSc-ILD and could significantly improve the prognosis of affected patients in the future.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Connective tissue disease; Interstitial lung disease; Organ involvement; Systemic sclerosis; Therapy

There is a need for new systemic sclerosis subset criteria. A content analytic approach - Johnson, S.; Soowamber, M.; Fransen, J.; Khanna, D.; Van Den Hoogen, F.; Baron, M.; Matucci-Cerinic, M.; Denton, C.; Medsger, T.; Carreira, P.; Riemekasten, G.; Distler, Jörg; et al. (Scandinavian Journal of Rheumatology, 2017)
Systemic sclerosis (SSc) is heterogenous. The objectives of this study were to evaluate the purpose, strengths and limitations of existing SSc subset criteria, and identify ideas among experts about subsets.We conducted semi-structured interviews with randomly sampled international SSc experts. The interview transcripts underwent an iterative process with text deconstructed to single thought units until a saturated conceptual framework with coding was achieved and respondent occurrence tabulated. Serial cross-referential analyses of clusters were developed.Thirty experts from 13 countries were included; 67% were male, 63% were from Europe and 37% from North America; median experience of 22.5 years, with a median of 55 new SSc patients annually. Three thematic clusters regarding subsetting were identified: research and communication; management; and prognosis (prediction of internal organ involvement, survival). The strength of the limited/diffuse system was its ease of use, however 10% stated this system had marginal value. Shortcomings of the diffuse/limited classification were the risk of misclassification, predictions/generalizations did not always hold true, and that the elbow or knee threshold was arbitrary. Eighty-seven percent use more than 2 subsets including: SSc sine scleroderma, overlap conditions, antibody-determined subsets, speed of progression, and age of onset (juvenile, elderly).We have synthesized an international view of the construct of SSc subsets in the modern era. We found a number of factors underlying the construct of SSc subsets. Considerations for the next phase include rate of change and hierarchal clustering (e.g. limited/diffuse, then by antibodies).
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The revised Bristol Rheumatoid Arthritis Fatigue measures and the Rheumatoid Arthritis Impact of Disease scale: validation in six countries - Hewlett, Sarah; Kirwan, John; Bode, Christina; Cramp, Fiona; Carmona, Loreto; Dures, Emma; Englbrecht, Matthias; Fransen, Jaap; Greenwood, Rosemary; Hagel, Sofia; Van De Laar, Maart; Molto, Anna; et al. (Rheumatology, 2017)
To evaluate the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire (BRAF-MDQ), the revised Bristol Rheumatoid Arthritis Numerical Rating Scales (BRAF-NRS V2) and the Rheumatoid Arthritis Impact of Disease (RAID) scale in six countries.We surveyed RA patients in France, Germany, The Netherlands, Spain, Sweden and the UK, including the HAQ, 36-item Short Form Health Survey (SF-36) and potential revisions of the BRAF-NRS coping and Spanish RAID coping items. Factor structure and internal consistency were examined by factor analysis and Cronbach's ? and construct validity by Spearman's correlation.A total of 1276 patients participated (76% female, 25% with a disease duration <5 years, median HAQ 1.0). The original BRAF-MDQ four-factor structure and RAID single-factor structure were confirmed in every country with ?66% of variation in items explained by each factor and all item factor loadings of 0.71-0.98. Internal consistency for the BRAF-MDQ total and subscales was a Cronbach's ? of 0.75-0.96 and for RAID, 0.93-0.96. Fatigue construct validity was shown for the BRAF-MDQ and BRAF-NRS severity and effect scales, correlated internally with SF-36 vitality and with RAID fatigue (r = 0.63-0.93). Broader construct validity for the BRAFs and RAID was shown by correlation with each other, HAQ and SF-36 domains (r = 0.46-0.82), with similar patterns in individual countries. The revised BRAF-NRS V2 Coping item had stronger validity than the original in all analyses. The revised Spanish RAID coping item performed as well as the original.Across six European countries, the BRAF-MDQ identifies the same four aspects of fatigue, and along with the RAID, shows strong factor structure and internal consistency and moderate-good construct validity. The revised BRAF-NRS V2 shows improved construct validity and replaces the original.
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The role of ACPAs in at-risk individuals: Early targeting of the bone and joints - Schett, Georg (Best Practice & Research in Clinical Rheumatology, 2017)
Autoimmunity precedes inflammation in patients with rheumatoid arthritis (RA), opening the possibility to search for early changes in the tissue preceding the onset of systemic inflammation. Autoantibodies are important and early drivers of bone damage in RA. This article summarizes current evidence for the role of RA-related autoantibodies in mediating bone loss. Rheumatoid factor (RF) and antibodies recognizing modified (citrullinated) proteins have been used as diagnostic markers for RA over many years. Their role as pathogenic players, however, has long been unrecognized. Recently, several pieces of evidence suggested that bone-resorbing osteoclasts are highly responsive to RA-related autoantibodies, providing a novel association between autoimmunity and bone. These developments have allowed the unraveling of the underlying mechanisms, which are responsible for the well-known clinical observation that anti-citrullinated protein antibodies and RF are associated with a more severe disease course. Furthermore, these mechanisms also explain the onset of inflammation in the joints of RA patients.
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The role of antifibrotics in the treatment of rheumatoid arthritis associated interstitial lung disease - Liang, Minrui; Matteson, Eric L.; Abril, Andy; Distler, Jörg (Therapeutic Advances in Musculoskeletal Disease, 2022)
The major pulmonary complication of rheumatoid arthritis (RA) is interstitial lung disease (ILD), which causes significant morbidity and mortality and influences the natural course of disease. Recent advances in the management of arthritis have improved patient outcomes. However, exceptionally high medical needs still remain for effective therapies for the patients with ILD in RA. Better understanding of the shared and distinct pathophysiology of fibrotic diseases led to the development of novel antifibrotic agents such as nintedanib and pirfenidone. The further stratification analysis of the phase III INBUILD trial demonstrated beneficial effects of nintedanib in RA-ILD with a progressive phenotype by reducing the rate of decline in forced vital capacity (FVC) over 52weeks by 60%. Pirfenidone is another antifibrotic agent currently under phase II clinical study (TRAIL1) aiming to evaluate its effects for RA-ILD. This review provides an overview of state-of-the-art pathogenesis and the current therapeutic options for RA-ILD, with a focus on antifibrotic strategies.
CRIS-Team WoS Importer:2022-03-18
Keywords: antifibrotics; fibrosis; interstitial lung disease (ILD); nintedanib; pirfenidone; rheumatoid arthritis (RA); treatment

The Role of Autoantibodies in Bone Metabolism and Bone Loss - Hauser, Barbara; Harre, Ulrike (Calcified Tissue International, 2018)
Many autoimmune diseases are associated with deranged bone metabolism. The resulting localized or systemic bone loss can compromise the quality of life of patients by causing local bone deformities or fragility fractures. There is emerging evidence that antibodies have a direct impact on key players of bone homeostasis, in particular osteoclasts. Clinical and pre-clinical studies provide insight into the function of autoantibodies related to Rheumatoid Arthritis (rheumatoid factor, anti-citrullinated protein antibodies, and anti-carbamylated protein antibodies) and their inflammation-independent interaction with bone cells. Furthermore, we summarize the current knowledge about neutralizing antibodies to the antiresorptive protein osteoprotegerin, which have been described in patients with Coeliac Disease, Rheumatoid Arthritis, and Spondyloarthritis.
Created from Fastlane, Scopus look-up
Keywords: ACPA; Autoantibodies; Bone loss; Osteoclast; Osteoprotegerin; Rheumatoid arthritis

The role of Butyrophilin 2a2 (Btn2a2) in T cell maturation - Frech, Michael; Uchil, P.; Azizov, Vugar; Schober, K.; Irla, M.; Sarter, Kerstin; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

The role of dead cell clearance in the etiology and pathogenesis of systemic lupus erythematosus: dendritic cells as potential targets - Biermann, Mona; Veissi, Susan; Maueröder, Christian; Chaurio Gonzalez, Ricardo Alfredo; Berens, Christian; Herrmann, Martin; Munoz Becerra, Luis (Expert Review of Clinical Immunology, 2014)
Overwhelming apoptosis combined with a deficiency in clearing apoptotic cells is thought to be an important etiopathogenic event in the autoimmune disease systemic lupus erythematosus (SLE). Lazy macrophages, complement or DNase I deficiency as well as insufficient natural IgM might be important factors leading to such a clearance deficiency. A defective clearance of apoptotic cells leads to the activation and maturation of plasmacytoid and myeloid dendritic cells (DCs) by material derived from secondary necrotic cells carrying modified autoantigens. This results in the presentation of autoantigens to autoreactive T and B cells in an immunogenic manner, thereby leading to autoantibody production, chronic inflammation and severe tissue damage. Since DC activation and IFN-? production by plasmacytoid dendritic cells play a critical role in the course of SLE pathogenesis, therapeutic intervention to end this vicious cycle might be a promising approach for treating the disease.
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The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study - Häger, Julian; Bang, Holger; Hagen, Melanie; Frech, Michael; Träger, Pascal; Sokolova, Maria V.; Steffen, Ulrike; Tascilar, Koray; Sarter, Kerstin; Schett, Georg; Rech, Jürgen; Zaiss, Mario (Nutrients, 2019)
Short-chain fatty acids are microbial metabolites that have been shown to be key regulators of the gut-joint axis in animal models. In humans, microbial dysbiosis was observed in rheumatoid arthritis (RA) patients as well as in those at-risk to develop RA, and is thought to be an environmental trigger for the development of clinical disease. At the same time, diet has a proven impact on maintaining intestinal microbial homeostasis. Given this association, we performed a feasibility study in RA patients using high-fiber dietary supplementation with the objective to restore microbial homeostasis and promote the secretion of beneficial immunomodulatory microbial metabolites. RA patients (n = 36) under routine care received daily high-fiber bars or cereals for 28 days. Clinical assessments and laboratory analysis of immune parameters in blood and stool samples from RA patients were done before and after the high-fiber dietary supplementation. We observed an increase in circulating regulatory T cell numbers, favorable Th1/Th17 ratios, as well as decreased markers of bone erosion in RA patients after 28 days of dietary intervention. Furthermore, patient-related outcomes of RA improved. Based on these results, we conclude that controlled clinical studies of high-fiber dietary interventions could be a viable approach to supplement or complement current pharmacological treatment strategies.
CRIS-Team Scopus Importer:2019-10-18
Keywords: gut–joint axis; high-fiber diet (HFD); microbiota; rheumatoid arthritis (RA); short chain fatty acids (SCFA)

The Role of Epigenetic Modifications in Systemic Sclerosis: A Druggable Target - Henderson, John; Distler, Jörg; O'Reilly, Steven (Trends in Molecular Medicine, 2019)
Systemic sclerosis (SSc) is a rare autoimmune disorder characterised by skin fibrosis that often also affects internal organs, eventually resulting in mortality. Although managementof thesymptomshas extendedlifespan, patients stillsuffer from poor quality of life, hence the need for improved therapies. Development of efficacious treatments has been stymied by the unknown aetiology, although recent advancements suggest a potentially key role for epigenetics-the regulation of geneexpression by noncoding RNAs and chemical modifications to DNA or DNA-associated proteins. Herein, the evidence implicating epigenetics in the pathogenesis of SSc is discussed with an emphasis on the therapeutic potential this introduces to the field-particularly the repurposing of epigenetic targeting cancer therapeutics and newly emerging miRNA-based strategies.
CRIS-Team WoS Importer:2019-05-09

The role of glucose transporter type 1 in plasma cells - Bierling, Theresa; Gumann, Amelie; Van Schie, Karin; Wichert, Magdalena; Hauke, Manuela; Wittner, Jens; Schuh, Wolfgang; Toes, Rene E. M.; Jäck, Hans-Martin; Pracht, Katharina (EUROPEAN JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

The role of IL-23 in joint disease - Schett, Georg (Rheumatology, 2021)
CRIS-Team WoS Importer:2022-02-11

The role of joint-draining lymph node stromal cells in inflammatory arthritis - Schälter, Fabian; Azizov, Vugar; Frech, Michael; Dürholz, Kerstin; Sokolova, Maria; Hendel, Anna; Focke, Kristin; Sarter-Zaiss, Kerstin; Van Baarsen, L. G. M.; Krautwald, S.; Schett, Georg; Zaiss, Mario (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

The role of Krueppel-like factor 2 in B cell activation and plasma cell homeostasis - Schubert, T.; Knipfer, Lisa; Wallrapp, Antonia; Wittner, Jens; Jäck, Hans-Martin; Schuh, Wolfgang (2017)
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The role of Kruppel-Like-Factor 2 (KLF2) in plasma cell homeostasis - Wittner, Jens; Schulz, Sebastian; Jäck, Hans-Martin; Schuh, Wolfgang (EUROPEAN JOURNAL OF IMMUNOLOGY, 2019)
CRIS-Team WoS Importer:2019-10-08

