Independent development of inflammation and new bone formation in ankylosing spondylitis - Schett, Georg (Arthritis & Rheumatism-Arthritis Care & Research, 2012)
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In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation - Jensen, Björn Erik Ole; Knops, Elena; Cords, Leon; Lübke, Nadine; Salgado, Maria; Busman-Sahay, Kathleen; Estes, Jacob D.; Huyveneers, Laura E.P.; Perdomo-Celis, Federico; Wittner, Melanie; Gálvez, Cristina; Mummert, Christiane; et al. (Nature Medicine, 2023)
Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterize a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridization assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.
CRIS-Team Scopus Importer:2023-03-03

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

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

Induction of necrosis in human macrophage cell lines by corynebacterium diphtheriae and corynebacterium ulcerans strains isolated from fatal cases of systemic infections - Weerasekera, Dulanthi; Hahn, Jonas; Herrmann, Martin; Burkovski, Andreas (International Journal of Molecular Sciences, 2019)
When infecting a human host, Corynebacterium diphtheriae and Corynebacterium ulcerans are able to impair macrophage maturation and induce cell death. However, the underlying molecular mechanisms are not well understood. As a framework for this project, a combination of fluorescence microscopy, cytotoxicity assays, live cell imaging, and fluorescence-activated cell sorting was applied to understand the pathogenicity of two Corynebacterium strains isolated from fatal cases of systemic infections. The results showed a clear cytotoxic effect of the bacteria. The observed survival of the pathogens in macrophages and, subsequent, necrotic lysis of cells may be mechanisms explaining dissemination of C. diphtheriae and C. ulcerans to distant organs in the body.
CRIS-Team Scopus Importer:2019-10-22
Keywords: Cell death; FACS; Host-pathogen interaction; Live cell imaging; Macrophages; THP-1 cells

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

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

Induction of proliferation and pro-inflammatory cytokine production in rheumatoid arthritis peripheral blood mononuclear cells by a 65 KDa chondrocyte membrane-specific, constitutive target autoantigen (CH65) - Alsalameh, Rayya J.; Casey, Rachael C.; Mollenhauer, Jürgen; Kalden, Joachim; Burmester, Gerd R.; Alsalameh, Saifeddin M. (International Journal of Rheumatic Diseases, 2013)
To analyze proliferation and pro-inflammatory cytokine production of peripheral blood mononuclear cells (PBMC) from rheumatoid arthritis (RA) patients following stimulation with a purified chondrocyte membrane-associated autoantigen (CH65).CH65 was highly purified from bovine chondrocyte membranes by solubilization and ion exchange chromatography. PBMC of RA patients (n = 37; 28 seropositive, nine seronegative) and non-arthritic donors (n = 20) were isolated by ficoll centrifugation and used in cell proliferation assays. The levels of interleukin (IL)-1, tumo necrosis factor (TNF) and IL-6 produced after stimulation with CH65 were determined by enzyme-linked immunosorbent assay (ELISA). Statistical analysis was performed using Mann-Whitney U-test and Spearman rank test and the software SPSS 13.0(TM) (SPSS Inc.; Chicago, IL, USA).Peripheral blood mononuclear cells exhibited a strong proliferative response to purified CH65 in approximately 50% of the RA patients (seropositive > seronegative), with a maximum reactivity at 0.15 or 0.30 ?g/mL culture medium. In contrast, PBMC from normal donors did not show a proliferative response to CH65 at any dose. The proliferative response in RA patients peaked at days 7-9 and returned to control levels at day 13, indicating an antigen-driven process. CH65-stimulated RA PBMC produced moderate to high amounts of IL-1, TNF and IL-6. This was comparable to the response after exposure to isolated whole chondrocyte membranes or purified collagen type II.These results demonstrate a significant cellular immune response to CH65 protein in RA patients. Given the high similarity between bovine and human CH65, the results suggest a pathogenetic involvement of this molecule as a cartilage-specific potential target autoantigen in RA.
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INDUCTION OF SUSTAINED REMISSION IN EARLY INFLAMMATORY ARTHRITIS WITH THE COMBINATION OF INFLIXIMAB PLUS METHOTREXATE, METHOTREXATE ALONE OR PLACEBO: THE DINORA TRIAL - Stamm, T. A.; Machold, K.; Aletaha, D.; Alasti, F.; Lipsky, P.; Pisetsky, D.; Landewe, R.; Van Der Heijde, D.; Sepriano, A.; Aringer, M.; Boumpas, D.; Burmester, G.; et al. (2017)
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Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial - Stamm, Tanja Alexandra; Machold, Klaus Peter; Aletaha, Daniel; Alasti, Farideh; Lipsky, Peter; Pisetsky, David; Landewe, Robert; Van Der Heijde, Desiree; Sepriano, Alexandre; Aringer, Martin; Boumpas, Dimitri; Burmester, Gerd; et al. (Arthritis Research & Therapy, 2018)
BACKGROUND: In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. METHODS: In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423 ), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0-2 tender joints, and an acute-phase reactant within the normal range. RESULTS: Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p < 0.05 over all three groups) was statistically significant for IFX + MTX vs PL (p < 0.05), but not for IFX + MTX vs MTX (p = 0.10), nor for MTX vs PL (p = 0.31). Remission was maintained during the second year on no therapy in 75% of the IFX + MTX patients compared with 20% of the MTX-only patients. CONCLUSIONS: These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone, suggesting that intensive treatment can alter the disease evolution. TRIAL REGISTRATION: The trial was registered at http://www.isrctn.com/ISRCTN21272423 on 4 October 2007 (date applied)/12 December 2007 (date assigned). The first patient was included on 24 October 2007.
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INDUCTION OF TH2 CELLS AND EOSINOPHIL BY INFECTION WITH NIPPOSTRONGYLUS BRASILIENSIS PROTECTS AGAINST RHEUMATOID ARTHRITIS - Chen, Zhu; Oeser, Katharina; Baum, Wolfgang; Vöhringer, David; Schett, Georg; Bozec, Aline (2014)
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Inefficient clearance of dying cells in patients with SLE: Anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players - Kruse, Kristin; Janko, Christina; Urbonaviciute, Vilma; Mierke, Claudia T.; Winkler, Thomas; Voll, Reinhard E.; Schett, Georg; Munoz, Luis E.; Herrmann, Martin (Apoptosis, 2010)
Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease. © 2010 Springer Science+Business Media, LLC.
Keywords: ANA; Biophysical features; Clearance; CRP; HMGB-1; MFG-E8; Phosphatidylserine; Plasma membrane

Inert Coats of Magnetic Nanoparticles Prevent Formation of Occlusive Intravascular Co-aggregates With Neutrophil Extracellular Traps - Bilyy, Rostyslav; Unterweger, Harald; Weigel, Bianca; Dumych, Tetiana; Paryzhak, Solomiya; Vovk, Volodymyr; Liao, Ziyu; Alexiou, Christoph; Herrmann, Martin; Janko, Christina (Frontiers in Immunology, 2018)
If foreign particles enter the human body, the immune system offers several mechanisms of response. Neutrophils forming the first line of the immune defense either remove pathogens by phagocytosis, inactivate them by degranulation or release of reactive oxygen species or immobilize them by the release of chromatin decorated with the granular proteins from cytoplasm as neutrophil extracellular traps (NETs). Besides viable microbes like fungi, bacteria or viruses, also several sterile inorganic particles including nanoparticles reportedly activate NET formation. The physicochemical nanoparticle characteristics fostering NET formation are still elusive. Here we show that agglomerations of non-stabilized superparamagnetic iron oxide nanoparticles (SPIONs) induce NET formation by isolated human neutrophils, in whole blood experiments under static and dynamic conditions as well as in vivo. Stabilization of nanoparticles with biocompatible layers of either human serum albumin or dextran reduced agglomeration and NET formation by neutrophils. Importantly, this passivation of the SPIONs prevented vascular occlusions in vivo even when magnetically accumulated. We conclude that higher order structures formed during nanoparticle agglomeration primarily trigger NET formation and the formation of SPION-aggregated NET-co-aggregates, whereas colloid-disperse nanoparticles behave inert and are alternatively cleared by phagocytosis.
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Infection with a small intestinal helminth, Heligmosomoides polygyrus bakeri, consistently alters microbial communities throughout the murine small and large intestine - Rapin, Alexis; Chuat, Audrey; Lebon, Luc; Zaiss, Mario M.; Marsland, Benjamin J.; Harris, Nicola L.; Zaiss, Mario (International Journal For Parasitology, 2020)
Increasing evidence suggests that intestinal helminth infection can alter intestinal microbial communities with important impacts on the mammalian host. However, all of the studies to date utilize different techniques to study the microbiome and access different sites of the intestine with little consistency noted between studies. In the present study, we set out to perform a comprehensive analysis of the impact of intestinal helminth infection on the mammalian intestinal bacterial microbiome. For this purpose, we investigated the impact of experimental infection using the natural murine small intestinal helminth, Heligmosomoides polygyrus bakeri and examined possible alterations in both the mucous and luminal bacterial communities along the entire small and large intestine. We also explored the impact of common experimental variables including the parasite batch and pre-infection microbiome, on the outcome of helminth-bacterial interactions. This work provides evidence that helminth infection reproducibly alters intestinal microbial communities, with an impact of infection noted along the entire length of the intestine. Although the exact nature of helminth-induced alterations to the intestinal microbiome differed depending on the microbiome community structure present prior to infection, changes extended well beyond the introduction of new bacterial species by the infecting larvae. Moreover, striking similarities between different experiments were noted, including the consistent outgrowth of a bacterium belonging to the Peptostreptococcaceae family throughout the intestine. (C) 2019 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.
CRIS-Team WoS Importer:2020-02-18

Inflammania 3D: Exploring the Use of the Metaverse Platform Roblox for Science Communication - Greiner, Rebecca; Merk, Simon; Reiß, Sylvia; Stief, Jonathan; Wüllner, Corinna; Morschheuser, Benedikt; Jeleazcov, Sandra (Presented poster at the 7th Annual International GamiFIN Conference 2023, 18-21 April 2023, Lapland, Finland, 2023)
3D metaverse platforms are gaining popularity in various fields as they facilitate the creation of social and immersive experiences. However, the potential of this emerging phenomenon for science communication has hardly been considered so far. Therefore, we developed a game on the metaverse platform Roblox that transfers knowledge about an innovative treatment for an autoimmune disease and examined how it is perceived by users. We conducted a user study based on think aloud protocols and a survey and investigated user enjoyment, perceived im- mersion, and perceived learning. The findings imply that science communication on metaverse platforms has the potential to convey complex scientific knowledge in a tangible, engaging, and cooperative manner and should be investigated further.<br
Keywords: Gamified education; Metaverse; science communication; game-based learning; inflammation

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

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

Inflammatory arthritis and systemic bone loss are attenuated by gastrointestinal helminth parasites - Sarter, Kerstin; Kulagin, Manuel; Schett, Georg; Harris, Nicola L.; Zaiss, Mario M. (Autoimmunity, 2017)
Infections with different helminth species have been observed to ameliorate a variety of chronic inflammatory diseases. Herein, we show that the natural murine helminth species, Heligmosomoides polygyrus bakeri (Hp) is capable of attenuating disease severity in two different inflammatory arthritis models. Furthermore, we show that excretory-secretory (ES) products from Hp directly suppress osteoclast differentiation in vitro. Taken together, these results demonstrate that helminth infections can dampen autoimmune diseases and highlight a previously unrecognized and important role for ES products, by directly impacting on bone destruction.
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Inflammatory bone spur formation in psoriatic arthritis is different from bone spur formation in hand osteoarthritis - Finzel, Stephanie; Sahinbegovic, Enijad; Kocijan, Roland; Engelke, Klaus; Englbrecht, Matthias; Schett, Georg (Arthritis and Rheumatology, 2014)
To investigate the different patterns of bone spur formation in psoriatic arthritis (PsA) and hand osteoarthritis (OA), using high-resolution peripheral quantitative computed tomography (QCT).The study group comprised 70 subjects (25 patients with PsA, 25 patients with hand OA, and 20 healthy controls). The 2 patient groups were similar with regard to age and sex distribution and clinical involvement of the metacarpophalangeal (MCP) joints. All patients underwent high-resolution peripheral QCT scanning of the second, third, and fourth MCP joints of the dominantly affected hand. Demographic and disease-specific data were recorded, and the number, size, and distribution of bone spurs were assessed and compared between patients with PsA and patients with hand OA.The overall number and size of bone spurs were similar in patients with PsA and patients with hand OA. However, localization of lesions within individual joints was substantially different between patients with PsA and those with hand OA. In PsA, bone spurs dominated the radial sides of the joints (for the metacarpal head of the second joint, P < 0.001 versus hand OA; for the base of the second phalangeal joint, P < 0.001 versus hand OA), whereas the palmar and dorsal quadrants were the predilection sites in hand OA. Detailed anatomic analysis showed that bone spurs in the entheseal regions were prominent in patients with PsA but rare in patients with hand OA, and that bone spurs in patients with hand OA typically emerged at the cartilage-bone interphase and the joint margins.Our findings show that the overall number and size of bone spurs are similar in patients with PsA and patients with hand OA. Nonetheless, the anatomic sites of bone proliferation are different between these 2 groups of patients.
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Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. - Seeling, Michaela; Hillenhoff, Ulrike; David, Jean Pierre; Schett, Georg; Tuckermann, Jan; Lux, Anja; Nimmerjahn, Falk (Proceedings of the National Academy of Sciences of the United States of America, 2013)
Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFα and receptor-ligand interactions, such as the receptor activator of nuclear factor-kappa B-receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)γ receptors (FcγR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcγRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcγR-expressing innate immune cells. To address this question, we studied FcγR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcγRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction.

Inflammatory osteolysis: a conspiracy against bone - Mbalaviele, Gabriel; Novack, Deborah V.; Schett, Georg; Teitelbaum, Steven L. (Journal of Clinical Investigation, 2017)
There are many causes of inflammatory osteolysis, but regardless of etiology and cellular contexts, the osteoclast is the bone-degrading cell. Thus, the impact of inflammatory cytokines on osteoclast formation and function was among the most important discoveries advancing the treatment of focal osteolysis, leading to development of therapeutic agents that either directly block the bone-resorptive cell or do so indirectly via cytokine arrest. Despite these advances, a substantial number of patients with inflammatory arthritis remain resistant to current therapies, and even effective anti-inflammatory drugs frequently do not repair damaged bone. Thus, insights into events such as those impacted by inflammasomes, which signal through cytokine-dependent and -independent mechanisms, are needed to optimize treatment of inflammatory osteolysis.
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Infliximab therapy of relapsing tracheal stenosis in a pediatric patient with granulomatosis with polyangiitis: a case report - Schnell, Alexander; Ruppel, Renate; Tremel, Christina; Galiano, Matthias; Meßbacher, Maria-Elena; Krickau, Tobias (Journal of Medical Case Reports, 2022)
Background: Granulomatosis with polyangiitis is a granulomatous, necrotizing small-vessel vasculitis affecting both children and adults. However, subglottic tracheal stenosis appears more frequently in the pediatric cohort. To date, granulomatosis with polyangiitis is often treated with steroids, cyclophosphamide, azathioprine, or rituximab, but tumor-necrosis-factor-α-antagonistic drugs are increasingly gaining significance in treatment of refractory cases. Case presentation: We report the case of a 15-year-old Caucasian male diagnosed with proteinase-3-positive granulomatosis with polyangiitis with acute shortness of breath. X-ray and magnet resonance imaging showed extensive subglottic narrowing. Forced expiratory volume in 1 s was reduced to 50% of age norm, with massively increased effective airway resistance. The patient initially responded very well to high-dose steroids and maintenance therapy with azathioprine. He was subsequently treated with four doses of rituximab, and levels of proteinase 3 antibodies normalized. After 6 months of clinical remission, the patient presented again with acute respiratory symptoms. Again, he was treated with high-dose steroids, but showed poor clinical response this time. Therefore, we decided to commence a tumor-necrosis-factor-α-antagonistic treatment with infliximab, under which our patient achieved clinical remission and normalization of lung function parameters. Conclusions: The use of tumor-necrosis-factor-α-antagonistic agents might be a promising alternative for the treatment of refractory tracheal stenosis in pediatric patients with granulomatosis with polyangiitis.
CRIS-Team Scopus Importer:2022-04-15
Keywords: Children; Granulomatosis with polyangiitis; TNF-α inhibitor; Tracheal stenosis

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

Influence of antiTNF-alpha antibody treatment on fracture healing under chronic inflammation - Timmen, Melanie; Hidding, Heriburg; Wieskoetter, Britta; Baum, Wolfgang; Pap, Thomas; Raschke, Michael J.; Schett, Georg; Zwerina, Jochen; Stange, Richard (BMC Musculoskeletal Disorders, 2014)
The overexpression of tumor necrosis factor (TNF)-? leads to systemic as well as local loss of bone and cartilage and is also an important regulator during fracture healing. In this study, we investigate how TNF-? inhibition using a targeted monoclonal antibody affects fracture healing in a TNF-? driven animal model of human rheumatoid arthritis (RA) and elucidate the question whether enduring the anti TNF-? therapy after trauma is beneficial or not.A standardized femur fracture was applied to wild type and human TNF-? transgenic mice (hTNFtg mice), which develop an RA-like chronic polyarthritis. hTNFtg animals were treated with anti-TNF antibody (Infliximab) during the fracture repair. Untreated animals served as controls. Fracture healing was evaluated after 14 and 28 days of treatment by clinical assessment, biomechanical testing and histomorphometry.High levels of TNF-? influence fracture healing negatively, lead to reduced cartilage and more soft tissue in the callus as well as decreased biomechanical bone stability. Blocking TNF-? in hTNFtg mice lead to similar biomechanical and histomorphometrical properties as in wild type.High levels of TNF-? during chronic inflammation have a negative impact on fracture healing. Our data suggest that TNF-? inhibition by an anti-TNF antibody does not interfere with fracture healing.
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INFLUENCE OF B-CATENIN ON THE PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS AND THE DEVELOPMENT OF CARDIAC ALLOGRAFT VASCULOPATHY IN MICE - Heim, Christian; Kuckhahn, Annika; Ramsperger-Gleixner, Martina; Distler, Jörg; Spriewald, Bernd M.; Weyand, Michael; Ensminger, Stephan M. (TRANSPLANTATION, 2020)
CRIS-Team WoS Importer:2021-03-05

Influence of Canakinumab Dosing on Long-term Efficacy and Safety in Patients with Cryopyrin-associated Periodic Syndromes (CAPS)-30-months Interim Analysis of the RELIANCE Registry - Kuemmerle-Deschner, Jasmin; Kortus-Goetze, Birgit; Oommen, Prasad T.; Janda, Ales; Rech, Jürgen; Kallinich, Tilmann; Weller-Heinemann, Frank; Horneff, Gerd; Foeldvari, Ivan; Schuetz, Catharina; Borte, Michael; Braner, Axel; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

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

Influence of Swiprosin2/EFhd1 on the metabolic control of B cell differentiation and humoral immunity - Urbanczyk, Sophia; Stein, Marcello F.; Duetting, S.; Mougiakakos, Dimitrios; Boesl, M.; Reimer, Dorothea; Steinmetz, Tobit; Schuh, Wolfgang; Bozec, Aline; Winkler, Thomas; Jäck, Hans-Martin; Mielenz, Dirk (2017)
EVALuna2:13653

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Inhibition of TNF-alpha reduces transplant arteriosclerosis in a murine aortic transplant model. - Wollin, Martina; Abele, Silke; Bruns, Heiko; Weyand, Michael; Kalden, Joachim; Ensminger, Stephan M.; Spriewald, Bernd M. (Transplant International, 2009)
Experimental and clinical data provide evidence that TNF-alpha contributes to acute and chronic allograft rejection. In this study, we explored the effect of TNF-alpha blockade using the chimeric monoclonal antibody infliximab on the development of transplant arterisoclerosis in a fully mismatched aortic allograft model. Post-transplant treatment of CBA (H2(k)) recipients with 250 mug infliximab (cumulative dose 1.25 mg) reduced luminal occlusion of C57Bl/6 (H2(b)) aortic grafts on day 30 from 77 +/- 5% in untreated controls to 52 +/- 6%. Increasing the dose of anti-TNF-alpha antibody had no further beneficial effect. Treatment with human control immunoglobulin had no effect on intima proliferation. Under TNF-alpha blockade, ICAM-1 and PDGF mRNA expression within the grafts was strongly reduced, whereas iNOS expression was enhanced. The data show that TNF-alpha blockade using infliximab can reduce the development of transplant arteriosclerosis in fully mismatched murine aortic grafts.

Inhibitory and Agonistic Autoantibodies Directed Against the β2-Adrenergic Receptor in Pseudoexfoliation Syndrome and Glaucoma - Hohberger, Bettina; Schlötzer-Schrehardt, Ursula; Mardin, Christian; Lämmer, Robert; Munoz, Luis Enrique; Kunze, Rudolf; Herrmann, Martin; Wallukat, Gerd (Frontiers in Neuroscience, 2021)
Pseudoexfoliation syndrome (PEXS) and glaucoma (PEXG) are assumed to be caused by a generalized elastosis leading to the accumulation of PEX material in ocular as well as in extraocular tissues. The exact pathophysiology of PEXS is still elusive. PEXG, the most common type of secondary open-angle glaucoma (OAG), is characterized by large peaks of intraocular pressure (IOP) with a progressive loss of the visual field. Agonistic autoantibodies (agAAbs) against the β2-adrenergic receptor (AR) have been shown to be present in sera of patients with primary and secondary OAG and ocular hypertension and are seemingly linked to IOP. In the present study, we investigated the autoantibodies directed against the β2-AR in sera of patients with PEXS and PEXG. We recruited 15, 10, and 15 patients with PEXG, PEXS, and primary OAG, respectively. Ten healthy individuals served as controls. All patients underwent standard ophthalmological examination with Octopus G1 perimetry. agAAbs prepared from serum samples were analyzed in a rat cardiomyocyte–based bioassay for the presence of agAAbs. We identified the interacting loop of the β2-AR and the immunoglobulin G (IgG) subclasses using synthetic peptides corresponding to the extracellular loops of the receptors and enzyme-linked immunosorbent assay, respectively. None of the controls were β2-agAAb–positive (0.2 ± 0.5 U). No β2-agAAbs (0.2 ± 0.4 U), but inhibitory β2-AAbs were observed in 80% of the patients that partially blocked the drug-induced β2-adrenergic stimulation; 5.8 ± 1.7 U vs. 11.1 ± 0.9 U for clenbuterol in the absence and the presence of sera from patients with PEXS, respectively. Epitope analyses identified the third extracellular loop of the β2-AR as the target of the inhibitory β2-AAbs, being of IgG3 subtype in PEXS patients. In contrast, patients with PEXG showed β2-agAAbs (5.6 ± 0.9 U), but no inhibitory ones. The β2-agAAbs levels of patients with PEXG and primary OAG patients (3.9 ± 2.8 U; p > 0.05) were at a similar level. In two cases of PEXG, the β2-agAAbs exert synergistic effects with clenbuterol. The activity increased from 11.5 ± 0.3 (clenbuterol only) to 16.3 ± 0.9 U. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma, agonistic and inhibitory β2-AAbs seem to be a part of this multifactorial interplay.
CRIS-Team Scopus Importer:2021-09-03
Keywords: autoantibodies; glaucoma; imbalanced autonomic theory; pseudoexfoliation; β

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

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

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

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

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

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

Inosine Released from Dying or Dead Cells Stimulates Cell Proliferation via Adenosine Receptors - Chen, Jin; Chaurio, Ricardo A.; Maueröder, Christian; Derer, Anja; Rauh, Manfred; Kost, Andriy; Liu, Yi; Mo, Xianming; Hueber, Axel; Bilyy, Rostyslav; Herrmann, Martin; Zhao, Yi; et al. (Frontiers in Immunology, 2017)
Many antitumor therapies induce apoptotic cell death in order to cause tumor regression. Paradoxically, apoptotic cells are also known to promote wound healing, cell proliferation, and tumor cell repopulation in multicellular organisms. We aimed to characterize the nature of the regenerative signals concentrated in the micromilieu of dead and dying cells.Cultures of viable melanoma B16F10 cells, mouse fibroblasts, and primary human fibroblast-like synoviocytes (FLS) in the presence of dead and dying cells, their supernatants (SNs), or purified agonists and antagonists were used to evaluate the stimulation of proliferation. Viable cell quantification was performed by either flow cytometry of harvested cells or by crystal violet staining of adherent cells. High-performance liquid chromatography and liquid chromatography coupled with mass spectrometry of cell SNs were deployed to identify the nature of growth-promoting factors. Coimplantation of living cells in the presence of SNs collected from dead and dying cells and specific agonists was used to evaluate tumor growth in vivo.The stimulation of proliferation of few surviving cells by bystander dead cells was confirmed for melanoma cells, mouse fibroblasts, and primary FLS. We found that small soluble molecules present in the protein-free fraction of SNs of dead and dying cells were responsible for the promotion of proliferation. The nucleoside inosine released by dead and dying cells acting via adenosine receptors was identified as putative inducer of proliferation of surviving tumor cells after irradiation and heat treatment.Inosine released by dead and dying cells mediates tumor cell proliferation via purinergic receptors. Therapeutic strategies surmounting this pathway may help to reduce the rate of recurrence after radio- and chemotherapy.
EVALuna2:13419

Insertional hypermutation in mineral oil-induced plasmacytomas - Knittel, Gero; Metzner, Mirjam; Beck-Engeser, Gabriele; Kan, Ada; Ahrends, Tomasz; Eilat, Dan; Huppi, Konrad; Wabl, Matthias (European Journal of Immunology, 2014)
Unless stimulated by a chronic inflammatory agent, such as mineral oil, plasma cell tumors are rare in young BALB/c mice. This raises the questions: What do inflammatory tissues provide to promote mutagenesis? And what is the nature of mutagenesis? We determined that mineral oil-induced plasmacytomas produce large amounts of endogenous retroelements–ecotropic and polytropic murine leukemia virus and intracisternal A particles. Therefore, plasmacytoma formation might occur, in part, by de novo insertion of these retroelements, induced or helped by the inflammation. We recovered up to ten de novo insertions in a single plasmacytoma, mostly in genes with common retroviral integration sites. Additional integrations accompany tumor evolution from a solid tumor through several generations in cell culture. The high frequency of de novo integrations into cancer genes suggests that endogenous retroelements are coresponsible for plasmacytoma formation and progression in BALB/c mice.
EVALuna2:13617

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

Interactions between canonical Wnt signaling pathway and MAPK pathway regulate differentiation, maturation and function of dendritic cells - Xu, Wang-Dong; Wang, Jia; Yuan, Tong-Ling; Li, Yan-Hong; Yang, Hang; Liu, Yi; Zhao, Yi; Herrmann, Martin (Cellular Immunology, 2016)
Antigen-presenting dendritic cells interpret environmental signals to orchestrate local and systemic immune responses. In this study, the roles of Wnt proteins and their signaling pathway members in the maturation and function of monocyte-derived DCs were investigated. The present study showed higher expression of ?-catenin, as well as pGSK-3? in DCs than those in monocytes. Wnt3a, Wnt5a and inhibition of GSK-3? promoted differentiation of DCs, but inhibited maturation of DCs. GSK-3? induced DCs maturation with unconventional phenotypes. Together with ?-catenin silence, these treatment lead to reduced secretion of cytokines and chemokines except for IL-10 in comparison with LPS treatment, and significantly promoted proliferation of T cells. Wnt3a and inhibition of GSK-3? increased expression of MAPK signalings (p-ERK, p-p38, p-JNK). However, inhibition of MAPK signalings in turn differently regulated Wnt signaling proteins expression. These data suggest that Wnt pathway regulates DCs differentiation, maturation and function with interaction of MAPK signaling pathways.
EVALuna2:13383

Interactions between the intestinal microbiome and helminth parasites - Zaiss, Mario; Harris, Nicola L. (Parasite Immunology, 2016)
Throughout evolution, both helminths and bacteria have inhabited our intestines. As intestinal helminths and bacteria inhabit the same environmental niche, it is likely that these organisms interact with, and impact on, each other. In addition, intestinal helminths are well known to alter intestinal physiology, permeability, mucous secretion and the production of antimicrobial peptides - all of which may impact on bacterial survival and spatial organization. Yet despite rapid advances in our understanding of host-intestinal bacteria interactions, the impact of helminths on this relationship has remained largely unexplored. Moreover, although intestinal helminths are generally accepted to possess potent immuno-modulatory activity, it is unknown whether this capacity requires interactions with intestinal bacteria. We propose that this 'ménage à trois' situation is likely to have exerted a strong selective pressure on the development of our metabolic and immune systems. Whilst such pressures remain in developing countries, the eradication of helminths in industrialized countries has shifted this evolutionary balance, possibly underlying the increased development of chronic inflammatory diseases. Thus, helminth-bacteria interactions may represent a key determinant of healthy homoeostasis.
EVALuna2:13260

Inter-domain communication in SARS-CoV-2 spike proteins controls protease-triggered cell entry - Qing, Enya; Li, Pengfei; Cooper, Laura; Schulz, Sebastian; Jäck, Hans-Martin; Rong, Lijun; Perlman, Stanley; Gallagher, Tom (Cell Reports, 2022)
SARS-CoV-2 continues to evolve into variants of concern (VOC), with greatest variability in the multidomain, entry-facilitating spike proteins. To recognize the significance of adaptive spike protein changes, we compare variant SARS-CoV-2 virus particles in several assays reflecting authentic virus-cell entry. Virus particles with adaptive changes in spike amino-terminal domains (NTDs) are hypersensitive to proteolytic activation of membrane fusion, an essential step in virus-cell entry. Proteolysis is within fusion domains (FDs), at sites over 10 nm from the VOC-specific NTD changes, indicating allosteric inter-domain control of fusion activation. In addition, NTD-specific antibodies block FD cleavage, membrane fusion, and virus-cell entry, suggesting restriction of inter-domain communication as a neutralization mechanism. Finally, using structure-guided mutagenesis, we identify an inter-monomer β sheet structure that facilitates NTD-to-FD transmissions and subsequent fusion activation. This NTD-to-FD axis that sensitizes viruses to infection and to NTD-specific antibody neutralization provides new context for understanding selective forces driving SARS-CoV-2 evolution.
CRIS-Team Scopus Importer:2022-05-27
Keywords: coronavirus; CP: Microbiology; membrane fusion; SARS-CoV-2; spike protein; virus entry; virus evolution; virus neutralization; virus variation