The role of somatic hypermutation in the generation of pathogenic antibodies in SLE - Kristin, Schröder; Herrmann, Martin; Winkler, Thomas (Autoimmunity, 2013)
The formation of antibodies against double-stranded (ds)DNA is considered to be the serologic hallmark of systemic lupus erythematosus (SLE) and anti-dsDNA antibodies play an important role in the pathogenesis of the disease. Anti-dsDNA antibodies from lupus mice and SLE patients arise by somatic mutation. Importantly, autoantibodies in which somatic mutations have been reverted to germ-line V regions did not show any measurable autoreactivity, suggesting that anti-dsDNA autoantibodies develop from non-autoreactive B-cells by somatic hypermutation, presumably during the germinal center reaction. As the random nature of somatic hypermutation will inevitably create autoreactive B cells, self-tolerance checkpoints at the postmutational stage of B cell differentiation have to exist that normally prevent the induction of pathogenic anti-dsDNA specificities. This review summarizes the proposed mechanisms for the generation of anti-dsDNA in murine lupus and in SLE patients. © Informa UK, Ltd.
Keywords: Anti-DNA antibodies; Germinal center; Somatic mutation; Systemic lupus erythematosus

THE ROLE OF THE IL-23/TH17 AXIS AS MODULATOR OF B CELL-MEDIATED (AUTO)IMMUNE RESPONSES - Pfeifle, René; Kittler, Julia; Rothe, Tobias; Schett, Georg; Krönke, Gerhard (2019)
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The role of the miR-148/-152 family in physiology and disease - Friedrich, Michael; Pracht, Katharina; Mashreghi, Mir-Farzin; Jäck, Hans-Martin; Radbruch, Andreas; Seliger, Barbara (European Journal of Immunology, 2017)
MicroRNAs (miRNAs) are endogenously encoded 22 nt small non-coding RNAs. They function as key players of many cellular processes by base pairing with target mRNAs and thereby impairing gene expression at the post-transcriptional level. Recent findings demonstrate a critical role of many miRNAs in immune cell differentiation and immune responses, which is also associated with the development and progression of many tumor and non-tumor diseases. Here we review the multifaceted miRNA-148/-152 family members consisting of miR-148a, miR-148b and miR-152. Next to regulation mechanisms that control the expression of this miRNA family, we will focus on (i) the role of miR-148a in regulating B and T lymphocyte function and its role in associated diseases and (ii) the importance of miR-148/-152 family members for cancer initiation, tumor growth and metastasis formation. In addition, this review aims to highlight some selected targets of the miRNA-148/-152 family members, which are involved in the biology of cancer and maintenance of epigenetic patterns. In conclusion, members of the miR-148/-152 family might represent prognostic markers and/or potential therapeutic targets for treatment of autoimmune disorders, chronic inflammatory diseases and multiple types of cancer.
EVALuna2:13649

The rubric “Pioneers of rheumatology” becomes “Milestones of rheumatology” Die Rubrik „Wegbereiter der Rheumatologie“ wird zu „Meilensteine der Rheumatologie“ - Mueller-Ladner, Ulf; Manger, Bernhard (Zeitschrift für Rheumatologie, 2022)
CRIS-Team Scopus Importer:2022-03-18

THE SEROTONIN RECEPTOR 2 INHIBITOR TERGURIDE HAS BENEFICIAL EFFECTS ON SKIN FIBROSIS: RESULTS FROM A PHASE 2 PROOF OF CONCEPT STUDY - Distler, O.; Maurer, B.; Vettori, S.; Blumhardt, S.; Frey, D.; Distler, A.; Beyer, Christian; Distler, Jörg (2016)
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The short-chain fatty acid pentanoate suppresses autoimmunity by modulating the metabolic-epigenetic crosstalk in lymphocytes - Luu, Maik; Pautz, Sabine; Kohl, Vanessa; Singh, Rajeev; Romero, Rossana; Lucas, Sebastien; Hofmann, Jörg; Raifer, Hartmann; Vachharajani, Niyati; Carrascosa, Lucia Campos; Lamp, Boris; Nist, Andrea; et al. (Nature Communications, 2019)
Short-chain fatty acids (SCFAs) have immunomodulatory effects, but the underlying mechanisms are not well understood. Here we show that pentanoate, a physiologically abundant SCFA, is a potent regulator of immunometabolism. Pentanoate induces IL-10 production in lymphocytes by reprogramming their metabolic activity towards elevated glucose oxidation. Mechanistically, this reprogramming is mediated by supplying additional pentanoate-originated acetyl-CoA for histone acetyltransferases, and by pentanoate-triggered enhancement of mTOR activity. In experimental mouse models of colitis and multiple sclerosis, pentanoate-induced regulatory B cells mediate protection from autoimmune pathology. Additionally, pentanoate shows a potent histone deacetylase-inhibitory activity in CD4(+) T cells, thereby reducing their IL-17A production. In germ-free mice monocolonized with segmented filamentous bacteria (SFB), pentanoate inhibits the generation of small-intestinal Th17 cells and ameliorates SFB-promoted inflammation in the central nervous system. Taken together, by enhancing IL-10 production and suppressing Th17 cells, the SCFA pentanoate might be of therapeutic relevance for inflammatory and autoimmune diseases.
CRIS-Team WoS Importer:2019-02-27

“The Simpler, the Better.” A Qualitative Study on Digital Health Transformation in Early Adopter Rheumatology Outpatient Clinics - May, Susann; Darkow, Robert; Knitza, Johannes; Boy, Katharina; Schwarz, Julian; Heinze, Martin; Hornig, Johannes; Aries, Peer; Welcker, Martin; Muehlensiepen, Felix (Inquiry-The Journal of Health Care Organization Provision and Financing, 2024)
Workforce shortage and the increasing burden of rheumatic and musculoskeletal diseases lead to extreme time constraints in rheumatology outpatient care. Digital services promise to facilitate care by relieving employees and unleash new capacities. This study aims to explore the perspectives of early adopter health care professionals (HCP) on digital transformation in outpatient rheumatology. In-depth qualitative interviews were conducted with rheumatology nurses and physicians in 3 German rheumatology outpatient clinics, each characterized by an advanced level of digital adaption. Qualitative data were subsequently analyzed using deductive-inductive qualitative content analysis. Interviews with 11 rheumatology nurses and 5 rheumatologists were completed. Three key themes emerged from the qualitative analysis: (i) Digital transformation of care; (ii) impact of digital transformation on health care delivery; and (iii) perceived drivers of successful digitalization. The interviews revealed that digital technologies are widely used throughout the complete patient pathway. Digitalization enables more continuity and flexibility in rheumatology care. Patient information can be electronically obtained in a standardized manner prior to planned visits, enabling an informed consultation and more time for in-depth patient discussion. Although digitalization restructures work, it can also increase the current workload. Improved accessibility for patient calls leads to more work for HCP. Important drivers of successful digital technology implementation are low-threshold and interoperable services, a medical team that is interested and educated in eHealth, and comprehensive patient information and onboarding. Digital transformation is increasingly redefining rheumatology care. While accelerating communication and workflows, improved service accessibility leads to more work for HCP.
CRIS-Team Scopus Importer:2024-06-07
Keywords: digital health; health services research; implementation research; qualitative research; rheumatology; telemedicine

The soluble CD83 protein prevents bone destruction by inhibiting the formation of osteoclasts and inducing resolution of inflammation in arthritis - Royzman, Dmytro; Andreev, Darja; Stich, Lena; Peckert, Katrin; Wild, Andreas; Zinser, Elisabeth; Mühl-Zürbes, Petra; Jones, Evan; Adam, Susanne; Frey, Silke; Fuchs, Maximilian; Kunz, Meik; et al. (Frontiers in Immunology, 2022)
Here we show that soluble CD83 induces the resolution of inflammation in an antigen-induced arthritis (AIA) model. Joint swelling and the arthritis-related expression levels of IL-1 beta, IL-6, RANKL, MMP9, and OC-Stamp were strongly reduced, while Foxp3 was induced. In addition, we observed a significant inhibition of TRAP(+) osteoclast formation, correlating with the reduced arthritic disease score. In contrast, cell-specific deletion of CD83 in human and murine precursor cells resulted in an enhanced formation of mature osteoclasts. RNA sequencing analyses, comparing sCD83- with mock treated cells, revealed a strong downregulation of osteoclastogenic factors, such as Oc-Stamp, Mmp9 and Nfatc1, Ctsk, and Trap. Concomitantly, transcripts typical for pro-resolving macrophages, e.g., Mrc1/2, Marco, Klf4, and Mertk, were upregulated. Interestingly, members of the metallothionein (MT) family, which have been associated with a reduced arthritic disease severity, were also highly induced by sCD83 in samples derived from RA patients. Finally, we elucidated the sCD83-induced signaling cascade downstream to its binding to the Toll-like receptor 4/(TLR4/MD2) receptor complex using CRISPR/Cas9-induced knockdowns of TLR4/MyD88/TRIF and MTs, revealing that sCD83 acts via the TRIF-signaling cascade. In conclusion, sCD83 represents a promising therapeutic approach to induce the resolution of inflammation and to prevent bone erosion in autoimmune arthritis.
CRIS-Team WoS Importer:2022-09-09

The special developmental biology of craniofacial tissues enables the understanding of oral and maxillofacial physiology and diseases - Weber, Manuel; Wehrhan, Falk; Deschner, James; Sander, Janina; Ries, Jutta; Möst, Tobias; Bozec, Aline; Gölz, Lina; Kesting, Marco Rainer; Lutz, Rainer (International Journal of Molecular Sciences, 2021)
Maxillofacial hard tissues have several differences compared to bones of other localiza-tions of the human body. These could be due to the different embryological development of the jaw bones compared to the extracranial skeleton. In particular, the immigration of neuroectodermally differentiated cells of the cranial neural crest (CNC) plays an important role. These cells differ from the mesenchymal structures of the extracranial skeleton. In the ontogenesis of the jaw bones, the development via the intermediate stage of the pharyngeal arches is another special developmental feature. The aim of this review was to illustrate how the development of maxillofacial hard tissues occurs via the cranial neural crest and pharyngeal arches, and what significance this could have for relevant pathologies in maxillofacial surgery, dentistry and orthodontic therapy. The pathogenesis of various growth anomalies and certain syndromes will also be discussed.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Cranial neural crest; Developmental biology; Maxillofacial development; Orthodontics

The spike protein of SARS-CoV-2 variant A.30 is heavily mutated and evades vaccine-induced antibodies with high efficiency - Arora, Prerna; Rocha, Cheila; Kempf, Amy; Nehlmeier, Inga; Graichen, Luise; Winkler, Martin S.; Lier, Martin; Schulz, Sebastian; Jäck, Hans-Martin; Cossmann, Anne; Stankov, Metodi V.; Behrens, Georg M. N.; et al. (Cellular & Molecular Immunology, 2021)
CRIS-Team Scopus Importer:2021-11-05

The structural basis of MRI bone erosions: An assessment by microCT - Albrecht, Andreas; Finzel, Stephanie; Englbrecht, Matthias; Rech, Jürgen; Hueber, Axel; Schlechtweg, Philipp; Uder, Michael; Schett, Georg (Annals of the Rheumatic Diseases, 2013)
Objective To determine whether erosions appearing in MRI in patients with rheumatoid arthritis (RA) represent true erosions. Methods 50 RA patients received 1.5 T MRI and microCT (μCT) of the dominant hand. Erosion counts were assessed in coronal T1 weighted MRI sections and in coronal as well as axial μCT sections of the metacarpophalangeal (MCP) joints II-IV. Extent of erosions was assessed by RA MRI Score (RAMRIS) erosion score (MRI) and by three-dimensional assessment of erosion volume (μCT). Results 111 of the 600 evaluated joint regions showed erosions in the MRI and 137 in the μCT. In only 28 regions false negative lesions (μCT positive, MRI negative) were found, all of which were very small lesions with a volume of less than 10 mm3. Only two results were false-positive (μCT negative, MRI positive). RAMRIS erosion scores were strongly correlated to erosion volumes in the μCT (Pearson's r=0.514, p<0.001). Mean RAMRIS erosion scores were below 1 with erosion volumes up to 1.5 mm3, below 2 with erosion volumes up to 20 mm3 and over 2 with volumes of more than 20 mm3. Discussion MRI erosions are generally based on true cortical breaks as shown by μCT. MRI is sensitive to detect bone erosions and only very small lesions escape detection. Moreover, RAMRIS erosion scores are closely linked to the absolute size of bone erosions in the μCT.
CRIS-Team Scopus Importer:2021-02-03