Interferon decreases VEGF levels in patients with chronic myeloid leukemia treated with imatinib - Legros, L.; Guilhot, J.; Huault, S.; Mahon, F. X.; Preudhomme, C.; Guilhot, F.; Hueber, Axel (Leukemia Research, 2014)
In chronic myeloid leukemia (CML), evidence is supporting the role of VEGF in growth, and survival of leukemia cells. The evaluation of plasma VEGF levels in 403 CML patients randomized within SPIRIT study to received imatinib-400mg versus imatinib+cytarabine versus imatinib+interferon (IFN) versus imatinib-600mg demonstrated that VEGF is an independent factor of BCR-ABL burden. VEGF low levels at diagnosis were associated with a progression-free survival of 100% at 48 months. Under treatment, significant lowest levels were observed in imatinib+IFN arm. These results support the use of VEGF as a parameter to predict CML evolution and let us to speculate about antiangiogenic properties of IFN.
EVALuna2:13066

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

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

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

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

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

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

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

Internal vascular anatomy of the human lacrimal gland: A protocol based on cadaver dissection and three-dimensional micro-computed tomography - Singh, Swati; Chopra, Prakshi; Necker, Fabian; Scholz, Michael; Liphardt, Anna-Maria; Schuster, Louis; Paulsen, Friedrich; Bräuer, Lars (Annals of Anatomy-Anatomischer Anzeiger, 2024)
Purpose: To evaluate the feasibility of studying the vascular supply of the orbital and palpebral lobes of the human lacrimal gland using micro-computed tomography (micro-CT) and microscopic dissection. Methods: The lacrimal gland artery of a fresh parasagittalized cadaver head (male, aged 76 years) was infused with a lead oxide-latex mixture near the occipital pole of the gland. The entire lacrimal gland was imaged using micro-CT and 3D cinematic rendering (CR) and then dissected under a surgical microscope. Results: Micro-CT and CR images showed well-demarcated internal vascular branches of the lacrimal artery and their distribution within the orbital and palpebral lobes. The entire course of the artery and its branches could be visualized by CR and microscopic dissection, with the former showing better spatial orientation and finer branching. The main artery runs along the free edge of the aponeurosis of the levator palpebrae superior muscle and lies in the isthmus portion of the gland (between the orbital and palpebral lobes). The branches of the main lacrimal artery include one branch to the orbital adipose tissue just before entering the gland, two branches to the orbital lobe (medial and lateral), and two branches to the palpebral lobe (medial and lateral). The main artery terminates as palpebral and orbital lobe branches in the lateral half of the lacrimal gland. Conclusion: Latex and contrast-enhanced micro-CT is very well suited to visualize the vascular anatomy of the lacrimal artery within the gland. A large number of lacrimal gland examinations using the method presented here are required to demonstrate and understand the variability of the vascular anatomy of the human lacrimal gland.
CRIS-Team Scopus Importer:2024-01-19
Keywords: Anatomy; CT; Dry eye disease; Lacrimal artery; Lacrimal gland

Interplay between COVID-19 and Secukinumab treatment in Spondylarthritis patients during the omicron surge: a retrospective cohort study - Wu, Tong; Li, Yanhong; Huang, Deying; Wu, Yinlan; Liang, Xiuping; Cheng, Lu; Liao, Zehui; Xu, Fang; Chen, Ye; Zhao, Jing; Xia, Zijing; Tan, Chunyu; et al. (Autoimmunity, 2023)
The objective of this retrospective cohort study was to assess the relationship between Corona Disease 2019 (COVID-19) and Secukinumab treatment in patients with Spondylarthritis (SpA) in China during the omicron surge. Researchers retrieved 1018 medical records of Secukinumab-treated patients between January 2020 and January 2023 from the West China Hospital of Sichuan University. Out of these, 190 SpA patients from the rheumatology clinic were selected for the study. Guided phone questionnaires were administered by research staff to collect baseline characteristics, SpA disease status, and COVID-19 clinical outcomes. Cohabitants served as the control group and provided COVID-19 related data. Of the 190 potential SpA patients, 122 (66%) completed the questionnaire via phone, along with 259 cohabitants. 84.4% of SpA patients were diagnosed with Ankylosing Spondylitis (AS), and 15.6% were diagnosed with Psoriatic Arthritis (PsA). The rate of SARS-CoV-2 infection was 83.6% in the Secukinumab group and 88.8% in the cohabitants control group, with no significant difference (OR = 0.684, CI 0.366–1.275). One instance of severe COVID-19 was observed in the Secukinumab group, while two were identified in the cohabitants control group. Patients in the Secukinumab group had less time with fever caused by COVID-19 (p = 0.004). Discontinuing Secukinumab after SARS-CoV-2 infection did not significantly affect the course of COVID-19 or worsen SpA status according to our data. Our study suggests that administering Secukinumab to SpA patients does not increase their susceptibility to contracting SARS-CoV-2, and may have a positive effect on the course of SARS-CoV-2 infection.
CRIS-Team Scopus Importer:2023-12-29
Keywords: Covid-19; IL-17 inhibitors; SARS-CoV-2; secukinumab; spondylarthritis

Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects - Bujok, Krystyna; Gläser, Hartmut; Schuh, Wolfgang; Rau, Tilman; Schmidt, Ingrid; Fromm, Martin; Mandery, Kathrin (Cellular Signalling, 2015)
Prostaglandins such as prostaglandin E2 (PGE2) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE2-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE2-mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [(3)H]-thymidine incorporation which was in line with a higher accumulation of AGS-OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE2-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible-factor 1? (HIF1?) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE2-mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa.
EVALuna2:6643

INTER SPA: SENSITIVITY AND SPECIFITY OF AUTOANTIBODIES AGAINST CD74 IN EARLY AXIAL SPONDYLOARTHRITIS - Riechers, E.; Baerlecken, N. T.; Baraliakos, X.; Bakhsh, K. Achilles-Mehr; Aries, P. M.; Bannert, B.; Becker, K.; Brandt-Jurgens, F.; Braun, J.; Ehrenstein, B.; Euler, H.; Fleck, M.; et al. (2016)
EVALuna2:35073

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

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

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

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

Intracellular African swine fever virus DNA remains unmethylated in infected Vero cells - Weber, Stefanie; Hakobyan, Astghik; Zakaryan, Hovakim; Dörfler, Walter (Epigenomics, 2018)
Aim: Sequence-specific CpG methylation of eukaryotic promoters is an important epigenetic signal for long-term gene silencing. We have now studied the methylation status of African swine fever virus (ASFV) DNA at various times after infection of Vero cells in culture. Methods & results: ASFV DNA was detectable throughout the infection cycle and was found unmethylated in productively infected Vero cells as documented by bisulfite sequencing of 13 viral DNA segments. Conclusion: ASFV DNA does not become de novo methylated in the course of infection in selected segments spread across the entire genome. Thus DNA methylation does not interfere with ASFV genome transcription. Lack of de novo methylation has previously been observed for free intracellular viral DNA in cells permissively infected with human adenoviruses, with human papillomaviruses and others.
EVALuna2:35287

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

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

In vivo models of human articular cartilage mechanosensitivity - Mündermann, Annegret; Liphardt, Anna-Maria; Herger, Simon (Elsevier, 2023)
Mechanical load is important for the development, maintenance, and regeneration of healthy musculoskeletal tissues, including articular cartilage. Elucidating the association between mechanical load applied to articular cartilage and changes in articular cartilage metabolism in the context of articular cartilage health will not only allow evaluating the role of mechanical loading in the pathophysiology of diseases affecting articular cartilage but also broaden the understanding of the effects of mechanical loading on joint health or their role in fostering articular cartilage regeneration after injury. In this chapter, we provide a critical overview of existing human in vivo models for articular cartilage mechanosensitivity. The material is based on studies investigating the response of biochemical markers of articular cartilage health to acute stimuli and interventions, including loading stress, immobilization, microgravity, and medical interventions, in healthy and pathological populations.
CRIS-Team Scopus Importer:2023-11-24
Keywords: exercise; human model; In vivo; joint load; stress test; tissue metabolism

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

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

IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity - Das Gupta, Dennis; Paul, Christoph; Samel, Nadine; Bieringer, Maria; Staudenraus, Daniel; Marini, Federico; Raifer, Hartmann; Menke, Lisa; Hansal, Lea; Camara, Baerbel; Roth, Edith; Daum, Patrick; et al. (Cell Death and Differentiation, 2022)
The processes leading from disturbed B-cell development to adult B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) remain poorly understood. Here, we describe Irf4−/− mice as prone to developing BCP-ALL with age. Irf4−/− preB-I cells exhibited impaired differentiation but enhanced proliferation in response to IL-7, along with reduced retention in the IL-7 providing bone marrow niche due to decreased CXCL12 responsiveness. Thus selected, preB-I cells acquired Jak3 mutations, probably following irregular AID activity, resulting in malignant transformation. We demonstrate heightened IL-7 sensitivity due to Jak3 mutants, devise a model to explain it, and describe structural and functional similarities to Jak2 mutations often occurring in human Ph-like ALL. Finally, targeting JAK signaling with Ruxolitinib in vivo prolonged survival of mice bearing established Irf4−/− leukemia. Intriguingly, organ infiltration including leukemic meningeosis was selectively reduced without affecting blood blast counts. In this work, we present spontaneous leukemogenesis following IRF4 deficiency with potential implications for high-risk BCP-ALL in adult humans.
CRIS-Team Scopus Importer:2022-05-06

Is the conservative treatment of sacral insufficiency fractures still up to date? Retrospective clinical observational study in 46 patients - Schramm, Simon; Kopschina, Carsten; Gaßmann, Karl Günter; Fujak, Albert (Orthopaedics & Traumatology-Surgery & Research, 2023)
Background: According to current forecasts, our society will grow older and older, so that the proportion of 6% of the German population from 2017 who were 80 years or older will increase further. The frequency of falls in this patient population lead to a further increase of sacral insufficiency fractures. Hypothesis: The aim of this study is to evaluate the multimodal interdisciplinary conservative therapy regime for sacral insufficiency fractures in geriatric patients, especially on the basis of mobility and the need for assistance. Patients and Methods: A cohort of patients, who were treated as inpatients at the Waldkrankenhaus St. Marien in Erlangen with ICD-10 for sacral fractures S32.1 as the main diagnosis, was retrospectively examined. Only newly diagnosed sacral insufficiency fractures were taken into account. Patients were divided into groups based on the factors hospital stay, fracture location on the sacrum, and location of concomitant pelvic ring injury. The Barthel Index, the Tinetti's Mobility Test and the Timed Up&Go Test were recorded. Results: 46 patients met the inclusion criteria. Using the conservative therapy, improvements were achieved in all patients in terms of need for care, mobility without aids and risk of falling, also patients with an anterior and posterior pelvic ring fracture. Regard a score improvement in the Barthel Index and Tinetti Mobility Test, patients with bilateral sacral insufficiency fracture (n = 17, 37.0%) did not differ significantly from patients with unilateral sacral insufficiency fracture (n = 22, 47.8%). Conclusion: In geriatric patients, decisions about therapy should always be made on an individual and interdisciplinary basis. The conservative therapy regimen continues to play an important role in this. The collected tests–consisting of Barthel Index, Tinetti Mobility Test and Timed Up&Go Test–are well suited for further reproducible, objective studies with a larger patient collective. Level of evidence: IV.
CRIS-Team Scopus Importer:2023-02-10
Keywords: Fragility Fractures of the Pelvis; geriatric medicine; Sacral insufficiency fracture

IS THERE AN UNIVERSAL TRANSLATOR? WHICH (ANIMAL) MODELS TELL US MOST? - Distler, Jörg (2018)
EVALuna2:34980

IVIg-mediated amelioration of ITP in mice is dependent on sialic acid and SIGNR1 - Schwab, Inessa; Biburger, Markus; Krönke, Gerhard; Schett, Georg; Nimmerjahn, Falk (European Journal of Immunology, 2012)
Intravenous immunoglobulin G (IVIg) therapy is widely used to treat autoimmune and inflammatory diseases. Recent evidence suggests that in mice, splenic resident cells might be important for the anti-inflammatory activity of IVIg in a model of serum transfer arthritis. Splenectomized human immunothrombocytopenia (ITP) patients, however, still respond to IVIg therapy. To investigate whether the requirement of the spleen is essential for mouse ITP, we used a passive model of induced ITP and demonstrated that IVIg activity was functional in splenectomized animals. Further analysis showed that the IVIg-mediated amelioration of platelet phagocytosis was fully dependent on terminal sialic acid residues in the IVIg preparation and could be blocked with a specific ICAM3 grabbing nonintegrin-related 1 (SIGNR1) specific antibody. These results suggest that, similar to the human system, a spleen-independent but sialic acid- and SIGNR1-dependent pathway is responsible for IVIg-mediated suppression of autoantibody-dependent platelet depletion in mice. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Keywords: Fc-receptor · ITP · IVIg · Sialic acid · SIGNR1

I would never take preventive medication! Perspectives and information needs of people who underwent predictive tests for rheumatoid arthritis - Mosor, Erika; Stoffer-Marx, Michaela; Steiner, Guenter; Raza, Karim; Stack, Rebecca J.; Simons, Gwenda; Falahee, Marie; Skingle, Diana; Dobrin, Mircia; Schett, Georg; Englbrecht, Matthias; Smolen, Josef S.; et al. (Arthritis & Rheumatism-Arthritis Care & Research, 2019)
OBJECTIVE: Little is known about the experiences, values and needs of people without arthritis who undergo predictive biomarker testing for the development of rheumatoid arthritis (RA). Our study aimed to explore the perspectives of these individuals and describe their information needs. METHODS: A qualitative, multicenter interview study with a thematic analysis was conducted in Austria, Germany and the UK. Individuals who underwent predictive biomarker testing for RA and had a positive test result, but no diagnosis of any inflammatory joint disease, were interviewed. Participants included patients with arthralgia and asymptomatic individuals. Information and education needs were developed from the qualitative codes and themes using the Arthritis Educational Needs Assessment Tool (ENAT) as a frame of reference. RESULTS: Thematic saturation was reached in 34 individuals (76% female; 24 [71%] with arthralgia and 10 [29%] asymptomatic individuals). Thirty-seven codes were summarized into four themes, namely (i) decision making around whether to undergo initial predictive testing, (ii) willingness to consider further predictive tests and/or (iii) preventive interventions, including medication and (iv) varying reactions after receiving a positive test result. Individuals with arthralgia were more likely to be willing to take preventive action, undergo further testing, and experience psychological distress than asymptomatic individuals. All participants expressed the need for tailored, lay-understandable information. CONCLUSION: Individuals at risk of RA are currently the subjects of research aimed at developing better predictive strategies and preventive approaches. Their perceptions and needs should be addressed to inform the future development of interventions combined with education. This article is protected by copyright. All rights reserved.
EVALuna2:102214

Ixekizumab Improves Signs and Symptoms of Patients with Radiographic and Non-radiographic Axial Spondyloarthritis and Extra-articular Manifestation of Enthesitis Through 16 Weeks - Schett, Georg; Van Den Bosch, Filip; Baraliakos, Xenofon; Sandoval, David; Geneus, Vladimir; Bolce, Rebecca; Liu-Leage, Soyi; Kronbergs, Andris; Mease, Philip (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment - Zhang, Yun; Liang, Ruifang; Chen, Chih-Wei; Mallano, Tatjana; Dees, Clara; Distler, Alfiya; Reich, Adam; Bergmann, Christina; Ramming, Andreas; Gelse, Kolja; Mielenz, Dirk; Distler, Oliver; et al. (Annals of the Rheumatic Diseases, 2017)
Janus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-?. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts.The antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance.The antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis.Fibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.
EVALuna2:13270

JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function - Adam, Susanne; Simon, Nils; Steffen, Ulrike; Andes, Fabian T.; Scholtysek, Carina; Müller, Dorothea; Weidner, Daniela; Andreev, Darja; Kleyer, Arnd; Culemann, Stephan; Hahn, Madelaine; Schett, Georg; et al. (Science Translational Medicine, 2020)
Janus kinase (JAK)-mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.
CRIS-Team Scopus Importer:2020-02-21

JAK Inhibition Re-balances Gene Expression Profile of Circulating Immune Cells in Patients with Psoriatic Arthritis - Raimondo, Maria Gabriella; Anchang, Charles Gwellem; Labinsky, Hannah; Saad, Mina saad aziz; Rauber, Simon; Vogg, Mario; Kampylafka, Eleni; Knitza, Johannes; Soare, Alina; Schett, Georg; Ramming, Andreas (ARTHRITIS & RHEUMATOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-13

JAK-INHIBITORS TOFACITINIB AND BARICITINIB IMPROVE PATHOLOGICAL BONE LOSS IN VIVO - Adam, Susanne; Simon, Nils; Steffen, Ulrike; Harre, Nee; Andes, Fabian; Mueller, Dorothea; Culemann, Stephan; Andreev, Darja; Hahn, Madelaine; Scholtysek, Carina; Schett, Georg; Krönke, Gerhard; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Jan Mikulicz-Radecki (1850-1905): return of the surgeon - Manger, Bernhard; Schett, Georg (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2020-10-16
Keywords: immune system diseases; sarcoidosis; sjogren's syndrome

Joachim Robert Kalden: One of the founders of autoimmunity research and immunotherapy - Burmester, Gerd R.; Manger, Bernhard; Schett, Georg; Schulze-Koops, Hendrik (Annals of the Rheumatic Diseases, 2021)
CRIS-Team Scopus Importer:2021-06-04
Keywords: autoantibodies; autoimmunity; therapeutics

Johann Lucas Schoenlein (1793-1864): impact without publications - Manger, Bernhard; Schett, Georg; Burmester, Gerd R. (Annals of the Rheumatic Diseases, 2020)
CRIS-Team Scopus Importer:2020-11-20
Keywords: arthritis; immune complex diseases; immune system diseases; rheumatoid; systemic vasculitis

Jumonji Domain Containing Protein 3 (JMJD3) As a Novel Epigenetic Mechanism of Fibroblast Activation By Regulation of Fra-2 - Bergmann, Christina; Brandt, Adrian; Dees, Clara; Zhang, Yun; Lin, Neng-Yu; Chen, Chih-Wei; Mallano, Tatjana; Liang, Ruifang; Kam, Pui-See; Distler, Oliver; Schett, Georg; Distler, Jörg (2016)
EVALuna2:35056

Kaempferol prevents aseptic loosening via enhance the Wnt/β-catenin signaling pathway in vitro and in vivo - Qiu, Wenkui; Li, Zhenghui; Su, Zhenyan; Cao, Lichao; Li, Lei; Chen, Xi; Zhang, Wanhong; Li, Yanqing (European Journal of Medical Research, 2023)
Kaempferol has demonstrated notable positive effects on the osteogenic differentiation of mesenchymal stem cells (MSC) and osteoblasts. A substantial body of research has emphasized the role of dislodged titanium particles in aseptic loosening following joint replacement surgery. This study predominantly investigates the suppressive influence of Kaempferol on osteolysis induced by titanium (Ti) alloy particles. In vitro investigations disclosed that Kaempferol effectively enhanced mineralization and alkaline phosphatase (ALP) activity in bone-marrow mesenchymal stem cells exposed to Ti particles. In addition, we conducted a comprehensive analysis of osteogenic differentiation microarray data_sets (GSE37676, GSE79814, and GSE114474) to identify differentially expressed genes. Significantly, Kaempferol upregulated the expression of critical osteogenic markers, including Runt-related transcription factor 2 (Runx2), osteocalcin (OCN), osterix/Sp-7, and β-catenin. In vivo experiments, including H&E staining and Immunohistochemistry, provided compelling evidence that Kaempferol exerted a robust inhibitory effect on periprosthetic osteolysis in mice, with particularly pronounced results at higher doses. Moreover, it elevated the expression levels of osteogenic factors and Wnt/β-catenin signaling components. These findings collectively indicate that Kaempferol mitigates the hindrance to osteogenesis posed by titanium particles by activating the Runx2 and Wnt/β-catenin signaling pathways. This research lays a solid foundation for the prospective utilization of Kaempferol in the management of aseptic loosening following arthroplasty, offering promising therapeutic potential.
CRIS-Team Scopus Importer:2023-11-17

Keratinocyte-derived S100A9 modulates neutrophil infiltration and affects psoriasis-like skin and joint disease - Mellor, Liliana F.; Gago-Lopez, Nuria; Bakiri, Latifa; Schmidt, Felix N.; Busse, Bjorn; Rauber, Simon; Jimenez, Maria; Megias, Diego; Oterino-Soto, Sergio; Sanchez-Prieto, Ricardo; Grivennikov, Sergei; Pu, Xinzhu; et al. (Annals of the Rheumatic Diseases, 2022)
Objectives S100A9, an alarmin that can form calprotectin (CP) heterodimers with S100A8, is mainly produced by keratinocytes and innate immune cells. The contribution of keratinocyte-derived S100A9 to psoriasis (Ps) and psoriatic arthritis (PsA) was evaluated using mouse models, and the potential usefulness of S100A9 as a Ps/PsA biomarker was assessed in patient samples. Methods Conditional S100A9 mice were crossed with DKO* mice, an established psoriasis-like mouse model based on inducible epidermal deletion of c-Jun and JunB to achieve additional epidermal deletion of S100A9 (TKO* mice). Psoriatic skin and joint disease were evaluated in DKO* and TKO* by histology, microCT, RNA and proteomic analyses. Furthermore, S100A9 expression was analysed in skin, serum and synovial fluid samples of patients with Ps and PsA. Results Compared with DKO* littermates, TKO* mice displayed enhanced skin disease severity, PsA incidence and neutrophil infiltration. Altered epidermal expression of selective pro-inflammatory genes and pathways, increased epidermal phosphorylation of STAT3 and higher circulating TNF alpha were observed in TKO* mice. In humans, synovial S100A9 levels were higher than the respective serum levels. Importantly, patients with PsA had significantly higher serum concentrations of S100A9, CP, VEGF, IL-6 and TNF alpha compared with patients with only Ps, but only S100A9 and CP could efficiently discriminate healthy individuals, patients with Ps and patients with PsA. Conclusions Keratinocyte-derived S100A9 plays a regulatory role in psoriatic skin and joint disease. In humans, S100A9/CP is a promising marker that could help in identifying patients with Ps at risk of developing PsA.
CRIS-Team WoS Importer:2022-07-15

Key opinion leaders — a critical perspective - Scher, Jose U.; Schett, Georg (Nature Reviews Rheumatology, 2020)
Enormous progress has been made in the field of rheumatology in the past several decades, historically led by publicly funded academic innovators but in more recent times with much greater involvement of the pharmaceutical industry. This shift in resources has created a complex new model for reinvestment in the medical community in which the vast majority of private funds are redirected towards influencing the prescription behaviour of practitioners through ‘key opinion leaders’, with the main purpose of enhancing and perpetuating profit rather than innovation and critical thinking, and often at the expense of partnerships with scientists (that is, basic and translational researchers) and academic collaborations. This new episteme brings multiple opportunities to rethink approaches to sustaining long-term critical research in the field, ultimately maximizing the return on investment: scientific knowledge for the benefit of patients and society. Central to such strategies should be the rebalancing of academia–industry partnerships towards academic research and the involvement of ‘innovation and knowledge leaders’, rather than mostly key opinion leaders.
CRIS-Team Scopus Importer:2020-12-11

Kidney involvement in Rosai-Dorfman disease - Mazzariol, Martina; Peyronel, Francesco; Fagni, Filippo; Minervini, Andrea; Santi, Raffaella; Agostini, Simone; Vaglio, Augusto (Kidney International, 2023)
CRIS-Team Scopus Importer:2023-01-06

Kidney-transplant patients receiving living- or dead-donor organs have similar psychological outcomes (findings from the PI-KT study) - Müller, Helge H.O.; Lücke, Caroline; Englbrecht, Matthias; Wiesener, Michael S.; Siller, Teresa; Eckardt, Kai-Uwe; Kornhuber, Johannes; Maler, Juan Manuel (Mental Illness, 2020)
Purpose: Kidney transplantation (KT) is the treatment of choice for end-stage chronic kidney disease (CKD) and is well known to improve the clinical outcome of patients. However, the impact of KT on comorbid psychological symptoms, particularly depression and anxiety, is less clear, and recipients of living-donor (LD) organs may have a different psychological outcome from recipients of dead-donor (DD) organs. Design/methodology/approach: In total, 152 patients were included and analyzed using a cross-sectional design. Of these patients, 25 were pre-KT, 13 were post-KT with a LD transplant and 114 were post-KT with a DD transplant. The patients were tested for a variety of psychometric outcomes using the Hospital Anxiety and Depression Scale, the 12-Item Short Form Health Survey (assessing physical and mental health-related quality of life), the Resilience Scale, the Coping Self-Questionnaire and the Social Support Questionnaire. Findings: The mean age of the patients was 51.25 years and 40 per cent of the patients were female. As expected, the post-KT patients had significantly better scores on the physical component of the Short Form Health Survey than the pre-KT patients, and there were no significant differences between the two post-KT groups. There were no significant differences among the groups in any of the other psychometric outcome parameters tested, including anxiety, depression and the mental component of health-related quality of life. Research limitations/implications: KT and the origin of the donor organ do not appear to have a significant impact on the psychological well-being of transplant patients with CKD. Although the diagnosis and early treatment of psychological symptoms, such as depression and anxiety, remain important for these patients, decisions regarding KT, including the mode of transplantation, should not be fundamentally influenced by concerns about psychological impairments at the population level. Originality/value: CKD is a serious condition involving profound impairment of the physical and psychological well-being of patients. KT is considered the treatment of choice for most of these patients. KT has notable advantages over dialysis with regard to the long-term physical functioning of the renal and cardiovascular system and increases the life expectancy of patients. However, the data on the improvement of psychological impairments after KT are less conclusive.
CRIS-Team Scopus Importer:2020-06-16
Keywords: Coping; Kidney transplantation

KLF2-a negative regulator of pre-B cell clonal expansion and B cell activation - Winkelmann, Rebecca; Sandrock, Lena; Kirberg, Joerg; Jäck, Hans-Martin; Schuh, Wolfgang (PLoS ONE, 2014)
Maturation as well as antigen-dependent activation of B cells is accompanied by alternating phases of proliferation and quiescence. We and others have previously shown that Krüppel-like factor 2 (KLF2), a regulator of T cell quiescence and migration, is upregulated in small resting precursor (pre)-B cells after assembly of the immature pre-B cell receptor (pre-BCR) and is downregulated upon antigen-induced proliferation of mature B cells. These findings suggest that KLF2, besides its function in maintaining follicular B cell identity, peripheral B cell homeostasis and homing of antigen-specific plasma cells to the bone marrow, also controls clonal expansion phases in the B cell lineage. Here, we demonstrate that enforced expression of KLF2 in primary pre-B cells results in a severe block of pre-BCR-induced proliferation, upregulation of the cell cycle inhibitors p21 and p27 and downregulation of c-myc. Furthermore, retroviral KLF2 transduction of primary B cells impairs LPS-induced activation, favors apoptosis and results in reduced abundance of factors, such as AID, IRF4 and BLIMP1, that control the antigen-dependent phase of B cell activation and plasma cell differentiation. Hence, we conclude that KLF2 is not only a key player in terminating pre-B cell clonal expansion but also a potent suppressor of B cell activation.
EVALuna2:13621

Knee biomechanics of single leg hop landings after primary anterior cruciate ligament repair and InternalBraceTM augmentation - Coppers, Birte; Bühl, Linda; Müller, Sebastian; Nüesch, Corina; Mündermann, Annegret; Egloff, Christian (28th Congress of the International Society of Biomechanics - ISB, 2021)

KNEE JOINT PAIN IN AN ELDERLY, HEALTHY POPULATION IS ASSOCIATED WITH INFLAMMATORY ARTICULAR AND ENTHESEAL CHANGES DETECTED BY ULTRASOUND - Simon, David; Kleyer, Arnd; Adinolfi, Antonella; Willeit, Johann; Kiechl, Stefan; Gasperi, Nina; Schett, Georg; Dejaco, Christian; Iagnocco, Annamaria; D'Agostino, Maria-Antonietta (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Krüppel-like factor 2: a central regulator of B cell differentiation and plasma cell homing - Wittner, Jens; Schuh, Wolfgang (Frontiers in Immunology, 2023)
The development of B cells, their activation and terminal differentiation into antibody-producing plasma cells are characterized by alternating phases of proliferation and quiescence that are controlled by complex transcriptional networks. The spatial and anatomical organization of B cells and plasma cells inside lymphoid organs as well as their migration within lymphoid structures and between organs are prerequisites for the generation and the maintenance of humoral immune responses. Transcription factors of the Krüppel-like family are critical regulators of immune cell differentiation, activation, and migration. Here, we discuss the functional relevance of Krüppel-like factor 2 (KLF2) for B cell development, B cell activation, plasma cell formation and maintenance. We elaborate on KLF2-mediated regulation of B cell and plasmablast migration in the context of immune responses. Moreover, we describe the importance of KLF2 for the onset and the progression of B cell-related diseases and malignancies.
CRIS-Team Scopus Importer:2023-06-02
Keywords: B cells; IgA; integrins; KLF2; mucosal immunity; multiple myeloma; plasma cells; quiescence

Krüppel-like factor 2 controls IgA plasma cell compartmentalization and IgA responses - Wittner, Jens; Schulz, Sebastian; Steinmetz, Tobit; Berges, Johannes; Hauke, Manuela; Channell, William M.; Cunningham, Adam F.; Hauser, Anja E.; Hutloff, Andreas; Mielenz, Dirk; Jäck, Hans-Martin; Schuh, Wolfgang (Mucosal Immunology, 2022)
Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral immunity remains elusive. Therefore, by using mice with a B cell-specific deletion of KLF2, we investigated plasma cell differentiation and antibody responses. We revealed that the deletion of KLF2 resulted in perturbed IgA plasma cell compartmentalization, characterized by the absence of IgA plasma cells in the bone marrow, their reductions in the spleen, the blood and the lamina propria of the colon and the small intestine, concomitant with their accumulation and retention in mesenteric lymph nodes and Peyer’s patches. Most intriguingly, secretory IgA in the intestinal lumen was almost absent, dimeric serum IgA was drastically reduced and antigen-specific IgA responses to soluble Salmonella flagellin were blunted in KLF2-deficient mice. Perturbance of IgA plasma cell localization was caused by deregulation of CCR9, Integrin chains αM, α4, β7, and sphingosine-1-phosphate receptors. Hence, KLF2 not only orchestrates the localization of IgA plasma cells by fine-tuning chemokine receptors and adhesion molecules but also controls IgA responses to Salmonella flagellin.
CRIS-Team Scopus Importer:2022-04-15

Krüppel-like factor 2 (Klf2) in immune cell migration - Wittner, Jens; Schuh, Wolfgang (Vaccines, 2021)
Krüppel-like factor 2 (KLF2), a transcription factor of the krüppel-like family, is a key regulator of activation, differentiation, and migration processes in various cell types. In this review, we focus on the functional relevance of KLF2 in immune cell migration and homing. We summarize the key functions of KLF2 in the regulation of chemokine receptors and adhesion molecules and discuss the relevance of the KLF2-mediated control of immune cell migration in the context of immune responses, infections, and diseases.
CRIS-Team Scopus Importer:2021-10-29
Keywords: B cells; KLF2; Krüppel-like factor 2; Migration; Monocytes; Neutrophils; NK cells; Plasma cells; S1PR1; T cells

Lack of inhibitory effects of the anti-fibrotic drug imatinib on endothelial cell functions in vitro and in vivo. - Venalis, Paulius; Maurer, Britta; Akhmetshina, Alfiya; Busch, Nicole; Dees, Clara; Stürzl, Michael; Zwerina, Jochen; Juengel, Astrid; Gay, Steffen; Schett, Georg; Distler, Oliver; Distler, Jörg (Journal of Cellular and Molecular Medicine, 2009)
Systemic sclerosis (SSc) is a systemic autoimmune disease that is characterized by microangiopathy with progressive loss of capillaries and tissue fibrosis. Imatinib exerts potent anti-fibrotic effects and is currently evaluated in clinical trials. The aim of the present study was to exclude that the anti-fibrotic effects of imatinib are complicated by inhibitory effects on endothelial cell functions, which might augment vascular disease in SSc. Endothelial cells and mice were treated with pharmacologically relevant concentrations of imatinib. The expression of markers of vascular activation was assessed with real-time PCR. Proliferation was analysed with the cell counting experiments and the MTT assay. Apoptosis was quantified with caspase 3 assays, annexin V in vitro and with TUNEL staining in vivo. Migration was studied with scratch and transwell assays. Tube forming was investigated with the matrigel assay. Imatinib did not alter the expression of markers of vascular activation. Imatinib did not increase the percentage of annexin V positive cells or the activity of caspase 3. No reduction in proliferation or metabolic activity of endothelial cells was observed. Imatinib did not affect migration of endothelial cells and did not reduce the formation of capillary tubes. Consistent with the in vitro data, no difference in the number of apoptotic endothelial cells was observed in vivo in mice treated with imatinib. Imatinib does not inhibit activation, viability, proliferation, migration or tube forming of endothelial cells in vitro and in vivo. Thus, treatment with imatinib might not augment further endothelial cell damage in SSc.

L-Arginine metabolism inhibits arthritis and inflammatory bone loss - Cao, Shan; Li, Yixuan; Song, Rui; Meng, Xianyi; Fuchs, Maximilian; Liang, Chunguang; Kachler, Katerina; Meng, Xinyu; Wen, Jinming; Schlötzer-Schrehardt, Ursula; Taudte, Verena; Geßner, Arne; et al. (Annals of the Rheumatic Diseases, 2023)
Objectives: To investigate the effect of the L-Arginine metabolism on arthritis and inflammation-mediated bone loss. Methods: L-Arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by μCT and histomorphometry. In vitro, effects of L-Arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-Associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients. Results: L-Arginine inhibited arthritis and bone loss in all three models and directly blocked TNFα-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-Arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-Arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients. Conclusion: Our study demonstrated that L-Arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Arthritis; Inflammation; Osteoporosis

L-ARGININE REPROGRAMS OSTEOCLAST PURINE METABOLISM AMELIORATING BONE LOSS IN RHEUMATOID ARTHRITIS - Cao, Shan; Song, Rui; Meng, Xianyi; Kachler, Katerina; Fuchs, Maximilian; Meng, X.; Li, Y.; Taudte, Verena; Kunz, Meik; Schlötzer-Schrehardt, Ursula; Schleicher, Ulrike; Chen, X.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

L-ARGININE SUPPLEMENTATION AMELIORATES BONE EROSION IN RHEUMATOID ARTHRITIS THROUGH INHIBITION OF RANKL/RANK/TRAF6 PATHWAY AND REPROGRAMMING OSTEOCLAST METABOLISM - Cao, Shan; Chen, X.; Schett, Georg; Bozec, Aline (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Latest perspectives on macrophages in bone homeostasis - Bozec, Aline; Soulat, Didier (Pflügers Archiv: European Journal of Physiology, 2017)
Knowledge about macrophages residing in the bone, also known as osteal macrophages or osteomacs, is still limited. A hallmark of this peculiar myeloid population is the expression of macrophage markers distinct from the markers found on osteoclast surface. In bone, osteomacs are in contact with osteoblasts, where they are involved in regulating bone homeostasis. However, additional macrophage subtypes already present in the bone marrow or recruited from the blood circulation could have further functions, which could be all important for the maintenance of the bone architecture and its associated functions. Indeed, bone marrow macrophages have been found to eliminate apoptotic cells, particularly apoptotic osteoblasts through a process named efferocytosis. This phagocytic process plays an essential role in bone tissue homeostasis and new bone formation. In addition, bone marrow macrophages can influence the hematopoietic stem cell (HSC) niches. They contribute to the regulation of the HSC progenitor cell maintenance, mobilization, and function. To do so, macrophages secrete cytokines in steady state or during stress conditions. These cytokines influence hematopoiesis either by a direct effect on HSCs or through the control of stromal cells that are essential for the HSC niches. Interestingly, the similarities between the niches for HSCs and the niche for metastatic tumor cells support the possibility that bone-resident macrophages could control the homing of tumor cells and their proliferation within the bone. In general, macrophage role during metastatic processes is well described; however, their direct involvement in bone metastasis is a rising research area. In this review, we will highlight the macrophage functions in the skeleton, in the maintenance of the HCS niches, and their importance in bone metastasis.
EVALuna2:7749

LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis - Shi, Xiangguang; Chen, Yahui; Liu, Qingmei; Mei, Xueqian; Liu, Jing; Tang, Yulong; Luo, Ruoyu; Sun, Dayan; Ma, Yanyun; Wu, Wenyu; Tu, Wenzhen; Zhao, Yinhuan; et al. (Clinical and Translational Medicine, 2022)
Treatments for pulmonary fibrosis (PF) are ineffective because its molecular pathogenesis and therapeutic targets are unclear. Here, we show that the expression of low-density lipoprotein receptor (LDLR) was significantly decreased in alveolar type II (ATII) and fibroblast cells, whereas it was increased in endothelial cells from systemic sclerosis-related PF (SSc-PF) patients and idiopathic PF (IPF) patients compared with healthy controls. However, the plasma levels of low-density lipoprotein (LDL) increased in SSc-PF and IPF patients. The disrupted LDL-LDLR metabolism was also observed in four mouse PF models. Upon bleomycin (BLM) treatment, Ldlr-deficient (Ldlr-/-) mice exhibited remarkably higher LDL levels, abundant apoptosis, increased fibroblast-like endothelial and ATII cells and significantly earlier and more severe fibrotic response compared to wild-type mice. In vitro experiments revealed that apoptosis and TGF-beta 1 production were induced by LDL, while fibroblast-like cell accumulation and ET-1 expression were induced by LDLR knockdown. Treatment of fibroblasts with LDL or culture medium derived from LDL-pretreated endothelial or epithelial cells led to obvious fibrotic responses in vitro. Similar results were observed after LDLR knockdown operation. These results suggest that disturbed LDL-LDLR metabolism contributes in various ways to the malfunction of endothelial and epithelial cells, and fibroblasts during pulmonary fibrogenesis. In addition, pharmacological restoration of LDLR levels by using a combination of atorvastatin and alirocumab inhibited BLM-induced LDL elevation, apoptosis, fibroblast-like cell accumulation and mitigated PF in mice. Therefore, LDL-LDLR may serve as an important mediator in PF, and LDLR enhancing strategies may have beneficial effects on PF.
CRIS-Team WoS Importer:2022-02-11
Keywords: apoptosis; combination treatment; LDL; LDLR; pulmonary fibrosis

Leitlinienreport zur DGRh-S2e-Leitlinie Diagnostik und Therapie des adulten Still-Syndroms (AOSD) - Vordenbaeumen, Stefan; Feist, Eugen; Rech, Jürgen; Fleck, Martin; Blank, Norbert; Haas, Johannes-Peter; Koetter, Ina; Krusche, Martin; Chehab, Gamal; Hoyer, Bimba; Kiltz, Uta; Fell, Dorothea; et al. (Zeitschrift für Rheumatologie, 2022)
CRIS-Team Scopus Importer:2022-11-25

Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway - Busch, Leonhard; Mougiakakos, Dimitrios; Büttner-Herold, Maike; Müller, Miriam J.; Volmer, Dietrich A.; Bach, Christian; Fabri, Mario; Bittenbring, Jörg T.; Neumann, Frank; Boxhammer, Rainer; Nolting, Jens; Bisht, Savita; et al. (Leukemia, 2018)
Macrophages are key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD38 antibody MOR202, currently introduced in multiple myeloma (MM) therapy. Therefore, it is important to understand how antibody-mediated effector functions of myeloma-associated macrophages (MAMs) are regulated. Here, we focused on the effects of vitamin D, a known regulator of macrophage effector functions. Consequently, it was the aim of this study to assess whether modulation of the vitamin D pathway alters the tumoricidal activity of MAMs. Here, we demonstrate that MAMs display a defective vitamin D pathway with reduced expression level of CYP27B1 and limited tumoricidal activity which can be restored by the IMiD lenalidomide in vitro. Furthermore, our data indicate that the vitamin D pathway of MAMs from MM patients does recover during an IMiD-containing therapy shown by an improved MOR202-mediated cytotoxic activity of these MAMs against primary MM cells ex vivo. Here, the ex vivo cytotoxic activity could be further enhanced by vitamin D supplementation. These data suggest that vitamin D holds a key role for the effector functions of MAMs and that vitamin D supplementation in IMiD combination trials could further increase the therapeutic efficacy of anti-CD38 antibodies such as MOR202, which remains to be investigated in clinical studies.
EVALuna2:34165

Leukocyte ?7 integrin targeted by Krüppel-like factors - Alles, Melanie; Turchinovich, Gleb; Zhang, Pumin; Schuh, Wolfgang; Agenes, Fabien; Kirberg, Joerg (Journal of Immunology, 2014)
Constitutive expression of Krüppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin ?7 (Itgb7, Ly69) by binding to the ?7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the ?7 promoter, indicating that these factors may compete for target sequence(s). Whereas ?7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because ?7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when ?7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer's patches, much like ?7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of ?7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of ?7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression.
EVALuna2:13624

Levels of target activation predict antifibrotic responses to tyrosine kinase inhibitors. - Maurer, Britta; Distler, Alfiya; Dees, Clara; Khan, Korsa; Denton, Christopher P.; Abraham, David; Gay, Renate E.; Michel, Beat A.; Gay, Steffen; Distler, Jörg; Distler, Oliver (Annals of the Rheumatic Diseases, 2013)
OBJECTIVES: To assess whether the discrepancy between the strong antifibrotic effects of tyrosine kinase inhibitors (TKIs) in animal models and the inconsistent results in clinical studies might be related to the activation levels of drug targets. METHODS: Skin sections of bleomycin, TSK1, Fra-2 transgenic mice, SSc patients and controls were analysed by histology and immunohistochemistry. Subgroups of mice were treated with the TKIs nilotinib or imatinib. Differences in the activation levels of the TKI targets p-PDGFRβ (platelet derived growth factor β) and p-c-abl were assessed. RESULTS: In bleomycin and TSK1 mice, expression of activated p-PDGFRβ (platelet derived growth factor receptor β) and p-c-abl was ubiquitous with strong upregulation compared with controls. Treatment with TKIs resulted in successful target inhibition and consequently reduced dermal fibrosis. In the Fra-2 model, the activation levels of p-PDGFRβ and p-c-abl were much lower than in the bleomycin and the TSK1 models. Accordingly, nilotinib did not prevent dermal fibrosis and target inhibition was unsuccessful. Notably, in skin biopsies of SSc patients, the mean activation levels of TKI targets were only moderate and in the majority of patients resembled those of the non-responsive Fra-2 model. CONCLUSIONS: Animal models for proof-of-concept studies should be selected based on a similar activation level and expression pattern of drug targets as in human SSc.
EVALuna2:478502

Lipid-gated monovalent ion fluxes regulate endocytic traffic and support immune surveillance - Freeman, Spencer A.; Uderhardt, Stefan; Saric, Amra; Collins, Richard F.; Buckley, Catherine M.; Mylvaganam, Sivakami; Boroumand, Parastoo; Plumb, Jonathan; Germain, Ronald N.; Ren, Dejian; Grinstein, Sergio (Science, 2020)
Despite ongoing (macro)pinocytosis of extracellular fluid, the volume of the endocytic pathway remains unchanged. To investigate the underlying mechanism, we used high-resolution video imaging to analyze the fate of macropinosomes formed by macrophages in vitro and in situ. Na+, the primary cationic osmolyte internalized, exited endocytic vacuoles via two-pore channels, accompanied by parallel efflux of Cl− and osmotically coupled water. The resulting shrinkage caused crenation of the membrane, which fostered recruitment of curvature-sensing proteins. These proteins stabilized tubules and promoted their elongation, driving vacuolar remodeling, receptor recycling, and resolution of the organelles. Failure to resolve internalized fluid impairs the tissue surveillance activity of resident macrophages. Thus, osmotically driven increases in the surface-to-volume ratio of endomembranes promote traffic between compartments and help to ensure tissue homeostasis.
CRIS-Team Scopus Importer:2020-02-04

Listening to patients, for the patients: The COVAD Study—Vision, organizational structure, and challenges - Joshi, Mrudula; Darooka, Naitica; Saha, Sreoshy; Dyball, Sarah; Sen, Parikshit; Yaadav, Praggya; Javaid, Mahnoor; Kadam, Esha; Shinjo, Samuel Katsuyuki; Dey, Dzifa; Cavagna, Lorenzo; Makol, Ashima; et al. (International Journal of Rheumatic Diseases, 2024)
Background: The pandemic presented unique challenges for individuals with autoimmune and rheumatic diseases (AIRDs) due to their underlying condition, the effects of immunosuppressive treatments, and increased vaccine hesitancy. Objectives: The COVID-19 vaccination in autoimmune diseases (COVAD) study, a series of ongoing, patient self-reported surveys were conceived with the vision of being a unique tool to gather patient perspectives on AIRDs. It involved a multinational, multicenter collaborative effort amidst a global lockdown. Methods: Leveraging social media as a research tool, COVAD collected data using validated patient-reported outcomes (PROs). The study, comprising a core team, steering committee, and global collaborators, facilitated data collection and analysis. A pilot-tested, validated survey, featuring questions regarding COVID-19 infection, vaccination and outcomes, patient demographics, and PROs was circulated to patients with AIRDs and healthy controls (HCs). Discussion: We present the challenges encountered during this international collaborative project, including coordination, data management, funding constraints, language barriers, and authorship concerns, while highlighting the measures taken to address them. Conclusion: Collaborative virtual models offer a dynamic new frontier in medical research and are vital to studying rare diseases. The COVAD study demonstrates the potential of online platforms for conducting large-scale, patient-focused research and underscores the importance of integrating patient perspective into clinical care. Care of patients is our central motivation, and it is essential to recognize their voices as equal stakeholders and valued partners in the study of the conditions that affect them.
CRIS-Team Scopus Importer:2024-05-17
Keywords: autoimmune; collaboration; digital; PROMs; research; rheumatology; survey