The TGF-?-inducible miR-23a cluster attenuates IFN-? levels and antigen-specific cytotoxicity in human CD8? T cells - Chandran, P. Anoop; Keller, Andreas; Weinmann, Lasse; Seida, Ahmed Adel; Braun, Matthias; Andreev, Katerina; Fischer, Birgitt; Horn, Evi; Schwinn, Stefanie; Junker, Markus; Houben, Roland; Dombrowski, Yvonne; et al. (Journal of Leukocyte Biology, 2014)
Cytokine secretion and degranulation represent key components of CD8(+) T-cell cytotoxicity. While transcriptional blockade of IFN-? and inhibition of degranulation by TGF-? are well established, we wondered whether TGF-? could also induce immune-regulatory miRNAs in human CD8(+) T cells. We used miRNA microarrays and high-throughput sequencing in combination with qRT-PCR and found that TGF-? promotes expression of the miR-23a cluster in human CD8(+) T cells. Likewise, TGF-? up-regulated expression of the cluster in CD8(+) T cells from wild-type mice, but not in cells from mice with tissue-specific expression of a dominant-negative TGF-? type II receptor. Reporter gene assays including site mutations confirmed that miR-23a specifically targets the 3'UTR of CD107a/LAMP1 mRNA, whereas the further miRNAs expressed in this cluster-namely, miR-27a and -24-target the 3'UTR of IFN-? mRNA. Upon modulation of the miR-23a cluster by the respective miRNA antagomirs and mimics, we observed significant changes in IFN-? expression, but only slight effects on CD107a/LAMP1 expression. Still, overexpression of the cluster attenuated the cytotoxic activity of antigen-specific CD8(+) T cells. These functional data thus reveal that the miR-23a cluster not only is induced by TGF-?, but also exerts a suppressive effect on CD8(+) T-cell effector functions, even in the absence of TGF-? signaling.
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The TH1 phenotype of follicular helper T cells indicates an IFN-?-associated immune dysregulation in patients with CD21low common variable immunodeficiency - Unger, Susanne; Seidl, Maximilian; van Schouwenburg, Pauline; Rakhmanov, Mirzokhid; Bulashevska, Alla; Frede, Natalie; Grimbacher, Bodo; Pfeiffer, Jens; Schrenk, Klaudia; Munoz, Luis Enrique; Hanitsch, Leif; Stumpf, Ina; et al. (Journal of Allergy and Clinical Immunology, 2017)
A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology.On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients.We quantified TH1/TH2/TH17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation.Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3(+)CCR6(-) TH1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-? production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-? production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)(+) B cells in lymph nodes, and an accumulation of T-bet(+)CD21(low) B cells in peripheral blood of affected patients.Identification of excessive IFN-? production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21(low) B cells might serve as a marker of this IFN-?-associated dysregulation.
EVALuna2:13449

The transcriptional regulator DREAM modulates glial cell proliferation dependent on the regional inflammatory microenvironment - Süß, Patrick; Masanetz, Rebecca Katharina; Baum, Wolfgang; Schett, Georg; Schlachetzki, Johannes; Winkler, Jürgen (JOURNAL OF NEUROCHEMISTRY, 2022)
CRIS-Team WoS Importer:2022-09-09

The Transcription Factor FRA-1/AP-1 Controls Lipocalin-2 Expression and Inflammation in Sepsis Model - Cao, Shan; Schnelzer, Anne; Hannemann, Nicole; Schett, Georg; Soulat, Didier; Bozec, Aline (Frontiers in Immunology, 2021)
Sepsis is a life-threatening condition characterized by excessive inflammation in its early phase. This is followed by an aberrant resolution phase associated to a prolonged period of immune suppression that can ultimately lead to multiple organ dysfunctions. This immunosuppression can be mediated by the functional reprogramming of gene transcription in monocytes/macrophages in response to prolonged lipopolysaccharide (LPS) exposure. Surprisingly, there is no report on the role of AP-1 transcription factors in this reprogramming process. Herein, we used the endotoxin tolerance model on murine bone marrow-derived macrophages in which tolerant cells stimulated twice with LPS were compared to naïve cells stimulated once. Out of all AP-1 transcription factors tested, Fosl1 gene stood out because of its unique regulation in tolerized cells. Moreover, we could correlate FRA-1 expression to the expression of an essential anti-inflammatory molecule involved in sepsis response, Lipocalin 2 aka NGAL. Identical results were obtained in human PBMC following the endotoxin tolerance model. When using FRA-1 deficient macrophages, we could confirm that FRA-1 regulates NGAL expression during the tolerant state. Interestingly, ChIP-seq and ChIP-qPCR revealed the binding of FRA-1 on Lcn2 promoter after LPS stimulation in these cells. Finally, we used an in vivo septic model of consecutive injection of LPS, in which the second stimulation is performed before the resolution of inflammation, in wild type and FRA-1 deficient mice. NGAL secretion was elevated in lung, spleen and serum of wild type tolerant mice, whereas it was significantly lower in tolerant FRA-1 deficient mice. Moreover, an increased inflammatory state likely dependent of the low level of NGAL was observed in these FRA-1 deficient mice. This was characterized by an increase of neutrophil infiltration in lung and an increase of apoptotic follicular cells in spleen. This suggests that FRA-1 expression supports resolution of inflammation in this model. Collectively, our data indicate that FRA-1 is involved in myeloid cell tolerance responses by mediating the functional reprogramming of Lcn2 transcription in response to prolonged LPS exposure. In conclusion, FRA-1 may have a protective role in the tolerance response of sepsis through the regulation of NGAL, leading to resolution of inflammation.
CRIS-Team Scopus Importer:2021-11-19
Keywords: AP-1/Fra-1; endotoxin tolerance; lipocalin-2; macrophage; sepsis; transcription factor

The transcription factor GLI2 as a downstream mediator of transforming growth factor-?-induced fibroblast activation in SSc - Liang, Ruifang; Sumova, Barbora; Cordazzo, Cinzia; Mallano, Tatjana; Zhang, Yun; Wohlfahrt, Thomas; Dees, Clara; Krasowska, Dorota; Michalska-Jakubus, Malgorzata; Distler, Oliver; Schett, Georg; Senolt, Ladislav; et al. (Annals of the Rheumatic Diseases, 2016)
Hedgehog signalling plays a critical role during the pathogenesis of fibrosis in systemic sclerosis (SSc). Besides canonical hedgehog signalling with smoothened (SMO)-dependent activation of GLI transcription factors, GLI can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). Here, we aimed to evaluate the role of non-canonical hedgehog signalling in SSc and to test the efficacy of direct GLI inhibitors that target simultaneously canonical and non-canonical hedgehog pathways.The GLI inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signalling, while the SMO inhibitor vismodegib was used to selectively target canonical hedgehog signalling. Furthermore, GLI2 was selectively depleted in fibroblasts using the Cre-LoxP system. The effects of pharmacological or genetic of GLI2 on transforming growth factor-? (TGF-?) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-? receptor I.TGF-? upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBR(act)-induced fibrosis. Combined targeting of canonical and non-canonical hedgehog signalling with direct GLI inhibitors exerted more potent antifibrotic effects than selective targeting of canonical hedgehog signalling with SMO inhibitors in experimental dermal and pulmonary fibrosis.Our data demonstrate that hedgehog pathways and TGF-? signalling both converge to GLI2 and that GLI2 integrates those signalling to promote tissue fibrosis. These findings may have translational implications as non-selective inhibitors of GLI2 are in clinical use and selective molecules are currently in development.
EVALuna2:13344

The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis - Zehender, Ariella; Huang, Jingang; Gyoerfi, Andrea-Hermina; Matei, Alexandru-Emil; Thuong Trinh-Minh,; Xu, Xiaohan; Li, Yi-Nan; Chen, Chih-Wei; Lin, Jianping; Dees, Clara; Beyer, Christian; Gelse, Kolja; et al. (Nature Communications, 2018)
Uncontrolled activation of TGFβ signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFβ-induced JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFβ stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFβ promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFβ-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis.
EVALuna2:34477

The ups and downs of bone in health and rheumatic disease - Harre, Ulrike; Schett, Georg (Nature Reviews Rheumatology, 2013)
Created from Fastlane, Scopus look-up

The Urge for Mobile Apps in Rheumatology - a German Patient Perspective - Knitza, Johannes; Raab, Christina; Lambrecht, Antonia; Simon, David; Hagen, Melanie; Bayat, Sara; Schett, Georg; Kleyer, Arnd; Hueber, Axel (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

The value of (18)F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study - Schoenau, Verena; Vogel, Kristin; Englbrecht, Matthias; Wacker, Jochen; Schmidt, Daniela; Manger, Bernhard; Kuwert, Torsten; Schett, Georg (Annals of the Rheumatic Diseases, 2017)
Fever of unknown origin (FUO) and inflammation of unknown origin (IUO) are diagnostically challenging conditions. Diagnosis of underlying disease may be improved by (18)F-fluorodesoxyglucose positron emission tomography ((18)F-FDG-PET).Prospective study to test diagnostic utility of (18)F-FDG-PET/CT in a large cohort of patients with FUO or IUO and to define parameters that increase the likelihood of diagnostic (18)F-FDG-PET/CT. Patients with FUO or IUO received (18)F-FDG-PET/CT scanning in addition to standard diagnostic work-up. (18)F-FDG-PET/CT results were classified as helpful or non-helpful in establishing final diagnosis. Binary logistic regression was used to identify clinical parameters associated with a diagnostic (18)F-FDG-PET/CT.240 patients were enrolled, 72 with FUO, 142 with IUO and 26 had FUO or IUO previously (exFUO/IUO). Diagnosis was established in 190 patients (79.2%). The leading diagnoses were adult-onset Still's disease (15.3%) in the FUO group, large vessel vasculitis (21.1%) and polymyalgia rheumatica (18.3%) in the IUO group and IgG4-related disease (15.4%) in the exFUO/IUO group. In 136 patients (56.7% of all patients and 71.6% of patients with a diagnosis), (18)F-FDG-PET/CT was positive and helpful in finding the diagnosis. Predictive markers for a diagnostic (18)F-FDG-PET/CT were age over 50 years (p=0.019), C-reactive protein (CRP) level over 30 mg/L (p=0.002) and absence of fever (p=0.001).(18)F-FDG-PET/CT scanning is helpful in ascertaining the correct diagnosis in more than 50% of the cases presenting with FUO and IUO. Absence of intermittent fever, higher age and elevated CRP level increase the likelihood for a diagnostic (18)F-FDG-PET/CT.
EVALuna2:13447

The virtual fishbowl: Bringing back dynamic debates to medical conferences - Muehlensiepen, Felix; Mucke, Johanna; Krusche, Martin; Kurkowski, Sandra; Bendzuck, Gerlinde; Koetter, Ina; Lemarié, Vanessa; Grahammer, Manuel; Heinze, Martin; Schulze-Koops, Hendrik; Knitza, Johannes (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2021-04-19
Keywords: COVID-19; economics; health care; health care; health services research; outcome and process assessment; quality indicators

The Wnt antagonists DKK1 and SFRP1 are downregulated by promoter hypermethylation in systemic sclerosis - Dees, Clara; Schlottmann, Inga; Funke, Robin; Distler, Alfiya; Palumbo-Zerr, Katrin; Zerr, Pawel; Lin, Neng-Yu; Beyer, Christian; Distler, Oliver; Schett, Georg; Distler, Jörg (Annals of the Rheumatic Diseases, 2014)
Activated Wnt signalling with decreased expression of endogenous inhibitors has recently been characterised as a central pathomechanism in systemic sclerosis (SSc). Aberrant epigenetic modifications also contribute to the persistent activation of SSc fibroblasts. We investigated whether increased Wnt signalling and epigenetic changes in SSc are causally linked via promoter hypermethylation-induced silencing of Wnt antagonists.The methylation status of endogenous Wnt antagonists in leucocytes and fibroblasts was evaluated by methylation-specific PCR. 5-aza-2'-deoxycytidine was used to inhibit DNA methyltransferases (Dnmts) in cultured fibroblasts and in the mouse model of bleomycin-induced skin fibrosis. Activation of Wnt signalling was assessed by analysing Axin2 mRNA levels and by staining for ?-catenin.The promoters of DKK1 and SFRP1 were hypermethylated in fibroblasts and peripheral blood mononuclear cells of patients with SSc. Promoter hypermethylation resulted in impaired transcription and decreased expression of DKK1 and SFRP1 in SSc. Treatment of SSc fibroblasts or bleomycin-challenged mice with 5-aza prevented promoter methylation-induced silencing and increased the expression of both genes to normal levels. Reactivation of DKK1 and SFRP1 transcription by 5-aza inhibited canonical Wnt signalling in vitro and in vivo and effectively ameliorated experimental fibrosis.We demonstrate that hypermethylation of the promoters of DKK1 and SFRP1 contributes to aberrant Wnt signalling in SSc and that Dnmt inhibition effectively reduces Wnt signalling. These data provide a novel link between epigenetic alterations and increased Wnt signalling in SSc and also have translational implications because Dnmt inhibitors are already approved for clinical use.
EVALuna2:12884

The α7 Nicotinic Acetylcholine Receptor: A Promising Target for the Treatment of Fibrotic Skin Disorders - Stegemann, Agatha; Flis, Damian; Ziolkowski, Wieslaw; Distler, Jörg; Steinbrink, Kerstin; Böhm, Markus (Journal of Investigative Dermatology, 2020)
Targeting neuroendocrine receptors can be considered as another interesting approach to treating fibrotic disorders. Previously, we could demonstrate that tropisetron, a classical serotonin receptor blocker, can modulate collagen synthesis and acts in vitro through the α7 nicotinic acetylcholine receptor (α7nAchR). Here, we used a pharmacologic approach with specific α7nAchR agonists to validate this hypothesis. PHA-543613, an α7nAchR-specific agonist, not only prevented but also reversed established skin fibrosis of mice injected with bleomycin. Interestingly, agonistic stimulation of α7nAchR also attenuated experimental skin fibrosis in the non–inflammation driven adenovirus coding for TGFβ receptor Iact mouse model, indicating fibroblast-mediated and not only anti-inflammatory effects of such agents. The fibroblast-mediated effects were confirmed in vitro using human dermal fibroblasts, in which the α7nAchR-specific agonists strongly reduced the impact of TGFβ1-mediated expression on collagen and myofibroblast marker expression. These actions were linked to modulation of the redox-sensitive transcription factor JunB and impairment of the mitochondrial respiratory system. Our results indicate that pharmacologic stimulation of the α7nAchR could be a promising target for treatment of patients with skin fibrotic diseases. Moreover, our results suggest a mechanistic axis of collagen synthesis regulation through the mitochondrial respiratory system.
CRIS-Team Scopus Importer:2020-06-02