Live cell imaging of macrophage/bacterium interaction demonstrates cell lysis induced by Corynebacterium diphtheriae and Corynebacterium ulcerans - Weerasekera, Dulanthi; Hahn, Jonas; Herrmann, Martin; Burkovski, Andreas (BMC Research Notes, 2019)
OBJECTIVES: In frame of a study to characterize the interaction of human macrophage-like cells with pathogenic corynebacteria, Corynebacterium diphtheriae and Corynebacterium ulcerans, live cell imaging experiments were carried out and time lapse fluorescence microscopy videos were generated, which are presented here. DATA DESCRIPTION: The time lapse fluorescence microscopy data revealed new insights in the interaction of corynebacteria with human macrophage-like THP-1 cells. In contrast to uninfected cells and infections with non-pathogenic C. glutamicum used as a control, pathogenic C. diphtheriae and C. ulcerans showed highly detrimental effects towards human cells and induction of cell death of macrophages.
CRIS-Team Scopus Importer:2019-11-05
Keywords: Cytotoxicity; Diphtheria; Live cell imaging; Phagocytes; THP-1; Time lapse fluorescence microscopy

Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss - Kleyer, Arnd; Scholtysek, Carina; Bottesch, Edith; Hillienhof, Ulrike; Beyer, Christian; Distler, Jörg; Tuckermann, Jan P.; Schett, Georg; Krönke, Gerhard (Journal of Bone and Mineral Research, 2012)
Osteoporosis is characterized by enhanced differentiation of bone-resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone-forming osteoblasts and osteoblast-derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro-osteoclastogenic cytokine receptor activator of NF-?B ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone-forming osteoblasts and bone-resorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast-mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)-induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX-induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases.
EVALuna2:12795

Load-induced changes in articular cartilage biomarkers before and after a high tibial osteotomy in patients with medial compartment knee osteoarthritis - Mundermann, A.; Liphardt, Anna-Maria; Pagenstert, G.; Egloff, C.; Nueesch, C. (BRITISH JOURNAL OF SURGERY, 2019)
CRIS-Team WoS Importer:2019-05-24

Load-induced changes in articular cartilage biomarkers before and after high tibial osteotomy in patients with medial knee osteoarthritis - Mundermann, Annegret; Liphardt, Anna-Maria; Egloff, Christian; Pagenstert, Geert; Nuesch, Corina (SWISS MEDICAL WEEKLY, 2019)
CRIS-Team WoS Importer:2019-07-19

Loading of nuclear autoantigens prototypically recognized by systemic lupus erythematosus sera into late apoptotic vesicles requires intact microtubules and myosin light chain kinase activity - Zirngibl, Matthias; Fuernrohr, B. G.; Janko, Christina; Munoz, L. E.; Voll, R. E.; Gregory, C. D.; Schett, Georg; Herrmann, Martin; Munoz Becerra, Luis (Clinical and Experimental Immunology, 2015)
Most cases of systemic lupus erythematosus (SLE) are characterized by an impaired clearance of apoptotic cells in various tissues. Non-cleared apoptotic waste is considered an immunogen driving the autoimmune response in patients with SLE. During the execution of apoptosis, membrane blebs are formed and filled with cellular components. Here, we evaluate the cytoskeletal pathway(s) responsible for the loading of SLE prototypic nuclear autoantigens into the apoptotic cell-derived membranous vesicles (ACMV) generated during late phases of apoptosis. HeLa cells expressing a fusion protein of histone H2B with green fluorescent protein (GFP) were irradiated with ultraviolet (UV)-B to induce apoptosis. The appearance and trafficking of chromatin-derived material was monitored by fluorescence microscopy. Specific inhibitors of cytoskeletal pathways were employed to identify the motile elements involved in translocation and trafficking of the nuclear components. We observed that immediately after their appearance the ACMV did not contain histone H2B(GFP) ; in this phase the fluorescence was contained in the nuclear remnants and the cytoplasm. Within consecutive minutes the ACMV were loaded with chromatin-derived material, whereas the loading of simultaneously created ACMV with histone H2B(GFP) was not uniform. Some ACMV were preferentially filled and, consequently, showed a remarkably higher histone H2B(GFP) accumulation. Inhibitors of the cytoskeleton revealed that functional microtubules and myosin light chain kinase are required for nuclear shrinkage and loading of nuclear material into the ACMV, respectively.
EVALuna2:12985

Locally renewing resident synovial macrophages provide a protective barrier for the joint - Culemann, Stephan; Grüneboom, Anika; Nicolás-Ávila, José Ángel; Weidner, Daniela; Lämmle, Katrin Franziska; Rothe, Tobias; Quintana, Juan A.; Kirchner, Philipp; Krljanac, Branislav; Eberhardt, Martin; Ferrazzi, Fulvia; Kretzschmar, Elke; et al. (Nature, 2019)
Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1− mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.
CRIS-Team Scopus Importer:2019-08-16

Locomotion replacement exercise cannot counteract cartilage biomarker response to 5 days of immobilization in healthy adults - Liphardt, Anna-Maria; Muendermann, Annegret; Heer, Martina; Achtzehn, Silvia; Niehoff, Anja; Mester, Joachim (Journal of Orthopaedic Research, 2020)
Biomarkers of cartilage metabolism are sensitive to changes in the biological and mechanical environment and can indicate early changes in cartilage homeostasis. The purpose of this study was to determine if a daily locomotion replacement program can serve as a countermeasure for changes in cartilage biomarker serum concentration caused by immobilization. Ten healthy male subjects (mean ± 1 standard deviation; age: 29.4 ± 5.9 years; body mass: 77.7 ± 4.1 kg) participated in the crossover 5-day bed rest study with three interventions: control (CON), standing (STA), and locomotion replacement training (LRT). Serum samples were taken before, during, and after bed rest. Biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. Cartilage oligomeric matrix protein (COMP) levels after 24 hours of bed rest decreased independently of the intervention (−16.8% to −9.8%) and continued to decrease until 72 hours of bed rest (minimum, −23.2% to −20.6%). LRT and STA did not affect COMP during bed rests (P =.056) but there was a strong tendency for a slower decrease with LRT (−9.4%) and STA (−11.7%) compared with CON (−16.8%). MMP-3 levels decreased within the first 24 hours of bed rest (CON: −22.3%; STA: −14.7%; LRT: −17%) without intervention effect. Both COMP and MMP-3 levels recovered to baseline levels during the 6-day recovery period. MMP-1, MMP-9, and TNF-α levels were not affected by immobilization or intervention. COMP and MMP-3 are mechano-sensitive cartilage biomarkers affected by immobilization, and simple interventions such as standing upright or LRT during bed rest cannot prevent these changes. Clinical significance: simple locomotion interventions cannot prevent cartilage biomarker change during bed rest.
CRIS-Team Scopus Importer:2020-07-31
Keywords: bed rest; cartilage biomarkers; cartilage degeneration; cartilage oligomeric matrix protein; immobilization

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation - Szewczykowski, Charlotte; Mardin, Christian; Lucio, Marianna; Wallukat, Gerd; Hoffmanns, Jakob; Schröder, Tim; Raith, Franziska; Rogge, Lennart; Heltmann, Felix; Moritz, Michael; Beitlich, Lorenz; Schottenhamml, Julia; et al. (International Journal of Molecular Sciences, 2022)
Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation. The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT–angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.
CRIS-Team Scopus Importer:2022-07-15
Keywords: chronic fatigue syndrome; COVID-19; functionally GPCR autoantibodies; glaucoma; Long-COVID syndrome; OCT–angiography

LONGITUDINAL CHANGE IN THE CENTRAL NERVOUS SYSTEM PAIN RESPONSE AFTER TREATMENT WITH CERTOLIZUMAB OR PLACEBO. A POST-HOC ANALYSIS FROM THE PRECEPRA TRIAL - Rech, Jürgen; Tascilar, K.; Schenker, Hannah; Hagen, Melanie; Sergeeva, Marina; Selvakumar, Mageshwar; Konerth, Laura; Prade, Jutta; Strobelt, Sandra; Schonau, V.; Valor, L.; Hueber, A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

LONG NONCODING RNA H19X AS A NEW THERAPEUTIC TARGET FOR FIBROSIS - Pachera, E.; Wunderlin, A.; Assassi, S.; Salazar, G.; Frank-Bertoncelj, M.; Dobrota, R.; Brock, M.; Feghali-Bostwick, C.; Rogler, G. Gerhard; Dijkstra, G.; Van Haaften, T.; Distler, Jörg; et al. (2017)
EVALuna2:35023

Long noncoding RNA H19X is a key mediator of TGF-β-driven fibrosis - Pachera, Elena; Assassi, Shervin; Salazar, Gloria A.; Stellato, Mara; Renoux, Florian; Wunderlin, Adam; Blyszczuk, Przemyslaw; Lafyatis, Robert; Kurreeman, Fina; de Vries-Bouwstra, Jeska; Messemaker, Tobias; Feghali-Bostwick, Carol A.; et al. (Journal of Clinical Investigation, 2020)
TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of the DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of TGF-β-induced ECM remodeling and fibrosis.
CRIS-Team Scopus Importer:2020-09-11
Keywords: Autoimmune diseases; Autoimmunity; Cell Biology; Epigenetics; Fibrosis

Long Noncoding RNA H19X Is a Key Regulator of Apoptosis and Proliferation of Fibroblasts in Systemic Sclerosis and Other TGF beta-riven Fibrotic Diseases - Pachera, Elena; Wunderlin, Adam; Assassi, Shervin; Salazar, Gloria; Bertoncelj, Mojca Frank; Dobrota, Rucsandra; Brock, Matthias; Feghali-Bostwick, Carol A.; Dijkstra, Gerard; Rogler, Gerhard; Wouter, Tobias Van Haaften; Distler, Jörg; et al. (2017)
EVALuna2:35018

LONG NONCODING RNA H19X IS A MASTER REGULATOR OF EXTRACELLULAR MATRIX PRODUCTION IN SYSTEMIC SCLEROSIS - Pachera, E.; Assassi, S.; Salazar, G.; Frank-Bertoncelj, M.; Distler, Jörg; Kania, G.; Distler, O. (2018)
EVALuna2:35009

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene-specific DNA methylation patterns - Bure, Irina; Geer, Sandra; Knopf, Jasmin; Roas, Maike; Henze, Sabine; Stroebel, Philipp; Agaimy, Abbas; Wiemann, Stefan; Hoheisel, Joerg D.; Hartmann, Arndt; Haller, Florian; Moskalev, Evgeny (Genes Chromosomes & Cancer, 2018)
Aberrant alterations of DNA methylation are common events in oncogenesis. The origin of cancer-associated epigenetic defects is of interest for mechanistic understanding of malignant transformation and-in the long run-therapeutic modulation of DNA methylation in a locus-specific manner. Given the ability of certain long noncoding RNAs to operate as an interface between DNA and the epigenetic modification machinery which can interact with DNA methyltransferases, we hypothesized-considering HOTAIR as an example-that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, n = 67) as a model, we confirmed upregulation of HOTAIR in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. HOTAIR knockdown in GIST-T1 cells triggered transcriptional response of genes involved in the organization and disassembly of the extracellular matrix and, notably, induced global locus-specific alterations of DNA methylation patterns. Hypomethylation was induced at a total of 507 CpG sites, whereas 382 CpG dinucleotides underwent gain of methylation upon HOTAIR depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer-related DPP4, RASSF1, ALDH1A3, and other targets. Collectively, our data indicate that HOTAIR enables target specificity of DNA methylation in GIST and is capable of dual (hypo- and hypermethylation) regulation by a yet to be defined mechanism. The results further suggest the feasibility of manipulating DNA methylation in a targeted manner and are of interest in the context of epigenetic cancer therapy.
EVALuna2:34849

LONG-TERM (156-WEEK) IMPROVEMENTS IN DACTYLITIS AND ENTHESITIS WITH APREMILAST INPSORIATIC ARTHRITIS SUBJECTS: ANALYSIS OF A LARGE, POOLED PALACE 1-3 DATABASE - Gladman, Dafna D.; Kavanaugh, Arthur; Gomez-Reino, Juan J.; Wollenhaupt, Jurgen; Cutolo, Maurizio; Schett, Georg; Lespessailles, Eric; Hub, Angela; Edwards, Christopher J.; Birbara, Charles A.; Mease, Philip J. (2018)
EVALuna2:34152

Long-Term (156-Week) Safety Profile of Apremilast, an Oral Phosphodiesterase 4 Inhibitor, in Patients with Psoriatic Arthritis: Pooled Safety Analysis of 3 Phase III, Randomized, Controlled Trials - Mease, Philip J.; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Kavanaugh, Arthur; Lespessailles, Eric; Schett, Georg; Shah, Kamal; Teng, Lichen; Wollenhaupt, Juergen (2016)
EVALuna2:35062

Longterm (52-week) Results of a Phase III Randomized, Controlled Trial of Apremilast in Patients with Psoriatic Arthritis - Kavanaugh, Arthur; Mease, Philip J.; Gomez-Reino, Juan J.; Adebajo, Adewale O.; Wollenhaupt, Juergen; Gladman, Dafna D.; Hochfeld, Marla; Teng, Lichen L.; Schett, Georg; Lespessailles, Eric; Hall, Stephen (Journal of Rheumatology, 2015)
To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, over 52 weeks in patients with active psoriatic arthritis (PsA) despite prior treatment.Patients were randomized to placebo (n = 168), apremilast 20 mg BID (n = 168), or apremilast 30 mg BID (n = 168). Patients whose swollen and tender joint counts had not improved by >= 20% at Week 16 were considered nonresponders and were required to be re-randomized (1:1) to apremilast 20 mg BID or 30 mg BID if they were initially randomized to placebo, or continued their initial treatment of apremilast dose. At Week 24, all remaining patients treated with placebo were re-randomized to apremilast 20 mg BID or 30 mg BID.An American College of Rheumatology 20 (ACR20) response at Week 16 was attained by significantly more patients receiving apremilast 20 mg BID (30.4%, p = 0.0166) or 30 mg BID (38.1%, p = 0.0001) than placebo (19.0%). Among patients receiving apremilast continuously for 52 weeks (n = 254), ACR20 response at Week 52 was observed in 63.0% (75/119, 20 mg BID) and 54.6% (71/130, 30 mg BID) of patients. Response was also maintained across secondary outcomes, including measures of PsA signs and symptoms, skin psoriasis severity, and physical function. The nature, incidence, and severity of adverse events were comparable over the 24-week and 52-week periods. The most common adverse events, diarrhea and nausea, generally occurred early and were self-limited.Continuous apremilast treatment resulted in sustained improvements in PsA for up to 52 weeks. Apremilast had an acceptable safety profile and was generally well tolerated.NCT01172938.
EVALuna2:13087