Three-dimensional modeling of a pre-B-cell receptor. - Lanig, Harald; Bradl, Harald; Jäck, Hans-Martin (Molecular Immunology, 2004)
Signals delivered by the immunoglobulin (Ig)-like pre-B-cell receptor (pre-BCR) are critical for efficient maturation of early precursor B (pre-B) cells. A pre-BCR contains two immunoglobulin mu-heavy chains (muHC), two surrogate light chains (SLC) consisting of the non-covalently associated polypeptides, VpreB and lambda5, and the heterodimeric signaling transducer Igalpha/beta. Although, it is generally accepted that signals initiated from the pre-BCR are required for efficient expansion and differentiation of pre-B cells, the three-dimensional structure of this receptor has not yet been determined by either NMR or X-ray spectroscopy. Therefore, we used indirect computer-assisted molecular modeling techniques to predict for the first time three-dimensional coordinates of the pre-BCR, the conformation of the SLC components, VpreB and lambda5, and the position and flexibility of the so-called non-Ig-like unique tails at the C-terminus of VpreB and the N-terminus of lambda5. Structure prediction revealed that these unique tails of VpreB and lambda5 protrude from the SLC at the position where the CDR3 of a conventional IgLchain would be located. Thus, the unique tails are accessible for ligand binding, which supports the recent finding that the lambda5 unique tail is required for pre-BCR/stroma cell interaction. Further, the non-covalent interaction of the extra beta-strand of lambda5 (beta8) with VpreB is predicted to result in a stabilization of the tertiary structure of VpreB. In summary, three-dimensional computer modeling suggests that the structure of a pre-BCR resembles that of a conventional B-cell receptor (BCR) and that the lambda5 unique tail could be a major binding site for pre-BCR ligands.

Three generations of suffering: cryopyrin-associated periodic syndrome with NLRP3 mutation in a family - Wagner, Nicola; Manger, Bernhard; Kittler, Julia; Rech, Jürgen; Sticherling, Michael; Berking, Carola; Kirchberger, Michael Constantin (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
CRIS-Team Scopus Importer:2021-12-24

Tibia Cortical Bone Segmentation in Micro-CT and X-ray Microscopy Data Using a Single Neural Network - Aust, Oliver; Thies, Mareike; Weidner, Daniela; Wagner, Fabian; Pechmann, Sabrina; Mill, Leonid; Andreev, Darja; Miyagawa, Ippei; Krönke, Gerhard; Christiansen, Silke; Uderhardt, Stefan; Maier, Andreas; et al. (Informatik aktuell, 2022)
CRIS-Team Scopus Importer:2022-05-06

Tie2 as a novel key factor of microangiopathy in systemic sclerosis - Moritz, Falk; Schniering, Janine; Distler, Jörg; Gay, Renate E.; Gay, Steffen; Distler, Oliver; Maurer, Britta (Arthritis Research & Therapy, 2017)
The angiopoietin(Ang)/Tie2 system is a key regulator of vascular biology. The expression of membrane bound (mb) Tie2 and Ang-1 ensures vessel stability, whereas Ang-2, inducible by vascular endothelial growth factor (VEGF), hypoxia, and inflammation, acts as an antagonist. Tie2 signalling is also attenuated by soluble Tie2 (sTie2), the extracellular domain of the receptor, which is shed upon stimulation with VEGF. Herein, we investigate the role of Ang/Tie2 in the peripheral vasculopathy in systemic sclerosis (SSc) including animal models.The expression of Ang-1/-2 and Tie2 in skin/serum of SSc patients was compared with healthy controls by immunohistochemistry (IHC)/ELISA. Expression of Ang/Tie2 was analysed in different animal models: VEGF transgenic (tg) mice, hypoxia model, bleomycin-induced skin fibrosis, and tight skin 1 (TSK1) mice.In SSc, dermal microvessels abundantly expressed Ang-2, but not Ang-1 compared with healthy controls. The percentage of mbTie2+ microvessels was profoundly decreased whereas the levels of sTie2 were increased already in early disease. Both in skin and sera of SSc patients, the Ang1/2 ratio was reduced, being lowest in patients with digital ulcers indicating vessel destabilizing conditions. We next studied potential influencing factors in animal models. The VEGF tg mouse model, the hypoxia, and the inflammation-dependent bleomycin model all showed a similar dysregulation of Ang/Tie2 as in SSc, which did not apply for the non-inflammatory TSK1 model.Peripheral microvasculopathy in SSc results from a complex dysregulation of angiogenic signalling networks including the VEGF and the Ang/Tie2 system. The profoundly disturbed Ang-/Tie-2 balance might represent an important target for vascular therapeutic approaches in SSc.
EVALuna2:13421

TIME TO FLARE AND GLUCOCORTICOID EXPOSURE IN PATIENTS WITH NEW-ONSET VERSUS RELAPSING GIANT CELL ARTERITIS TREATED WITH TOCILIZUMAB OR PLACEBO PLUS PREDNISONE TAPERING: 3-YEAR RESULTS FROM A RANDOMIZED CONTROLLED PHASE 3 TRIAL - Stone, J. H.; Spotswood, H.; Unizony, S.; Aringer, M.; Blockmans, D.; Brouwer, E.; Cid, M. C.; Dasgupta, B.; Rech, Jürgen; Salvarani, C.; Spiera, R.; Bao, M. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Time to Flare in Patients with New-Onset versus Relapsing Giant Cell Arteritis Treated with Tocilizumab or Placebo Plus Prednisone Tapering: 3-Year Results from a Randomized Controlled Phase 3 Trial - Stone, John; Spotswood, Helen; Unizony, Sebastian; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Spiera, Robert; Bao, Min (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

Tixagevimab/cilgavimab for the prevention of COVID-19 in vaccine-refractory patients with autoimmune diseases: a prospective cohort study. - Minopoulou, Ioanna; Tascilar, Koray; Corte, Giulia; Mutlu, Melek Yalcin; Schmidt, Katja; Bohr, Daniela; Hartmann, Fabian; Manger, Karin; Manger, Bernhard; Korn, Klaus; Kleyer, Arnd; Simon, David; et al. (Rheumatology, 2024)
OBJECTIVES: To investigate the effects of passive immunization with the anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies tixagevimab/cilgavimab on humoral responses and on coronavirus disease 2019 (COVID-19) outcomes in vaccine-refractory patients with immune-mediated inflammatory diseases (IMIDs) at high risk of severe COVID-19. METHODS: A prospective cohort study was performed on a cohort of high-risk vaccine-refractory IMID patients treated with a single dose of tixagevimab/cilgavimab (150 mg/150 mg). COVID-19 outcomes as well as serum and salivary anti-SARS-CoV-2 IgG were assessed at baseline and for at least 6 months. Results were compared with an untreated high-risk vaccine-refractory IMID population. Standardized incidence ratios (SIRs) of COVID-19 compared with the general population were calculated for both groups. RESULTS: A total of 38 high-risk IMID patients received tixagevimab/cilgavimab and were compared with 114 untreated high-risk IMID controls. Serum anti-spike IgG increased to 6.6 OD (s.d. 0.8) at day 1 and remained positive up to month 6 [6.3 OD (s.d. 1.4)]. Salivary anti-spike IgG peaked at month 2 [1.6 OD (s.d. 1.1)] and decreased from month 3 [0.8 OD (s.d. 0.3)]. No severe or extended infection was observed in the tixagevimab/cilgavimab group. Compared with the general population, the SIR of COVID-19 in treated patients was 0.76 (95% CI 0.24, 1.58) despite the increased risk profile. The SIR of the control group was 1.51 (95% CI 1.07, 2.02), corresponding to a significantly increased incidence. CONCLUSIONS: Passive immunization with tixagevimab/cilgavimab is safe and effective in inducing anti-SARS-CoV-2 immunity and potentially in preventing COVID-19 in high-risk vaccine-refractory IMID patients. These data provide a proof of concept for the use of monoclonal antibodies as a preventative strategy against SARS-CoV-2 in vulnerable populations.
EVALuna2:540332

TOCILIZUMAB ACHIEVES BETTER REPAIR OF FOCAL BONE EROSIONS THAN TUMOUR NECROSIS FACTOR INHIBITION IN RA PATIENTS - DATA FROM THE PROSPECTIVE REBONE STUDY ON EROSION REPAIR - Schett, Georg; Finze, S.; Kraus, Sebastian; Regensburger, Adrian; Kocijan, R.; Rech, Jürgen (2018)
EVALuna2:34991

Tocilizumab for systemic sclerosis: implications for future trials - Distler, Oliver; Distler, Jörg (Lancet, 2016)
EVALuna2:13282

To NET or not to NET: current opinions and state of the science regarding the formation of neutrophil extracellular traps - Boeltz, Sebastian; Amini, Poorya; Anders, Hans-Joachim; Andrade, Felipe; Bilyy, Rostyslav; Chatfield, Simon; Cichon, Iwona; Clancy, Danielle M.; Desai, Jyaysi; Dumych, Tetiana; Dwivedi, Nishant; Gordon, Rachael Ann; et al. (Cell Death and Differentiation, 2019)
Since the discovery and definition of neutrophil extracellular traps (NETs) 14 years ago, numerous characteristics and physiological functions of NETs have been uncovered. Nowadays, the field continues to expand and novel mechanisms that orchestrate formation of NETs, their previously unknown properties, and novel implications in disease continue to emerge. The abundance of available data has also led to some confusion in the NET research community due to contradictory results and divergent scientific concepts, such as pro- and anti-inflammatory roles in pathologic conditions, demarcation from other forms of cell death, or the origin of the DNA that forms the NET scaffold. Here, we present prevailing concepts and state of the science in NET-related research and elaborate on open questions and areas of dispute.
CRIS-Team WoS Importer:2019-02-22

TOPHUS RESOLUTION WITH PEGLOTICASE A PROSPECTIVE DUAL ENERGY COMPUTED TOMOGRAPHY STUDY - Schett, Georg; Araujo, E.; Bayat, Sara; Petsch, Christina; Englbrecht, Matthias; Faustini, F.; Kleyer, Arnd; Hueber, A.; Cavallaro, A.; Lell, Michael; Dalbeth, N.; Manger, Bernhard; et al. (2015)
EVALuna2:34461

Tophus resolution with pegloticase: a prospective dual-energy CT study - Araujo, Elizabeth G.; Bayat, Sara; Petsch, Christina; Englbrecht, Matthias; Faustini, Francesca; Kleyer, Arnd; Hueber, Axel; Lell, Michael; Dalbeth, Nicola; Manger, Bernhard; Schett, Georg; Rech, Juergen; et al. (RMD Open, 2015)
To investigate the effect of intensive lowering of serum uric acid (SUA) levels by pegloticase on the resolution of tophi in patients with refractory gout.Descriptive study in patients with refractory gout receiving pegloticase treatment. SUA levels were measured before and after each infusion. Dual-energy CT (DECT) scans were taken from all patients before the first infusion and after the last infusion. Computerised tophus volumes were calculated for the baseline and follow-up assessments and compared with each other.10 patients with refractory gout and baseline mean SUA level of 8.1 mg/dL were enrolled. Patients were treated for a mean of 13.3 weeks. Pegloticase effectively reduced tophi in all patients showing a decrease in volume by 71.4%. Responders, showing reduction of SUA level below 6 mg/dL during at least 80% of the treatment time, were virtually cleared from tophi (-94.8%). Dependent on their anatomical localisation, resolution of tophi showed different dynamics, with articular tophi showing fast, and tendon tophi slow, resolution.Tophi are highly sensitive to pegloticase treatment, particularly when located at articular sites. Debulking of disease and a tophus-free state can be reached within a few months of pegloticase treatment. DECT allows for comprehensively assessing tophus burden and monitoring treatment responses.
EVALuna2:13180

Toward a Better Understanding of the Atypical Features of Chronic Graft-Versus-Host Disease: A Report from the 2020 National Institutes of Health Consensus Project Task Force - Cuvelier, Geoffrey D.E.; Schoettler, Michelle; Buxbaum, Nataliya P.; Pinal-Fernandez, Iago; Schmalzing, Marc; Distler, Jörg; Penack, Olaf; Santomasso, Bianca D.; Zeiser, Robert; Angstwurm, Klemens; MacDonald, Kelli P.A.; Kimberly, W. Taylor; et al. (Transplantation and Cellular Therapy, 2022)
Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features.
CRIS-Team Scopus Importer:2022-07-15
Keywords: Atypical; Chronic graft-versus-host disease; National Institutes of Health Consensus Project Task Force