Long-term B-lymphocyte depletion and remission of granulomatosis with polyangiitis after two courses of rituximab treatment - Valor-Méndez, Larissa; Kleyer, Arnd; Rech, Jürgen; Manger, Bernhard; Schett, Georg (Rheumatology, 2021)
CRIS-Team Scopus Importer:2021-06-11

Long-term Combination Therapy with Anti-TNF plus Vedolizumab Induces and Maintains Remission in Therapy-refractory Ulcerative Colitis - Fischer, Sören; Rath, Timo; Geppert, Carol-Immanuel; Manger, Bernhard; Schett, Georg; Neurath, Markus; Atreya, Raja (American Journal of Gastroenterology, 2017)
EVALuna2:6885

Long-term effect of tocilizumab in patients with giant cell arteritis: open-label extension phase of the Giant Cell Arteritis Actemra (GiACTA) trial - Stone, John H.; Han, Jian; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Spiera, Robert; Unizony, Sebastian H.; Bao, Min (The Lancet Rheumatology, 2021)
Background: The combination of tocilizumab plus a glucocorticoid taper is effective in maintaining clinical remission without requiring additional glucocorticoid therapy in patients with giant cell arteritis, as shown in part one of the Giant Cell Arteritis Actemra (GiACTA) trial. However, the duration of the tocilizumab effect after discontinuation is unknown. Here, we explored the maintenance of efficacy 1 year after discontinuation of tocilizumab treatment, the effectiveness of retreatment with tocilizumab after relapse, and the long-term glucocorticoid-sparing effect of tocilizumab. Methods: In part one of the GiACTA trial, 251 patients were randomly assigned (2:1:1:1) to receive subcutaneous tocilizumab (162 mg) once a week 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. Patients in clinical remission stopped masked injections at 1 year (the conclusion of part one). In part two, treatment was at the investigators' discretion and could consist of no treatment, tocilizumab, glucocorticoids, methotrexate, or combinations of these, for two years. Maintenance of efficacy as assessed by clinical remission (defined as absence of relapse determined by the investigator), cumulative glucocorticoid dose, and long-term safety were exploratory objectives in part two of the trial. This trial is registered at ClinicalTrials.gov, NCT01791153. Findings: 215 patients participated in part two of the trial; 81 patients who were randomly assigned to tocilizumab once a week in part one were in clinical remission after 1 year, of whom 59 started part two on no treatment. 25 of these 59 patients (42%) maintained tocilizumab-free and glucocorticoid-free clinical remission throughout part two. Median (95% CI) cumulative glucocorticoid doses over 3 years were 2647 mg (1987–3507) for tocilizumab once a week, 3948 mg (2352–5186) for tocilizumab-every-other-week, 5277 mg (3944–6685) for placebo with a 26-week prednisone taper, and 5323 mg (3900–6951) for placebo with a 52-week prednisone taper (van Elteren p≤0·001, tocilizumab once a week vs placebo groups; p<0·05, tocilizumab-every-other-week vs placebo groups). Tocilizumab-based regimens restored clinical remission among patients who experienced relapse in part two and were treated (median time to remission: 15 days for tocilizumab alone [n=17]; 16 days for tocilizumab plus glucocorticoids [n=36]; and 54 days for glucocorticoids alone [n=27]). No new or unexpected safety findings were reported over the full 3 years of the study. Interpretation: Giant cell arteritis remains a chronic disease that entails ongoing management and careful vigilance for disease relapse, but continuous indefinite treatment with immunosuppressive drugs is not required for all patients. A substantial proportion of patients treated with tocilizumab for one year maintain drug-free remission during the two years after tocilizumab cessation. For patients who experience relapse, tocilizumab can be used to manage relapses, but it remains prudent to include prednisone for patients who experience relapse because of the risk for vision loss. Funding: F Hoffmann-La Roche.
CRIS-Team Scopus Importer:2021-04-19

LONG-TERM EFFICACY AND SAFETY OF CANAKINUMAB IN PATIENTS WITH HIDS (HYPER-IGD SYNDROME) - INTERIM ANALYSIS OF THE RELIANCE REGISTRY - Oommen, P.; Kallinich, T.; Rech, Jürgen; Blank, N.; Weber-Arden, J.; Kuemmerle-Deschner, J. B. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long-term efficacy and safety of secukinumab in patients with psoriatic arthritis: 5-year (end-of-study) results from the phase 3 FUTURE 2 study - McInnes, Iain B.; Mease, Philip J.; Kivitz, Alan J.; Nash, Peter; Rahman, Proton; Rech, Jürgen; Conaghan, Philip G.; Kirkham, Bruce; Navarra, Sandra; Belsare, Ashwini D.; Delicha, Eumoprhia M.; Pricop, Luminita (The Lancet Rheumatology, 2020)
Background: Secukinumab is an interleukin-17A inhibitor used in the treatment of patients with active psoriatic arthritis. In the phase 3 FUTURE 2 trial, secukinumab showed sustained improvement in clinical outcomes over 2 years. Because scarce data exists on the long-term treatment with biological therapies in patients with psoriatic arthritis, we aimed to assess and describe the 5-year (end-of-study) results on the efficacy and safety of secukinumab 300 mg and 150 mg doses, as well as dose escalation, from the FUTURE 2 study. Methods: FUTURE 2 is a phase 3, double-blind, placebo-controlled study done at 76 centres in Asia, Australia, Canada, Europe, and the USA. Patients with active psoriatic arthritis aged 18 years or older were randomly assigned to either secukinumab (300 mg, 150 mg, or 75 mg) or placebo weekly from baseline and then every 4 weeks from week 4. Secukinumab dose was escalated from 150 mg to 300 mg and from 75 mg to 150 mg or 300 mg starting at week 128, if active signs of disease were observed in patients, on the basis of the physician's assessment, with the escalated dose maintained thereafter. We assessed key efficacy endpoints at week 260 (5 years) for secukinumab 300 mg and 150 mg, including American College of Rheumatology (ACR) and Psoriasis Area and Severity Index (PASI) responses. The safety analysis included all patients who received one or more doses of secukinumab. We report data as observed. This study is registered with ClinicalTrials.gov, NCT01752634. Findings: At randomisation, 65% of patients were naive to tumour necrosis factor inhibitors and 47% were receiving concomitant methotrexate. Of 397 patients randomly assigned in FUTURE 2, 248 (62%) completed 5 years of treatment, including 64 (64%) of 100 patients in the original secukinumab 300 mg group, 65 (65%) of 100 in the 150 mg group, 59 (60%) of 99 in the 75 mg group, and 60 (61%) of 98 in the placebo group. Overall, 127 (52%) of 242 patients required dose escalation during the study. ACR responses at 5 years were 71 (74%; ACR20), 50 (52%; ACR50), and 31 (32%; ACR70) of 96 evaluable patients in the secukinumab 300 mg group, and 67 (70%; ACR20), 41 (43%; ACR50), and 28 (29%; ACR70) of 96 evaluable patients in the secukinumab 150 mg group. From 24 to 32 weeks and from 48 to 84 weeks after dose escalation from secukinumab 150 mg to 300 mg, the proportions of ACR and PASI non-responders decreased, whereas the proportions of ACR and PASI responders increased. During the entire treatment period, the most frequent treatment-emergent serious adverse event was serious infection (exposure-adjusted incidence 1·7, 95% CI 1·1–2·5; n=25) in the any secukinumab group. No new or unexpected safety signals were reported. Interpretation: Secukinumab 300 mg and 150 mg provided sustained improvement in the signs and symptoms of psoriatic arthritis, with consistent safety over 5 years. This study supports the clinical benefit and safety of long-term treatment with secukinumab in patients with psoriatic arthritis. Funding: Novartis.
CRIS-Team Scopus Importer:2020-03-31

Long-term experience with apremilast in patients with psoriatic arthritis: 5-year results from a PALACE 1-3 pooled analysis - Kavanaugh, Arthur; Gladman, Dafna D.; Edwards, Christopher J.; Schett, Georg; Guerette, Benoit; Delev, Nikolay; Teng, Lichen; Paris, Maria; Mease, Philip J. (Arthritis Research & Therapy, 2019)
Background: The efficacy and safety of apremilast were assessed in patients with psoriatic arthritis (PsA) in three phase III clinical trials with similar designs (PALACE 1, 2, and 3). Methods: Following a 24-week, randomized (1:1:1 to apremilast 30 mg twice daily, 20 mg twice daily, or placebo), double-blind phase and a 28-week blinded active treatment phase, patients could receive apremilast in open-label extension studies for an additional 4 years. Eligible adult patients had active PsA for ≥ 6 months and three or more swollen joints and three or more tender joints despite prior treatment with disease-modifying anti-rheumatic drugs. Results: A total of 1493 randomized patients received one or more doses of study medication (placebo: n = 496; apremilast 30 mg twice daily: n = 497; apremilast 20 mg twice daily: n = 500). In patients continuing apremilast treatment, response was sustained without new safety issues. At week 260, 67.2% of remaining patients achieved an ACR20 response, and 44.4% and 27.4% achieved ACR50 and ACR70 responses, respectively. Among patients with baseline enthesitis and dactylitis, 62.4% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 80.9% achieved a dactylitis count of 0, respectively. In patients who had ≥ 3% baseline psoriasis body surface area involvement, 43.6% achieved ≥ 75% reduction from the baseline Psoriasis Area and Severity Index scores. The most commonly reported adverse events (AEs) were diarrhea, nausea, headache, upper respiratory tract infection, and nasopharyngitis, with most diarrhea and nausea AEs occurring within the first 2 weeks of treatment and usually resolving within 4 weeks. Reported rates of depression during the study were low (≤ 1.8%). The majority of patients maintained their weight within 5% of baseline during the study. No new safety concerns or increases in the incidence or severity of AEs were observed over the long term. Conclusions: Apremilast maintained clinical benefit and a favorable safety profile for up to 5 years among patients with PsA. Trial registration: ClinicalTrials.gov NCT01172938, NCT01212757, NCT01212770
CRIS-Team Scopus Importer:2019-05-21
Keywords: Apremilast; Drug safety; Psoriatic arthritis; Treatment efficacy

Long-term follow-up of HIV-1-infected adults who received the F4/AS01(B) HIV-1 vaccine candidate in two randomised controlled trials - Harrer, Thomas; Dinges, Warren; Roman, Francois (Vaccine, 2018)
This Phase I/II open, long-term follow-up study was conducted in antiretroviral therapy (ART)-naive (N = 212) and ART-treated (N = 19) human immunodeficiency virus 1 (HIV-1)-infected adults, who received an HIV-1 investigational vaccine (F4/AS01(B)) or placebo in two previous studies (NCT00814762 and NCT01218113). After a minimum of two years and a maximum of four years of follow-up postvaccination per patient, no significant differences were observed between F4/AS01(B) and placebo groups in terms of viral load, CD4(+) T-cell count and incidence of specific clinical events. Vaccine-induced polyfunctional CD4(+) T-cells persisted up to study end and no relevant vaccine-related safety events were reported in F4/AS01(B) groups. (C) 2018 The Authors. Published by Elsevier Ltd.
EVALuna2:213268

LONG-TERM HUMORAL RESPONSE TO SARS-COV-2 VACCINATION IN PATIENTS WITH IMMUNE-MEDIATED INFLAMMATORY DISEASE - Tascilar, Koray; Simon, David; Kleyer, Arnd; Fagni, Filippo; Krönke, Gerhard; Meder, Christine; Dietrich, Peter; Orlemann, Till; Kliem, Thorsten; Moessner, J.; Liphardt, Anna-Maria; Schönau, Verena; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long-Term Outcome of Tocilizumab for Patients with Giant Cell Arteritis: Results from Part 2 of a Randomized Controlled Phase 3 Trial - Stone, John; Bao, Min; Han, Jian; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Spiera, Robert; Unizony, Sebastian (ARTHRITIS & RHEUMATOLOGY, 2019)
CRIS-Team WoS Importer:2020-02-07

LONG-TERM OUTCOME OF TOCILIZUMAB FOR PATIENTS WITH GIANT CELL ARTERITIS: RESULTS FROM PART 2 OF THE GIACTA TRIAL - Stone, John H.; Bao, Min; Han, Jian; Aringer, Martin; Blockmans, Daniel; Brouwer, Elisabeth; Cid, Maria C.; Dasgupta, Bhaskar; Rech, Jürgen; Salvarani, Carlo; Spiera, Robert; Unizony, Sebastian (ANNALS OF THE RHEUMATIC DISEASES, 2019)
CRIS-Team WoS Importer:2019-07-12

Long term outcomes of immunomodulatory drugs in SSc-ILD - data from the German SSc-network - Kreuter, Michael; Bonella, Francesco; Blank, Norbert; Siegert, Elise; Henes, Joerg; Worm, Margitta; Sunderkoetter, Cord; Schmalzing, Marc; Kreuter, Alexander; Günther, Claudia; Susok, Laura; Zeidler, Gabriele; et al. (EUROPEAN RESPIRATORY JOURNAL, 2019)
CRIS-Team WoS Importer:2020-01-31

LONG-TERM REPEATABILITY OF CARTILAGE OLIGOMERIC MATRIX PROTEIN KINETICS IN RESPONSE TO WALKING STRESS - Herger, S.; Liphardt, Anna-Maria; Egloff, C.; Corina, N.; Mundermann, A. (OSTEOARTHRITIS AND CARTILAGE, 2021)
CRIS-Team WoS Importer:2021-05-21

Long-Term Retention Rate of Golimumab in Patients With Rheumatoid Arthritis, Psoriatic Arthritis, and Spondyloarthritis in a Real-Life Setting - Serrano-Benavente, Belen; Valor, Larissa; Del Rio Blasco, Tamara; Janta, Iustina; Gonzalez Benitez, Roberto; Nieto-Gonzalez, Juan Carlos; Martinez-Barrio, Julia; Ovalles Bonilla, Juan Gabriel; Ariza, Alfonso; Lopez-Longo, Francisco Javier; Alvaro-Gracia, Jose Maria; Monteagudo, Indalecio; et al. (Jcr-Journal of Clinical Rheumatology, 2022)
Objective The aims of this study were to describe the long-term retention rate of golimumab (GLM) treatment in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA) in real life, and to analyze determinants of discontinuation. Methods We conducted a single-center, medical records review study of all patients with RA, PsA, and SpA on GLM treatment attending a large rheumatology department from 2010 to 2017. Times from start to end of GLM treatment were collected, as well as sociodemographic, clinical, and safety variables. Golimumab retention rate was estimated by the Kaplan-Meier method, and comparison across diseases was analyzed with the Mantel-Haenszel statistic (log-rank test). Cox proportional hazards regression models were used to identify factors associated with GLM discontinuation. Results In the study period, a total of 212 patients (61 RA, 48 PsA, 103 SpA) were prescribed GLM. Retention rates were 72% in the first year, 61% in the second, 56% in the third, and 38% at 5 years. Differences were statistically significant across diseases (median times to GLM discontinuation were 50.2, 46.0, and 38.7 months for RA, SpA, and PsA, respectively) and according to the number of previous biologic therapies (55.2 months in biologic-naive patients vs 14.0 months in patients with >= 2 previous biologics; p < 0.001). The use of concomitant conventional synthetic disease-modifying antirheumatic drugs was associated with a lower probability of discontinuation (hazards ratio [HR], 0.57; 95% confidence interval [CI], 0.33-0.97). Female sex (HR, 1.84; 95% CI, 1.07-3.17) and having used 2 biologics before GLM (HR, 2.99; 95% CI, 1.76-5.06) were associated with increased discontinuation rates. Twenty-three patients (10.9%) had at least 1 serious adverse event. Conclusions In a real-life setting, GLM shows appropriate long-term safety-effectiveness ratio.
CRIS-Team WoS Importer:2021-12-31