Toward Earlier Diagnosis Using Combined eHealth Tools in Rheumatology: The Joint Pain Assessment Scoring Tool (JPAST) Project - Knitza, Johannes; Knevel, Rachel; Raza, Karim; Bruce, Tor; Eimer, Ekaterina; Gehring, Isabel; Mathsson-Alm, Linda; Poorafshar, Maryam; Hueber, Axel; Schett, Georg; Johannesson, Martina; Catrina, Anca; et al. (JMIR mHealth and uHealth, 2020)
Outcomes of patients with inflammatory rheumatic diseases have significantly improved over the last three decades, mainly due to therapeutic innovations, more timely treatment, and a recognition of the need to monitor response to treatment and to titrate treatments accordingly. Diagnostic delay remains a major challenge for all stakeholders. The combination of electronic health (eHealth) and serologic and genetic markers holds great promise to improve the current management of patients with inflammatory rheumatic diseases by speeding up access to appropriate care. The Joint Pain Assessment Scoring Tool (JPAST) project, funded by the European Union (EU) European Institute of Innovation and Technology (EIT) Health program, is a unique European project aiming to enable and accelerate personalized precision medicine for early treatment in rheumatology, ultimately also enabling prevention. The aim of the project is to facilitate these goals while at the same time, reducing cost for society and patients.
CRIS-Team Scopus Importer:2020-05-29
Keywords: apps; eHealth; mHealth; rheumatology; symptom-checkers

Towards a Computable Data Corpus of Temporal Correlations between Drug Administration and Lab Value Changes - Newe, Axel; Wimmer, Stefan; Neubert, Antje; Becker, Linda; Prokosch, Hans-Ulrich; Beckmann, Matthias; Fietkau, Rainer; Forster, Christian; Neurath, Markus; Schett, Georg; Ganslandt, Thomas (PLoS ONE, 2015)
Background The analysis of electronic health records for an automated detection of adverse drug reactions is an approach to solve the problems that arise from traditional methods like spontaneous reporting or manual chart review. Algorithms addressing this task should be modeled on the criteria for a standardized case causality assessment defined by the World Health Organization. One of these criteria is the temporal relationship between drug intake and the occurrence of a reaction or a laboratory test abnormality. Appropriate data that would allow for developing or validating related algorithms is not publicly available, though. Methods In order to provide such data, retrospective routine data of drug administrations and temporally corresponding laboratory observations from a university clinic were extracted, transformed and evaluated by experts in terms of a reasonable time relationship between drug administration and lab value alteration. Result The result is a data corpus of 400 episodes of normalized laboratory parameter values in temporal context with drug administrations. Each episode has been manually classified whether it contains data that might indicate a temporal correlation between the drug administration and the change of the lab value course, whether such a change is not observable or whether a decision between those two options is not possible due to the data. In addition, each episode has been assigned a concordance value which indicates how difficult it is to assess. This is the first open data corpus of a computable ground truth of temporal correlations between drug administration and lab value alterations. Discussion The main purpose of this data corpus is the provision of data for further research and the provision of a ground truth which allows for comparing the outcome of other assessments of this data with the outcome of assessments made by human experts. It can serve as a contribution towards systematic, computerized ADR detection in retrospective data. With this lab value curve data as a basis, algorithms for detecting temporal relationships can be developed, and with the classification made by human experts, these algorithms can immediately be validated. Due to the normalization of the lab value data, it allows for a generic approach rather than for specific or solitary drug/lab value combination

Towards a pro-resolving concept in systemic lupus erythematosus - Böltz, Sebastian; Hagen, Melanie; Knopf, Jasmin; Mahajan, Aparna; Schick, Maximilian; Zhao, Yi; Erfurt-Berge, Cornelia; Rech, Jürgen; Munoz Becerra, Luis; Herrmann, Martin (Seminars in Immunopathology, 2019)
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with prominent chronic inflammatory aspects. SLE most often affects women (9:1) in childbearing age. The multifactorial nature of the etiopathogenesis of SLE involves a deficient clearance of dead and dying cells. This is supported by the occurrence of autoantibodies directed against autoantigens modified in dying and dead cells (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12) that are deposited in various tissues, including skin, kidneys, joints, muscles, and brain. The subsequent hyperinflammatory response often leads to irreparable tissue damage and organ destruction. In healthy individuals, dead and dying cells are rapidly removed by macrophages in an anti-inflammatory manner, referred to as efferocytosis. In SLE, extensive and prolonged cell death (apoptosis, necrosis, neutrophil extracellular trap (NET) formation) leads to autoantigens leaking out of the not cleared cell debris. These neo-epitopes are subsequently presented to B cells by follicular dendritic cells in the germinal centers of secondary lymphoid tissues conditioning the break of self-tolerance. Activation of autoreactive B cells and subsequent production of autoantibodies facilitate the formation of immune complexes (ICs) fueling the inflammatory response and leading to further tissue damage. ICs may also be ingested by phagocytes, which then produce further pro-inflammatory cytokines. These processes establish a vicious circle that leads to sustained inflammation. This review highlights the cell death–related events in SLE, the protagonists involved in SLE pathogenesis, the resolution of inflammation in various tissues affected in SLE, and explores strategies for intervention to restore hemostasis in a hyperinflammatory state.
CRIS-Team Scopus Importer:2019-11-19
Keywords: Apoptosis; Clearance; Inflammation; Neutrophil extracellular traps (NETs); Resolution; Secondary necrosis; Systemic lupus erythematosus (SLE)

TOWARDS DEVELOPMENT OF AN ULTRASOUND ENTHESITIS SCORE IN PSORIATIC ARTHRITIS: 24-WEEK RESULTS FROM THE PHASE III RANDOMISED ULTIMATE STUDY - D'Agostino, M. A.; Conaghan, P. G.; Gaillez, C.; Boers, M.; Naredo, E.; Carron, P.; Hanova, P.; Cazenave, T.; Bakewell, C.; Duggan, A. M.; Goyanka, P.; Schett, Georg (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Towards In-Vivo X-Ray Nanoscopy: Acquisition Parameters vs. Image Quality - Mill, Leonid; Kling, Lasse; Grüneboom, Anika; Schett, Georg; Christiansen, Silke; Maier, Andreas (Informatik aktuell, 2019)
X-ray microscopy is a powerful imaging technique that permits the investigation of specimen on nanoscale with resolution of up to 700 nm in 3-D. In the context of bio-medical research this is a promising technology that allows to study the microstructure of biological tissues. However, X-ray microscopy (XRM) systems are not designed for in-vivo applications and are mainly used in the field of material sciences in which dose is irrelevant. High resolution scans may take up to 10 hours. Our long-term goal is to utilize this modality to study the effects of disease dynamics and treatment in-vivo on mice bones. Therefore, a first step towards this ambitious goal is to evaluate the current state-of-the-art to determine the required system parameters. In this work, we investigate the impact of different XRM settings on the image quality. By changing various acquisition parameters such as exposure time, voltage, current and number of projections, we simulate the outcome of XRM scans, while reducing the X-ray energy. We base our simulations on a high resolution ex-vivo scan of a mouse tibia. The resulting reconstructions are evaluated qualitatively as well as quantitatively by calculating the contrast-to-noise ratio (CNR). We demonstrate that we can reach comparable image quality while reducing the total X-ray energy which forms a foundation towards the upcoming experiments.
CRIS-Team Scopus Importer:2019-05-14

Towards in-vivo X-ray nanoscopy: The effect of motion on image quality - Mill, Leonid; Bier, Bastian; Syben-Leisner, Christopher; Kling, Lasse; Grüneboom, Anika; Christiansen, Silke; Schett, Georg; Maier, Andreas (Informatik aktuell, 2018)
Novel X-Ray Microscopy (XRM) systems allow to study the internal structure of a specimen on nanoscale. A possible use of this non-destructive technology is motivated in the medical research area. In-Vivo investigation of medication over a period of time and its effects on perfusion and bony structure might lead to a better understanding of drug mechanisms and diseases like Osteoporosis and could lead to new approaches to their treatment. The first step towards in-vivo XRM imaging is to investigate the suitability of recent XRM systems for this task and subsequently to determine the system parameters. In this context, the impact of mice motion on the image quality is studied in this work. This paper aims to simulate the effects of breathing motion and muscle relaxation of the mice on the reconstructed images, which already effects the projection images. We therefore assume a mouse’s respiration motion pattern, which happens four time during a single projection acquisitions, and the muscle relaxation movement due to anesthesia and simulate its impacts on image quality. Additionally, we show that a frame rate of at least 16 fps is needed to capture in-vivo movements in order to apply state-of-the-art motion correction methods.<br

Towards optimal control grasping simulations with the full hand - Heinrich, Simon; Phutane, Uday; Coppers, Birte; Liphardt, Anna-Maria; Leyendecker, Sigrid (conference, 9th GACM Colloquium on Computational Mechanics - for Young Scientists from Academia and Industry, 2022)

Towards preventive treatment of rheumatoid arthritis - Rech, Jürgen; Schett, Georg (Lancet, 2022)
CRIS-Team Scopus Importer:2022-08-05

Towards Super-resolution CEST MRI for Visualization of Small Structures - Folle, Lukas; Tkotz, Katharina; Gadjimuradov, Fasil; Kapsner, Lorenz; Fabian, Moritz; Bickelhaupt, Sebastian; Simon, David; Kleyer, Arnd; Krönke, Gerhard; Zaiß, Moritz; Nagel, Armin Michael; Maier, Andreas (Bildverarbeitung für die Medizin 2022, 2022)
The onset of rheumatic diseases such as rheumatoid arthritis is typically subclinical, which results in challenging early detection of the disease. However, characteristic changes in the anatomy can be detected using imaging techniques such as MRI or CT. Modern imaging techniques such as chemical exchange saturation transfer (CEST) MRI drive the hope to improve early detection even further through the imaging of metabolites in the body. To image small structures in the joints of patients, typically one of the first regions where changes due to the disease occur, a high resolution for the CEST MR imaging is necessary. Currently, however, CEST MR suffers from an inherently low resolution due to the underlying physical constraints of the acquisition. In this work we compared established up-sampling techniques to neural network-based super-resolution approaches. We could show, that neural networks are able to learn the mapping from low-resolution to high-resolution unsaturated CEST images considerably better than present methods. On the test set a PSNR of 32.29 dB (+10%), a NRMSE of 0.14 (+28%), and a SSIM of 0.85 (+15%) could be achieved using a ResNet neural network, improving the baseline considerably. This work paves the way for the prospective investigation of neural networks for super-resolution CEST MRI and, followingly, might lead to a earlier detection of the onset of rheumatic diseases.
Keywords: Deep Learning; Rheumatic diseases; Reconstruction

Towards the generation of B-cell receptor retrogenic mice - Freitag, Jenny; Heink, Sylvia; Roth, Edith; Wittmann, Jürgen; Jäck, Hans-Martin; Kamradt, Thomas (PLoS ONE, 2014)
Transgenic expression of B- and T-cell receptors (BCRs and TCRs, respectively) has been a standard tool to study lymphocyte development and function in vivo. The generation of transgenic mice is time-consuming and, therefore, a faster method to study the biology of defined lymphocyte receptors in vivo would be highly welcome. Using 2A peptide-linked multicistronic retroviral vectors to transduce stem cells, TCRs can be expressed rapidly in mice of any background. We aimed at adopting this retrogenic technology to the in vivo expression of BCRs. Using a well characterised BCR specific for hen egg lysozyme (HEL), we achieved surface expression of the retrogenically encoded BCR in a Rag-deficient pro B-cell line in vitro. In vivo, retrogenic BCRs were detectable only intracellularly but not on the surface of B cells from wild type or Rag2-deficient mice. This data, together with the fact that no BCR retrogenic mouse model has been published in the 7 years since the method was originally published for TCRs, strongly suggests that achieving BCR-expression in vivo with retrogenic technology is highly challenging if not impossible.
EVALuna2:13620

To what extend is nail ultrasound discriminative between psoriasis, psoriatic arthritis and healthy subjects? - Naredo, Esperanza; Janta, Iustina; Baniandres-Rodriguez, Ofelia; Valor, Lara; Hinojosa, Michelle; Bello, Natalia; Serrano, Belen; Garrido, Jesus (Rheumatology International, 2019)
To assess the discriminative utility of nail features detected by B-mode (BM) and color Doppler (CD) ultrasound (US) between patients with psoriasis (PsO) and psoriatic arthritis (PsA) and healthy controls. Sixty patients with PsA, 21 patients with PsO, and 20 healthy controls were prospectively included. All patients underwent a dermatologic assessment and PsA patients also a rheumatologic assessment. All patients and controls underwent a US assessment of the finger nails that included a BM score for nail plate integrity and four different CD scores based on the amount and location of CD signals in the nail bed/matrix. In addition, we measured the thickness of the nail bed (TNB) and nail plate (TNP). The BM score and the CD score based on the amount of signals in the nail bed in contact with the ventral plate discriminated between the control group (median, range 0.0, 0–4 and 2.0, 0–9, respectively) and the PsO/PsA group (median, range: 7.0, 0–31 and 5.14, 0–13, respectively) (p < 0.05) with or without clinical nail involvement. The CD scores based on the percentage of the nail bed/matrix occupied by Doppler signals did not discriminate between controls and PsO/PsA patients. TNB and TNP were significantly higher in psoriatic nails with or without clinical involvement than in control nails. In PsO/PsA patients, the BM score, TNB and TNP were significantly higher in clinically involved nail than in clinically non-involved nails. Our results showed discriminative utility of BM US and some CD US features for PsO/PsA nails.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Doppler; Nail; Psoriasis; Psoriatic arthritis; Ultrasound

Train to target – How we might learn in the future - Krusche, Martin; Knitza, Johannes; Burmester, Gerd Rüdiger (Joint Bone Spine, 2021)
CRIS-Team Scopus Importer:2021-02-05

"Train to target" - How we might learn in the future « Train to Target » – Les méthodes d'apprentissage de demain - Krusche, Martin; Knitza, Johannes; Burmester, Gerd Rüdiger (Revue du Rhumatisme (Edition Francaise), 2022)
CRIS-Team Scopus Importer:2022-01-07

Transcriptional activation of endogenous retroviral sequences in human epidermal keratinocytes by UVB irradiation. - Hohenadl, Christine; Germaier, Herbert; Walchner, Monika; Hagenhofer, Manuela; Herrmann, Martin; Stürzl, Michael; Kind, Peter; Hehlmann, Ruediger; Erfle, Volker; Leib-Mösch, Christine (Journal of Investigative Dermatology, 1999)
Ultraviolet radiation is a pathogenic factor in various diseases, e. g., autoimmune disorders such as lupus erythematosus. On the other hand, endogenous retroviruses are discussed as etiologic agents in lupus erythematosus. Therefore, we investigated the influence of ultraviolet irradiation on expression of human endogenous retroviral sequences and human endogenous retroviral sequence promoter-driven transcription of cellular genes using human epidermal keratinocytes as a model system. First, conserved sequences of endogenous retroviral pol genes were amplified from cellular mRNA by reverse transcriptase polymerase chain reaction with degenerate oligonucleotide primers. Polymerase chain reaction products were hybridized in a reverse dot blot hybridization assay to a representative number of distinct cloned human endogenous retroviral pol fragments. Using this method, we could show that irradiation with 30 mJ per cm2 ultraviolet B activates transcription of various endogenous retroviral pol sequences in primary epidermal keratinocytes as well as in a spontaneously immortalized keratinocyte cell line (HaCaT). Interestingly, some of these sequences were found to be closely related to pol sequences of human endogenous retroviral sequences which have been shown to be expressed in autoimmune patients. Analysis of human endogenous retroviral pol expression in vivo using skin biopsies of lupus erythematosus patients revealed similar activation patterns. In a second approach, ultraviolet B- induced chimeric transcripts were isolated which are initiated by human endogenous retroviral promoters and proceed into cellular sequences using a newly established modified differential display polymerase chain reaction technique. The activation of human endogenous retroviral sequence transcription by ultraviolet B may contribute to the pathogenesis of lupus erythematosus, where inappropriate antigenic presentation of ultraviolet B-induced viral and cellular proteins could stimulate autoantibody production.
Keywords: autoantigens; differential display polymerase chain reaction; lupus erythematosus; reverse dot blot hybridization

Transcription factor Fra-1 targets arginase-1 to enhance macrophage-mediated inflammation in arthritis - Hannemann, Nicole; Cao, Shan; Eriksson, Daniel; Schnelzer, Anne; Jordan, Jutta; Eberhardt, Martin; Schleicher, Ulrike; Rech, Jürgen; Uebe, Steffen; Ekici, Arif Bülent; Canete, Juan D.; Chen, Xiaoxiang; et al. (Journal of Clinical Investigation, 2019)
The polarization of macrophages is regulated by transcription factors, such as NF-κB and activator protein 1 (AP-1). In this manuscript, we delineated the role of the transcription factor Fos-related antigen 1 (Fra-1) during macrophage activation and development of arthritis. Network level interaction analysis of microarray data derived from Fra-1- or Fra-2-deficient macrophages revealed a central role of Fra-1, but not of Fra-2, in orchestrating the expression of genes related to wound response, Toll-like receptor activation, and interleukin signaling. ChIP sequencing and standard ChIP analyses of macrophages identified arginase 1 (Arg1) as a target of Fra-1. Luciferase reporter assays revealed that Fra-1 downregulated Arg1 expression by direct binding to the promoter region. Using macrophage-specific Fra-1- or Fra-2-deficient mice, we observed enhanced expression and activity of Arg1 and a reduction of arthritis in the absence of Fra-1, but not of Fra-2. This phenotype was reversed by treatment with the arginase inhibitor Nω-hydroxy-nor-arginine, while -arginine supplementation increased arginase activity and alleviated arthritis, supporting the notion that reduced arthritis in macrophage-specific Fra-1-deficient mice resulted from enhanced Arg1 expression and activity. Moreover, patients with active rheumatoid arthritis (RA) showed increased Fra-1 expression in the peripheral blood and elevated Fra-1 protein in synovial macrophages compared with RA patients in remission. In addition, the Fra-1/ARG1 ratio in synovial macrophages was related to RA disease activity. In conclusion, these data suggest that Fra-1 orchestrates the inflammatory state of macrophages by inhibition of Arg1 expression and thereby impedes the resolution of inflammation.
CRIS-Team Scopus Importer:2019-07-16

Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis - Sales, Lucas Peixoto; Hounkpe, Bidossessi Wilfried; Perez, Mariana Ortega; Caparbo, Valéria Falco; Domiciano, Diogo Souza; Borba, Eduardo Ferreira; Schett, Georg; Figueiredo, Camille Pinto; Pereira, Rosa Maria Rodrigues (Frontiers in Immunology, 2023)
Introduction: Evidence-based data suggest that under inflammatory conditions, classical monocytes are the main source of osteoclasts and might be involved in bone erosion pathophysiology. Here, we analyze the transcriptomic profile of classical monocytes in erosive and non-erosive rheumatoid arthritis patients in order to better understand their contribution to bone erosion. Methods: Thirty-nine premenopausal RA patients were consecutively enrolled and divided into two groups based on the presence of bone erosions on hand joints. Classical monocytes were isolated from peripheral blood through negative selection, and RNA-seq was performed using a poly-A enrichment kit and Illumina® platform. Classical monocytes transcriptome from healthy age-matched women were also included to identify differentially expressed genes (DEGs). Therefore, gene sets analysis was performed to identify the enriched biological pathways. Results: RNA-seq analysis resulted in the identification of 1,140 DEGs of which 89 were up-regulated and 1,051 down-regulated in RA patients with bone erosion compared to those without bone erosions. Among up-regulated genes, there was a highlighted expression of IL18RAP and KLF14 related to the production of pro-inflammatory cytokines, innate and adaptive immune response. Genes related to collagen metabolism (LARP6) and bone formation process (PAPPA) were down-regulated in RA patients with erosions. Enriched pathways in patients with erosions were associated with greater activation of immune activation, and inflammation. Interestingly, pathways associated with osteoblast differentiation and regulation of Wnt signaling were less activated in RA patients with erosions. Conclusion: These findings suggest that alterations in expression of monocyte genes related to the inflammatory process and impairment of bone formation might have an important role in the pathophysiology of bone erosions in RA patients.
CRIS-Team Scopus Importer:2023-11-03
Keywords: bone erosions; bone formation; classical monocytes; inflammation; rheumatoid arthritis

Transferrin receptor 2 controls bone mass and pathological bone formation via BMP and Wnt signalling - Rauner, Martina; Baschant, Ulrike; Roetto, Antonella; Pellegrino, Rosa Maria; Rother, Sandra; Salbach-Hirsch, Juliane; Weidner, Heike; Hintze, Vera; Campbell, Graeme; Petzold, Andreas; Lemaitre, Regis; Henry, Ian; et al. (Nature Metabolism, 2019)
Transferrin receptor 2 (Tfr2) is mainly expressed in the liver and controls iron homeostasis. Here, we identify Tfr2 as a regulator of bone homeostasis that inhibits bone formation. Mice lacking Tfr2 display increased bone mass and mineralization independent of iron homeostasis and hepatic Tfr2. Bone marrow transplantation experiments and studies of cell-specific Tfr2-knockout mice demonstrate that Tfr2 impairs BMP-p38MAPK signalling and decreases expression of the Wnt inhibitor sclerostin, specifically in osteoblasts. Reactivation of MAPK or overexpression of sclerostin rescues skeletal abnormalities in Tfr2-knockout mice. We further show that the extracellular domain of Tfr2 binds bone morphogenic proteins (BMPs) and inhibits BMP-2-induced heterotopic ossification by acting as a decoy receptor. These data indicate that Tfr2 limits bone formation by modulating BMP signalling, possibly through direct interaction with BMP either as a receptor or as a co-receptor in complex with other BMP receptors. Finally, the Tfr2 extracellular domain may be effective in the treatment of conditions associated with pathological bone formation.
CRIS-Team Scopus Importer:2019-10-29

Transferrin receptor 2 mitigates periodontitis-driven alveolar bone loss - Lösser, Lennart; Ledesma-Colunga, Maria G.; Sastre, Enrique Andrés; Scholtysek, Carina; Hofbauer, Lorenz C.; Noack, Barbara; Baschant, Ulrike; Rauner, Martina (Journal of Cellular Physiology, 2024)
Periodontitis is associated with significant alveolar bone loss. Patients with iron overload suffer more frequently from periodontitis, however, the underlying mechanisms remain largely elusive. Here, we investigated the role of transferrin receptor 2 (Tfr2), one of the main regulators of iron homeostasis, in the pathogenesis of periodontitis and the dental phenotype under basal conditions in mice. As Tfr2 suppresses osteoclastogenesis, we hypothesized that deficiency of Tfr2 may exacerbate periodontitis-induced bone loss. Mice lacking Tfr2 (Tfr2−/−) and wild-type (Tfr2+/+) littermates were challenged with experimental periodontitis. Mandibles and maxillae were collected for microcomputed tomography and histology analyses. Osteoclast cultures from Tfr2+/+ and Tfr2−/− mice were established and analyzed for differentiation efficiency, by performing messenger RNA expression and protein signaling pathways. After 8 days, Tfr2-deficient mice revealed a more severe course of periodontitis paralleled by higher immune cell infiltration and a higher histological inflammation index than Tfr2+/+ mice. Moreover, Tfr2-deficient mice lost more alveolar bone compared to Tfr2+/+ littermates, an effect that was only partially iron-dependent. Histological analysis revealed a higher number of osteoclasts in the alveolar bone of Tfr2-deficient mice. In line, Tfr2-deficient osteoclastic differentiation ex vivo was faster and more efficient as reflected by a higher number of osteoclasts, a higher expression of osteoclast markers, and an increased resorptive activity. Mechanistically, Tfr2-deficient osteoclasts showed a higher p38-MAPK signaling and inhibition of p38-MAPK signaling in Tfr2-deficient cells reverted osteoclast formation to Tfr2+/+ levels. Taken together, our data indicate that Tfr2 modulates the inflammatory response in periodontitis thereby mitigating effects on alveolar bone loss.
CRIS-Team Scopus Importer:2024-02-02
Keywords: osteoclast; periodontitis; Tfr2

Transient receptor potential melastatin 2 regulates neutrophil extracellular traps formation and delays resolution of neutrophil-driven sterile inflammation - Cao, Xue; Li, Yanhong; Luo, Yubin; Chu, Tianshu; Yang, Hang; Wen, Ji; Liu, Yi; Zhao, Yi; Herrmann, Martin (Journal of Inflammation-London, 2023)
The formation of neutrophil extracellular traps (NETs) is a process releasing into the extracellular space networks of chromatin fibers decorated with granular proteins. It is implicated in infection-related as well as sterile inflammation. Monosodium urate (MSU) crystals serve as damage-associated molecular pattern (DAMP) in various conditions of disease. Formation of NETs or aggregated NETs (aggNETs) orchestrates initiation and resolution of MSU crystals-triggered inflammation, respectively. Elevated intracellular calcium levels and the generation of reactive oxygen species (ROS) are crucial for the formation of MSU crystal-induced NETs. However, the exact signaling pathways involved are still elusive. Herein, we demonstrate that the ROS-sensing, non-selective calcium-permeable channel transient receptor potential cation channel subfamily M member 2 (TRPM2) is required for a full-blown MSU crystal-induced NET formation. Primary neutrophils from TRPM2−/− mice showed reduced calcium influx and ROS production and, consequently a reduced formation of MSU crystal-induced NETs and aggNETs. Furthermore, in TRPM2−/− mice the infiltration of inflammatory cells into infected tissues and their production of inflammatory mediators was suppressed. Taken together these results describe an inflammatory role of TRPM2 for neutrophil-driven inflammation and identify TRPM2 as potential target for therapeutic intervention.
CRIS-Team Scopus Importer:2023-03-10
Keywords: MSU crystals; NET formation; Neutrophil extracellular traps; ROS; Sterile inflammation; TRPM2

Translational engagement of lysophosphatidic acid receptor 1 in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse - Ledein, Laetitia; Léger, Bertrand; Dees, Clara; Beyer, Christian; Distler, Alfiya; Vettori, Serena; Boukaiba, Rachid; Bidouard, Jean Pierre; Schaefer, Matthias; Pernerstorfer, Josef; Ruetten, Hartmut; Jagerschmidt, Alexandre; et al. (British Journal of Pharmacology, 2020)
Background and Purpose: Genetic deletion and pharmacological studies suggest a role for lysophosphatidic acid (LPA1) receptor in fibrosis. We investigated the therapeutic potential in systemic sclerosis (SSc) of a new orally active selective LPA1 receptor antagonist using dermal fibroblasts from patients and an animal model of skin fibrosis. Experimental Approach: Dermal fibroblast and skin biopsies from systemic sclerosis patients were used. Myofibroblast differentiation, gene expression and cytokine secretion were measured following LPA and/or SAR100842 treatment. Pharmacolgical effect of SAR100842 was assessed in the tight skin 1 (Tsk1) mouse model. Key Results: SAR100842 is equipotent against various LPA isoforms. Dermal fibroblasts and skin biopsies from patients with systemic sclerosis expressed high levels of LPA1 receptor. The LPA functional response (Ca2+) in systemic sclerosis dermal fibroblasts was fully antagonized with SAR100842. LPA induced myofibroblast differentiation in systemic sclerosis dermal and idiopathic pulmonary fibrosis lung fibroblasts and the secretion of inflammatory markers and activated Wnt markers. Results from systemic sclerosis dermal fibroblasts mirror those obtained in a mouse Tsk1 model of skin fibrosis. Using a therapeutic protocol, SAR100842 consistently reversed dermal thickening, inhibited myofibroblast differentiation and reduced skin collagen content. Inflammatory and Wnt pathway markers were also inhibited by SAR100842 in the skin of Tsk1 mice. Conclusion and Implications: The effects of SAR100842 on LPA-induced inflammation and on mechanisms linked to fibrosis like myofibroblast differentiation and Wnt pathway activation indicate that LPA1 receptor activation plays a key role in skin fibrosis. Our results support the therapeutic potential of LPA1 receptor antagonists in systemic sclerosis.
CRIS-Team Scopus Importer:2020-08-14
Keywords: fibrosis; LPA; lysophosphatidic acid; SAR100842; systemic sclerosis; tight skin mouse

Translocation of Distinct Alpha Synuclein Species from the Nucleus to Neuronal Processes during Neuronal Differentiation - Pieger, Katharina; Schmitt, Verena; Gauer, Carina; Gießl, Nadja; Prots, Iryna; Winner, Beate; Winkler, Jürgen; Brandstätter, Johann Helmut; Xiang, Wei (Biomolecules, 2022)
Alpha synuclein (aSyn) and its aggregation are crucial for the neurodegeneration of Parkinson's disease (PD). aSyn was initially described in the nucleus and presynaptic nerve terminals. However, the biology of nuclear aSyn and the link of aSyn between subcellular compartments are less understood. Current knowledge suggests the existence of various aSyn species with distinct structural and biochemical properties. Here, we identified a C-terminal-targeting aSyn antibody (Nu-aSyn-C), which has a high immunoaffinity towards aSyn in the nucleus. Comparing the Nu-aSyn-C antibody to aSyn antibodies developed against phosphorylated or aggregated forms, we observed that nuclear aSyn differs from cytosolic aSyn by an increased phosphorylation and assembly level in proliferating cells. Employing Nu-aSyn-C, we characterized aSyn distribution during neuronal differentiation in midbrain dopaminergic neurons (mDANs) derived from human-induced pluripotent stem cells (hiPSCs) and Lund human mesencephalic cells, and in primary rat hippocampal neurons. We detected a specific translocation pattern of aSyn during neuronal differentiation from the nucleus to the soma and finally to neuronal processes. Interestingly, a remarkable shift of Nu-aSyn-C-positive species towards neurites was detected in hiPSC mDANs from a PD patient carrying aSyn gene duplication. Together, our results reveal distinct nuclear and cytosolic aSyn species that redistribute during neuronal differentiation-a process that is altered in PD-derived neurons.
CRIS-Team WoS Importer:2022-09-09

Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis - Kaaij, Merlijn H.; van Tok, Melissa N.; Blijdorp, Iris C.; Ambarus, Carmen A.; Stock, Michael; Pots, Désiree; Knaup, Véronique L.; Armaka, Marietta; Christodoulou-Vafeiadou, Eleni; van Melsen, Tessa K.; Masdar, Huriatul; Eskes, Harry J.P.P.; et al. (Journal of Experimental Medicine, 2020)
TNF plays a key role in immune-mediated inflammatory diseases including rheumatoid arthritis (RA) and spondyloarthritis (SpA). It remains incompletely understood how TNF can lead to different disease phenotypes such as destructive peripheral polysynovitis in RA versus axial and peripheral osteoproliferative inflammation in SpA. We observed a marked increase of transmembrane (tm) versus soluble (s) TNF in SpA versus RA together with a decrease in the enzymatic activity of ADAM17. In contrast with the destructive polysynovitis observed in classical TNF overexpression models, mice overexpressing tmTNF developed axial and peripheral joint disease with synovitis, enthesitis, and osteitis. Histological and radiological assessment evidenced marked endochondral new bone formation leading to joint ankylosis over time. SpA-like inflammation, but not osteoproliferation, was dependent on TNF-receptor I and mediated by stromal tmTNF overexpression. Collectively, these data indicate that TNF can drive distinct inflammatory pathologies. We propose that tmTNF is responsible for the key pathological features of SpA.
CRIS-Team Scopus Importer:2020-07-24

Transoral submandibulotomy for deep hilar submandibular gland sialolithiasis - Schapher, Mirco; Mantsopoulos, Konstantinos; Meßbacher, Maria-Elena; Iro, Heinrich; Koch, Michael (Laryngoscope, 2017)
OBJECTIVES/HYPOTHESIS: To assess the long-term results after transoral submandibulotomy for stones located in the deep hilar and intraparenchymal submandibular region. STUDY DESIGN: Retrospective cohort analysis. METHODS: Retrospective evaluation including all patients treated with transoral submandibulotomy for sialolithiasis at a tertiary referral center. RESULTS: Complete stone removal at the first transoral surgical treatment was achieved in 185 of 234 patients (79.1%). One hundred seventy-five of the 234 patients were followed up for a mean of 31.2 ( ± 20.5) months. During the follow-up period, 140 of the 175 patients (80.0%) became symptom free after one operation. In patients with residual symptoms, no further treatment was needed in 12 patients (6.9%) due to the mildness of the symptoms; 23 patients (13.1%) received further therapy, which was successful in 15 cases. Submandibulectomy only had to be performed in 3.4% of the patients with follow-up (6/175). In a questionnaire survey, 91.4% of the patients stated that they would be prepared to have the same operation again. CONCLUSIONS: These findings show that transoral removal of submandibular sialoliths located in the deep hilum or adjacent intraglandular parenchyma is an effective treatment that can be assisted by additional measures. The techniques described show high success rates, good long-term results, low complication rates, and they avoided the need for submandibulectomy in >95% of cases. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2038-2044, 2017.
EVALuna2:33207

Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. - Bergmann, Christina; Müller, Fabian; Distler, Jörg; Györfi, Andrea Hermina; Völkl, Simon; Aigner, Michael; Kretschmann, Sascha; Reimann, Hannah; Harrer, Thomas; Bayerl, Nadine; Böltz, Sebastian; Wirsching, Andreas; et al. (Annals of the Rheumatic Diseases, 2023)
EVALuna2:537682

Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor - Kavanaugh, Arthur; Mease, Philip J.; Gomez-Reino, Juan J.; Adebajo, Adewale O.; Wollenhaupt, Juergen; Gladman, Dafna D.; Lespessailles, Eric; Hall, Stephen; Hochfeld, Marla; Hu, Chiachi; Hough, Douglas; Stevens, Randall M.; et al. (Annals of the Rheumatic Diseases, 2014)
Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy.In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without >=20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16.At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed.Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated.NCT01172938.
EVALuna2:12921

Treatment of refractory hypocomplementaemic urticarial vasculitis syndrome progressing to systemic lupus erythematosus with belimumab. - Valor-Méndez, Larissa; Schett, Georg; Manger, Bernhard (Clinical and Experimental Rheumatology, 2022)
EVALuna2:474272

Treatment of vitiligo using targeted UVB-Intense Pulsed Light (IPL)- phototherapy: evaluation of variables affecting therapeutic success - Hartmann, Arndt; Schmidt-Habel, Anne; Löhberg, Lisa; Zajitschek, Jörg; Englbrecht, Matthias; Eichner, Saskia; Schuler, Gerold (European Journal of Dermatology, 2014)
Targeted UVB intense pulsed light (IPL)-phototherapy has gained interest for repigmentation of vitiligo as it allows selective treatment, sparing the surrounding skin. However, optimal treatment frequency and duration are not known.We compared the efficacy and safety of two treatment protocols, weekly and every two weeks, for a maximum of 12 months. Variables affecting treatment response were evaluated.22 patients (16 female, 6 male; aged 15 - 67 years) with generalised vitiligo were evaluated retrospectively. UVB-IPL had been administered weekly (13 patients, group A), or every second week (9 patients, group B). In cases of no response, treatment stopped after 6 months. Regimentation was evaluated qualitatively and quantitatively.After 6 months, 12/13 patients (A), 3/9 patients (B) showed repigmentation. Due to lack of success, treatment was stopped after 6 months in 1 group A patient and 6/9 group B patients. After 12 months, lesions on the face and trunk in group A showed a mean of 70 ± 27% and 60 ± 29% repigmentation, respectively. Moderate to good repigmentation was seen in 78% of group A patients on the ulnar region on the forearms and the shins. Side effects were minimal. Treatment success depended on treatment frequency, number of treatments and the anatomical site of lesions.UVB-IPL phototherapy seems to be effective and well-tolerated in non-segmental vitiligo. A treatment frequency of weekly intervals rather than every two weeks appears preferable. Our observations will help in designing a sufficiently powered prospective clinical trial to test this hypothesis.
EVALuna2:13137

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS) - Herrick, Ariane L.; Pan, Xiaoyan; Peytrignet, Sebastien; Lunt, Mark; Hesselstrand, Roger; Mouthon, Luc; Silman, Alan; Brown, Edith; Czirjak, Laszlo; Distler, Jörg; Distler, Oliver; Fligelstone, Kim; et al. (Annals of the Rheumatic Diseases, 2017)
The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.NCT02339441.
EVALuna2:13405

TREATMENT PATTERNS OF IDIOPATHIC INFLAMMATORY MYOPATHIES: RESULTS FROM AN INTERNATIONAL COHORT OF OVER 1,400 PATIENTS - Aoude, M.; Gupta, L.; Hmamouchi, I.; Grignaschi, S.; Cavagna, L.; Kim, M.; R, N.; Lilleker, J. B.; Sen, P.; Agarwal, V.; Kardes, S.; Day, J.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Treatment patterns of individualized real-life tapering approaches based on shared decision-making in rheumatoid arthritis - Birkner, Benjamin; Rech, Jürgen; Edelmann, Edmund; Verheyen, Frank; Schett, Georg; Stargardt, Tom (Zeitschrift für Rheumatologie, 2023)
Objective: To provide real-world evidence on patient-individual tapering patterns of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients in daily clinical practice. Methods: Data obtained through a controlled prospective cohort study in Germany conducted from July 2018 to March 2021 were analyzed. Participants consist of RA patients in sustained remission who were eligible for DMARD tapering at enrolment. Data from RA patients who experienced tapering of DMARDs at least once during the observational period (n = 200) were used. Descriptive analyses of medical outcomes at baseline and at time of first tapering, time to first tapering, tapering patterns by substance group, and tapering intensity were documented. Results: We did not observe meaningful differences in either disease activity or quality of life measures between substance groups at enrolment, time of first tapering, and at 6 or 12 months after tapering. Median time until first tapering varied between substance groups (csDMARDs: 108 days; bDMARDs: 189 days; combination: 119 days). Most patients received one iteration of tapering only (147/200 patients, 73.5%). Dose reduction was applied for patients treated with csDMARDs (79/86 patients, 91.8%), spacing of interval was the most frequent strategy for patients treated with bDMARDs only (43/48 patients, 89.5%). Necessity for increased DMARD dosage was observed in only 10% of patients (20/200). Tapering intensity by substance was overall heterogenous, indicating high individualization. Conclusion: We identify highly heterogeneous tapering patterns between substance groups and within substances. Identification and recognition of patient-individual approaches of tapering will help to further improve the management of RA for both patients and rheumatologists.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Cohort study; Disease-modifying antirheumatic drugs (DMARD’s); Dose tapering; Real world conditions; Rheumatoid arthritis

Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial - Tascilar, Koray; Hagen, Melanie; Kleyer, Arnd; Simon, David; Reiser, Michaela; Hueber, Axel; Manger, Bernhard; Englbrecht, Matthias; Finzel, Stephanie; Tony, Hans Peter; Schuch, Florian; Kleinert, Stefan; et al. (The Lancet Rheumatology, 2021)
Background: Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. Methods: RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel-group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score <2·6 units). Eligible patients were recruited consecutively from 14 German hospitals or rheumatology practices and randomly assigned (1:1:1) without stratification and regardless of baseline treatment, using a sequence that was computer-generated by the study statistician, to continue 100% dose DMARD (continue group), taper to 50% dose DMARD (taper group), or 50% dose DMARD for 6 months before stopping DMARDs (stop group). Neither patients nor investigators were masked to the treatment assignment. Patients were assessed every 3 months and screened for disease activity and relapse. The primary endpoint was the proportion of patients in sustained DAS28-ESR remission without relapse at 12 months, analysed using a log-rank test of trend and Cox regression. Analysis by a trained statistician of the primary outcome and safety was done in a modified intention-to-treat population that included participants with non-missing baseline data. This study is completed and closed to new participants and is registered with ClinicalTrials.gov (NCT02779114). Findings: Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81·2% (95% CI 73·3–90·0) in the continue group, 58·6% (49·2–70·0) in the taper group, and 43·3% (34·6–55·5) in the stop group (p=0·0005 with log-rank test for trend). Hazard ratios for relapse were 3·02 (1·69–5·40; p=0.0003) for the taper group and 4·34 (2·48–7·60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9). Interpretation: Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. Funding: None.
CRIS-Team Scopus Importer:2021-11-05

TREATMENT TAPERING AND WITHDRAWAL IN RHEUMATOID ARTHRITIS WITH STABLE REMISSION - FINAL ANALYSIS OF THE RETRO STUDY - Hagen, Melanie; Tascilar, Koray; Reiser, Maximilian; Valor, L.; Haschka, J.; Kleyer, Arnd; Hueber, A.; Manger, Bernhard; Cobra, J.; Figuereido, C.; Finzel, S.; Tony, H. P.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Treatment with DNases rescues hidden neutrophil elastase from aggregated NETs - Podolska, Malgorzata; Mahajan, Aparna; Hahn, Jonas; Knopf, Jasmin; Maueröder, Christian; Petru, Lenka; Ullmann, Marc; Schett, Georg; Leppkes, Moritz; Herrmann, Martin; Munoz, Luis Enrique; Schauer, Christine (Journal of Leukocyte Biology, 2019)
The release of neutrophil extracellular traps (NETs) is one of the weapons neutrophils have in their armory. NETs consist of extracellular chromatin fibers decorated with a plethora of cytoplasmic and granular proteins, such as the antimicrobial serine protease neutrophil elastase (NE). Because the first description of NETs as beneficial to the host, reports on their double-faced role in health and disease have considerably increased recently. On one hand, NETs reportedly trap and kill bacteria and also participate in the resolution of the acute inflammation associated with infection and with tissue damage. On the other hand, numerous negative aspects of NETs contribute to the etiopathogenesis of autoimmune disorders. Employing soluble and solid fluorescent substrates, we demonstrate the interaction of NE with aggregated NETs (aggNETs), the limitation of its enzymatic activity and the containment of the enzyme from surrounding tissues. These events prevent the spread of inflammation and tissue damage. The detection of DNase 1-dependent elevation of NE activity attests the continuous presence of patrolling neutrophils forming NETs and aggNETs even under conditions physiologic conditions.
CRIS-Team Scopus Importer:2019-09-17
Keywords: aggregated NETs; DNase 1; NETs; neutrophil elastase; neutrophils

Treatment with Upadacitinib in Active Psoriatic Arthritis: Efficacy and Safety Data of the First 192 Patients from the UPJOINT Study, a Multicentre, Observational Study in Clinical Practice - Werner, Stephanie G.; Baraliakos, Xenofon; Reckert, Sabine; Bohl-Bühler, Martin; Laliberté, Marie Claude; Girard, Tanya; Jeromin, Katharina; Baschuk, Nikola; Fritz, Björn; Bessette, Louis; Hueber, Axel (Rheumatology and Therapy, 2023)
Introduction: Our aim was to investigate the efficacy and safety of upadacitinib (UPA) in patients with either oligo- or polyarticular active psoriatic arthritis (PsA) using routine clinical practice data from an observational, prospective, multicentre study. Methods: This interim analysis contains upadacitinib efficacy and safety data from the UPJOINT study, collected from baseline to the week 24 visit with a focus on composite measures, clinical assessments and patient-reported outcomes, amongst others, including minimal disease activity (MDA), very low disease activity (VLDA), Disease Activity Index for Psoriatic Arthritis (DAPSA), Leeds Enthesitis Index (LEI), resolution of dactylitis and nail psoriasis and body surface area affected by skin psoriasis (BSA). Results: A total of 296 patients with baseline data and 192 with completed week 24 visits were included in the analysis. The proportion of patients achieving MDA increased from 2.7% at baseline to 39.1% at week 24 (95% CI 32.1, 46.3). Similarly, the number of patients in DAPSA remission (DAPSA ≤ 4) increased from 0 at baseline to 32 (16.7%) by week 24. At that time, 59.4% of the patients were either in DAPSA remission or had low disease activity (DAPSA ≤ 14). During the 24 weeks time frame, the proportion of patients with BSA ≤ 3 increased from 80.7% to 91.1%. Furthermore, at weeks 12 and 24, 45.14% and 47.19% of affected patients showed a resolution of enthesitis. Active dactylitis and nail psoriasis at baseline were reported to affect 10.5% and 22.0%, decreasing to 2.6% and 5.7% at week 24, respectively. The safety findings are consistent with the known safety profile of upadacitinib in rheumatoid arthritis and PsA; no new safety risks were identified. Conclusion: The data from this study confirm the findings of previous randomized controlled trials suggesting UPA is an effective treatment for active PsA without any new safety signals in patients from daily clinical practice. Clinical Trial Registration: ClinicalTrials.gov identifier, NCT04758117.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Disease activity index for psoriatic arthritis; Efficacy; Minimal disease activity; Patient-reported outcomes; Psoriatic arthritis; Remission; Safety; Upadacitinib; Very low disease activity

T Regulatory Cells in Bone Remodelling - Bozec, Aline; Zaiss, Mario (Current Osteoporosis Reports, 2017)
In this review, we present the role of regulatory T (Treg) cells in bone remodelling and bone-related disease such as osteoporosis or inflammatory bone loss. We also discuss the cellular and molecular mechanism how Treg cells regulate osteoclastogenesis.Treg cells could regulate osteoclastogenesis by secreting TGF-? and IL-10 as well as IL-4 cytokines. Moreover, Treg cells can additionally regulate osteoclast differentiation, in a cell-to-cell contact via the cytotoxic T lymphocyte antigen (CTLA-4). The latter induces the apoptosis of osteoclasts dependent on CD80/86 in vitro and in vivo. Treg cells mediate immunosuppressive function that controls undesired immune reactions, such as autoimmunity. Recently, Treg cells have been shown to influence non-immunological processes, such as bone homeostasis. Accumulated evidences have demonstrated that Treg cells can suppress osteoclast differentiation in vitro and in vivo.
EVALuna2:13416

Trial of Tocilizumab in Giant-Cell Arteritis - Stone, J. H.; Tuckwell, K.; Dimonaco, S.; Klearman, M.; Aringer, M.; Blockmans, D.; Brouwer, E.; Cid, M. C.; Dasgupta, B.; Rech, J.; Salvarani, C.; Schett, Georg; et al. (New England Journal of Medicine, 2017)
Giant-cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin-6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant-cell arteritis.In this 1-year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid-free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26-week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52-week prednisone taper. Dosing of prednisone and safety were also assessed.Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week.Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01791153 .).
EVALuna2:13434

Tribbles homologue 3 stimulates canonical TGF-? signalling to regulate fibroblast activation and tissue fibrosis - Tomcik, Michal; Palumbo-Zerr, Katrin; Zerr, Pawel; Sumova, Barbora; Avouac, Jerome; Dees, Clara; Distler, Alfiya; Becvar, Radim; Distler, Oliver; Schett, Georg; Senolt, Ladislav; Distler, Jörg (Annals of the Rheumatic Diseases, 2016)
Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc).The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3.TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-? (TGF-?)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-? signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-? and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-? receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation.The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-? induces TRB3, which in turn activates canonical TGF-?/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-? signalling in SSc.
EVALuna2:13129

Triggering of NF-κB in cytokine-matured human DCs generates superior DCs for T-cell priming in cancer immunotherapy. - Pfeiffer, Isabell; Hoyer, Stefanie; Gerer, Kerstin; Voll, Reinhard E.; Knippertz, Ilka; Gueckel, Eva; Schuler, Gerold; Schaft, Niels; Dörrie, Jan (European Journal of Immunology, 2014)
Understanding the signaling that governs the immunogenicity of human dendritic cells (DCs) is a prerequisite for improving DC-based therapeutic vaccination strategies, in which the ability of DCs to induce robust and lasting Ag-specific CTL responses is of critical importance. Cytokine-matured DCs are regularly used, but to induce memory-type CTLs, they require additional activation stimuli, such as CD4+ T-cell help or TLR activation. One common denominator of these stimuli is the activation of NF-?B. Here, we show that human monocyte-derived, cytokine cocktail-matured DCs transfected with constitutively active mutants of I?B kinases (caIKKs) by mRNA electroporation, further upregulated maturation markers, and secreted enhanced amounts of cytokines, including IL-12p70, which was produced for more than 48 h after transfection. Most importantly, cytotoxic T cells induced by caIKK-transfected DCs combined high CD27 expression, indicating a more memory-like phenotype, and a markedly enhanced secondary expandability with a high lytic capacity. In contrast, CTLs primed and expanded with unmodified cytokine cocktail-matured DCs did not maintain their proliferative capacity upon repetitive stimulations. We hypothesize that "designer" DCs expressing constitutively active I?B kinases will prove highly immunogenic also in vivo and possibly emerge as a new strategy to improve the clinical efficacy of therapeutic vaccinations against cancer and other chronic diseases.
EVALuna2:19501

Tumor biology: with a little help from my dying friends - Lauber, Kirsten; Herrmann, Martin (Current Biology, 2015)
Apoptosis is an essential form of cell death underlying daily tissue regeneration. In tumor biology, apoptosis resistance is a well-established hallmark of cancer that is targeted by therapeutic approaches. A new study assigns a hitherto-underestimated function to this 'deadly friend': apoptotic cells promote tumor growth, accumulation of tumor-associated macrophages, and angiogenesis.
EVALuna2:13147

Tumor immunotherapy: lessons from autoimmunity - Maueröder, Christian; Munoz Becerra, Luis; Chaurio Gonzalez, Ricardo Alfredo; Herrmann, Martin; Schett, Georg; Berens, Christian (Frontiers in Immunology, 2014)
EVALuna2:12986

Tumor microenvironment-dependent epigenetic imprinting in the vasculature predicts colon cancer outcome - Naschberger, Elisabeth; Fuchs, Maximilian; Dickel, Nicholas; Kunz, Meik; Popp, Bernt; Anchang, Charles Gwellem; Demmler, Richard; Lyu, Yanmin; Uebe, Steffen; Ekici, Arif Bülent; Geppert, Carol-Immanuel; Hartmann, Arndt; et al. (Cancer Communications, 2023)
CRIS-Team Scopus Importer:2023-10-27

Tumor necrosis factor α and RANKL blockade cannot halt bony spur formation in experimental inflammatory arthritis - Schett, Georg; Stolina, Marina; Dwyer, Denise; Zack, Debra; Uderhardt, Stefan; Krönke, Gerhard; Kostenuik, Paul; Feige, Ulrich (Arthritis and Rheumatism, 2009)
Objective. To investigate the kinetics of bony spur formation and the relationship of bony spur formation to synovial inflammation and bone erosion in 2 rat arthritis models, and to address whether bony spur formation depends on the expression of tumor necrosis factor α (TNFα) or RANKL. Methods. Analysis of the kinetics of synovial inflammation, bone erosion, osteoclast formation, and growth of bony spurs was performed in rat collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). In addition, inhibition experiments were performed to assess whether inhibition of TNFα and RANKL by pegylated soluble TNF receptor type I (pegTNFRI) and osteoprotegerin (OPG), respectively, affected bony spur formation. Results. Bony spurs emerged from the periosteal surface close to joints, and initial proliferation of mesenchymal cells was noted as early as 3 days and 5 days after onset of CIA and AIA, respectively. Initiation of bony spur formation occurred shortly after the onset of inflammation and bone erosion. Neither pegTNFRI nor OPG could significantly halt the osteophytic responses in CIA and AIA. Conclusion. These results suggest that bony spur formation is triggered by inflammation and initial structural damage in these rat models of inflammatory arthritis. Moreover, emergence of bony spurs depends on periosteal proliferation and is not affected by inhibition of either TNFα or RANKL. Bony spur formation can thus be considered a process that occurs independent of TNFα and RANKL and is triggered by destructive arthritis. © 2009, American College of Rheumatology.
CRIS-Team Scopus Importer:2020-11-20

TYK2 inhibition and its potential in the treatment of chronic inflammatory immune diseases - Ghoreschi, Kamran; Augustin, Matthias; Baraliakos, Xenofon; Krönke, Gerhard; Schneider, Matthias; Schreiber, Stefan; Schulze-Koops, Hendrik; Zeissig, Sebastian; Thaci, Diamant (Journal der Deutschen Dermatologischen Gesellschaft, 2021)
Immune-mediated chronic inflammatory diseases have emerged as a leading cause of morbidity and mortality in Western countries over the last decades. Although multiple putative factors have been suspected to be causally related to the diseases, their overarching etiology remains unknown. This review article summarizes the current state of scientific knowledge and understanding of the role of non-receptor tyrosine kinases, with a special focus on the Janus kinase TYK2 in autoimmune and immune mediated diseases as well as on the clinical properties of its inhibition. A panel of experts in the field discussed the scientific evidence and molecular rationale for TYK2 inhibition and its clinical application. Reviewing this meeting, we aim at providing an integrated overview of the clinical profile of TYK2 inhibition and its potential in targeted pharmacological therapy of chronic autoimmune and immune-mediated diseases, with a special focus on inflammatory diseases of the skin.
CRIS-Team WoS Importer:2021-10-08