LONG-TERM SAFETY AND EFFECTIVENESS OF CANAKINUMAB IN CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS)-30-MONTH DATA FROM THE RELIANCE REGISTRY - Kuemmerle-Deschner, J. B.; Kortus-Goetze, B.; Oommen, P.; Janda, A.; Rech, Jürgen; Kallinich, T.; Weller-Heinemann, F.; Horneff, G.; Foeldvari, I.; Schuetz, C.; Borte, M.; Braner, A.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2021)
CRIS-Team WoS Importer:2021-10-01

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry - Kuemmerle-Deschner, Jasmin B.; Kallinich, Tilmann; Henes, Joerg; Kortus-Götze, Birgit; Oommen, Prasad T.; Rech, Jürgen; Krickau, Tobias; Weller-Heinemann, Frank; Horneff, Gerd; Janda, Aleš; Foeldvari, Ivan; Schuetz, Catharina; et al. (RMD Open, 2024)
Objective Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). Methods From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. Results At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (∼70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. Conclusion Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.
CRIS-Team Scopus Importer:2024-03-01
Keywords: Cryopyrin-Associated Periodic Syndromes; Familial Mediterranean Fever; Inflammation

Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials - Mease, Philip J.; Gladman, Dafna D.; Gomez-Reino, Juan J.; Hall, Stephen; Kavanaugh, Arthur; Lespessailles, Eric; Schett, Georg; Paris, Maria; Delev, Nikolay; Teng, Lichen; Wollenhaupt, Juergen (ACR Open Rheumatology, 2020)
ObjectivePsoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA.
CRIS-Team WoS Importer:2021-07-16

LONG-TERM SAFETY OF CANAKINUMAB IN PATIENTS WITH AUTOINFLAMMATORY DISEASES - INTERIM ANALYSIS OF THE RELIANCE REGISTRY - Kuemmerle-Deschner, J. B.; Henes, J.; Kortus-Goetze, B.; Kallinich, T.; Oommen, P.; Rech, Jürgen; Krickau, Tobias; Weller-Heinemann, F.; Horneff, G.; Janda, A.; Foeldvari, I.; Schuetz, C.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Long-term Safety of Canakinumab in Patients with Autoinflammatory Periodic Fever Syndromes - Interim Analysis of the RELIANCE Registry - Kuemmerle-Deschner, Jasmin; Henes, Jorg; Kortus-Goetze, Birgit; Kallinich, Tilmann; Oommen, Prasad T.; Rech, Jürgen; Weller-Heinemann, Frank; Horneff, Gerd; Foeldvari, Ivan; Janda, Ales; Schuetz, Catharina; Dressler, Frank; et al. (ARTHRITIS & RHEUMATOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-11

Long-term safety of COVID vaccination in individuals with idiopathic inflammatory myopathies: results from the COVAD study - Doskaliuk, Bohdana; Ravichandran, Naveen; Sen, Parikshit; Day, Jessica; Joshi, Mrudula; Nune, Arvind; Nikiphorou, Elena; Saha, Sreoshy; Tan, Ai Lyn; Shinjo, Samuel Katsuyuki; Ziade, Nelly; Velikova, Tsvetelina; et al. (Rheumatology International, 2023)
Limited evidence on long-term COVID-19 vaccine safety in patients with idiopathic inflammatory myopathies (IIMs) continues to contribute to vaccine hesitancy. We studied delayed-onset vaccine adverse events (AEs) in patients with IIMs, other systemic autoimmune and inflammatory disorders (SAIDs), and healthy controls (HCs), using data from the second COVID-19 Vaccination in Autoimmune Diseases (COVAD) study. A validated self-reporting e-survey was circulated by the COVAD study group (157 collaborators, 106 countries) from Feb–June 2022. We collected data on demographics, comorbidities, IIM/SAID details, COVID-19 history, and vaccination details. Delayed-onset (> 7 day) AEs were analyzed using regression models. A total of 15165 respondents undertook the survey, of whom 8759 responses from vaccinated individuals [median age 46 (35–58) years, 74.4% females, 45.4% Caucasians] were analyzed. Of these, 1390 (15.9%) had IIMs, 50.6% other SAIDs, and 33.5% HCs. Among IIMs, 16.3% and 10.2% patients reported minor and major AEs, respectively, and 0.72% (n = 10) required hospitalization. Notably patients with IIMs experienced fewer minor AEs than other SAIDs, though rashes were expectedly more than HCs [OR 4.0; 95% CI 2.2–7.0, p < 0.001]. IIM patients with active disease, overlap myositis, autoimmune comorbidities, and ChadOx1 nCOV-19 (Oxford/AstraZeneca) recipients reported AEs more often, while those with inclusion body myositis, and BNT162b2 (Pfizer) recipients reported fewer AEs. Vaccination is reassuringly safe in individuals with IIMs, with AEs, hospitalizations comparable to SAIDs, and largely limited to those with autoimmune multimorbidity and active disease. These observations may inform guidelines to identify high-risk patients warranting close monitoring in the post-vaccination period.
CRIS-Team Scopus Importer:2023-07-07
Keywords: Adverse event; Autoimmunity; COVID-19; Myositis; Surveys and questionnaires; Vaccination

Long-term treatment in rheumatoid arthritis: do biological and targeted-synthetic DMARDs increase the risk of malignancy? - Fagni, Filippo; Simon, David (Rheumatology, 2022)
CRIS-Team WoS Importer:2022-05-20

LOOSING DAS28-ESR, BUT STAYING IN BOOLEAN REMISSION-IS IT POSSIBLE? DATA FROM THE PROSPECTIVE, RANDOMISED RETRO TRIAL ON RHEUMATOID ARTHRITIS PATIENTS IN STABLE REMISSION - Erhard, J.; Hagen, Melanie; Englbrecht, Matthias; Haschka, J.; Reiser, M.; Kleyer, Arnd; Hueber, Axel; Manger, Bernhard; Figueiredo, C.; Cobra, J. F.; Tony, H. -P.; Finzel, S.; et al. (2018)
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Loss of menin in osteoblast lineage affects osteocyte-osteoclast crosstalk causing osteoporosis - Liu, Peng; Lee, Sooyeon; Knoll, Jeanette; Rauch, Alexander; Ostermay, Susanne; Luther, Julia; Malkusch, Nicole; Lerner, Ulf H.; Zaiss, Mario; Neven, Mona; Wittig, Rainer; Rauner, Martina; et al. (Cell Death and Differentiation, 2017)
During osteoporosis bone formation by osteoblasts is reduced and/or bone resorption by osteoclasts is enhanced. Currently, only a few factors have been identified in the regulation of bone integrity by osteoblast-derived osteocytes. In this study, we show that specific disruption of menin, encoded by multiple endocrine neoplasia type 1 (Men1), in osteoblasts and osteocytes caused osteoporosis despite the preservation of osteoblast differentiation and the bone formation rate. Instead, an increase in osteoclast numbers and bone resorption was detected that persisted even when the deletion of Men1 was restricted to osteocytes. We demonstrate that isolated Men1-deficient osteocytes expressed numerous soluble mediators, such as C-X-C motif chemokine 10 (CXCL10), and that CXCL10-mediated osteoclastogenesis was reduced by CXCL10-neutralizing antibodies. Collectively, our data reveal a novel role for Men1 in osteocyte-osteoclast crosstalk by controlling osteoclastogenesis through the action of soluble factors. A role for Men1 in maintaining bone integrity and thereby preventing osteoporosis is proposed.Cell Death and Differentiation advance online publication, 20 January 2017; doi:10.1038/cdd.2016.165.
EVALuna2:13407

Loss of Phosphatase and Tensin Homolog in APCs Impedes Th17-Mediated Autoimmune Encephalomyelitis - Sahin, Emine; Brunner, Julia S.; Kral, Julia B.; Kuttke, Mario; Hanzl, Leslie; Datler, Hannes; Paar, Hannah; Neuwinger, Nick; Saferding, Victoria; Zinser, Elisabeth; Halfmann, Angela; Soukup, Klara; et al. (Journal of Immunology, 2015)
The PI3K signaling cascade in APCs has been recognized as an essential pathway to initiate, maintain, and resolve immune responses. In this study, we demonstrate that a cell type-specific loss of the PI3K antagonist phosphatase and tensin homolog (PTEN) in myeloid cells renders APCs toward a regulatory phenotype. APCs deficient for PTEN exhibit reduced activation of p38 MAPK and reduced expression of T cell-polarizing cytokines. Furthermore, PTEN deficiency leads to upregulation of markers for alternative activation, such as Arginase 1, with concomitant downregulation of inducible NO synthase in APCs in vitro and in vivo. As a result, T cell polarization was dysfunctional in PTEN(-/-) APCs, in particular affecting the Th17 cell subset. Intriguingly, mice with cell type-specific deletions of PTEN-targeting APCs were protected from experimental autoimmune encephalomyelitis, which was accompanied by a pronounced reduction of IL-17- and IL-22-producing autoreactive T cells and reduced CNS influx of classically activated monocytes/macrophages. These observations support the notion that activation of the PI3K signaling cascade promotes regulatory APC properties and suppresses pathogenic T cell polarization, thereby reducing the clinical symptoms and pathology of experimental autoimmune encephalomyelitis.
EVALuna2:13151

Low amounts of bisecting glycans characterize cerebrospinal fluid-borne IgG - Knopf, Jasmin; Magorivska, Iryna; Maier, Jan-Niklas; Spitzer, Philipp; Bilyy, Rostyslav; Biermann, Mona; Hychka, Kateryna; Bondt, Albert; Wuhrer, Manfred; Toes, Rene E. M.; Schett, Georg; Herrmann, Martin; et al. (Journal of Neuroimmunology, 2018)
Immunoglobulin G (IgG) harbors a conserved N-glycosylation site which is important for its effector functions. Changes in glycosylation of IgG occur in many autoimmune diseases but also in physiological conditions. Therefore, the glycosylation pattern of serum IgG is well characterized. However, limited data is available on the glycosylation pattern of IgG in cerebrospinal fluid (CSF) compared to serum. Here, we report significantly reduced levels of bisected glycans in CSF IgG. Galactosylation and sialylation of IgG4 also differed significantly. Therefore, we propose a common mechanism mediating glycosylation changes of IgG at the transition from serum to CSF in steady state conditions.
EVALuna2:34466

Low dose ionising radiation leads to a NF-?B dependent decreased secretion of active IL-1? by activated macrophages with a discontinuous dose-dependency - Lödermann, Barbara; Wunderlich, Roland; Frey, Silke; Schorn, Christine; Stangl, Sonja; Roedel, Franz; Keilholz, Ludwig; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (International Journal of Radiation Biology, 2012)
Therapy with low doses of ionising radiation (X-rays) exerts anti-inflammatory effects. Little is known about whether and how low doses of X-ray treatment modulate the inflammatory phenotype of macrophages, especially the secretion of Interleukin-1beta (IL-1?).Macrophages were differentiated from human THP-1 monocytes, activated with lipopolysaccharide (LPS), treated with distinct low doses of X-rays, and co-activated with monosodium urate crystals (MSU) to induce inflammasome activation. Secretion of IL-1? was analysed by an enzyme-linked immunosorbent assay (ELISA) and Western blot. Furthermore, we analysed the intracellular amounts of the serine/threonine protein kinase B (named: Akt), mitogen-activated protein kinase p38 (p38), the v-rel reticuloendotheliosis viral oncogene homolog A (RelA), and pro- and cleaved IL-1?.Low dose X-rays led to decreased secretion of active IL-1? in a manner discontinuous with dose which was most pronounced after 0.5 or 0.7 Gy. Passive release of lactate dehydrogenase (LDH) was not influenced by X-rays. The decreased secretion of IL-1? correlated with reduced translocation of RelA, being part of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) complex, into the nucleus. After 0.5 or 0.7 Gy of X-rays, the intracellular protein amounts of up (p38) and downstream molecules (Akt) of NF-?B were reduced in activated macrophages, as were the pro- and cleaved forms of IL-1?.Distinct low doses of X-rays induce an anti-inflammatory phenotype of activated macrophages by lowering the amount of secreted IL-1? in a NF-?B dependent manner.
EVALuna2:12777

LOW DOSE RADIATION ALTERS THE INFLAMMATORY PHENOTYPE OF FIBROBLAST-LIKE SYNOVIOCYTES AND MACROPHAGES AND STIMULATES OSTEOBLASTS - Deloch, Lisa; Liberg, Jana; Rückert, Michael; Hueber, Axel; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2017)
EVALuna2:32907

LOW DOSE RADIATION HAS A POSITIVE IMPACT ON BONE METABOLISM IN AN EXPERIMENTAL MODEL OF INFLAMMATORY ARTHRITIS - Deloch, Lisa; Rückert, Michael; Hueber, Axel; Herrmann, Martin; Fietkau, Rainer; Frey, Benjamin; Gaipl, Udo (2018)
EVALuna2:36516

Low Dose Radiation Therapy Induces Long-Lasting Reduction of Pain and Immune Modulations in the Peripheral Blood - Interim Analysis of the IMMO-LDRT01 Trial - Donaubauer, Anna-Jasmina; Becker, Ina; Weissmann, Thomas; Fröhlich, Birgitta; Munoz, Luis Enrique; Gryc, Thomas; Denzler, Manuel; Ott, Oliver; Fietkau, Rainer; Gaipl, Udo; Frey, Benjamin (Frontiers in Immunology, 2021)
The treatment of chronic inflammatory and degenerative diseases by low dose radiation therapy (LDRT) is promising especially for patients who were refractory for classical therapies. LDRT aims to reduce pain of patients and to increase their mobility. Although LDRT has been applied since the late 19th century, the immunological mechanisms remain elusive. Within the prospective IMMO-LDRT01 trial (NCT02653079) the effects of LDRT on the peripheral blood immune status, as well as on pain and life quality of patients have been analyzed. Blood is taken before and after every serial irradiation with a single dose per fraction of 0.5Gy, as well as during follow-up appointments in order to determine a detailed longitudinal immune status by multicolor flow cytometry. Here, we report the results of an interim analysis of 125 patients, representing half the number of patients to be recruited. LDRT significantly improved patients' pain levels and induced distinct systemic immune modulations. While the total number of leukocytes remained unchanged in the peripheral blood, LDRT induced a slight reduction of eosinophils, basophils and plasmacytoid dendritic cells and an increase of B cells. Furthermore, activated immune cells were decreased following LDRT. Especially cells of the monocytic lineage correlated to LDRT-induced improvements of clinical symptoms, qualifying these immune cells as predictive biomarkers for the therapeutic success. We conclude that LDRT improves pain of the patients by inducing systemic immune modulations and that immune biomarkers could be defined for prediction by improved patient stratification in the future.
CRIS-Team WoS Importer:2021-11-12

Low-Dose Radiotherapy Ameliorates Advanced Arthritis in hTNF-α tg Mice by Particularly Positively Impacting on Bone Metabolism - Deloch, Lisa; Derer, Anja; Hueber, Axel; Herrmann, Martin; Schett, Georg; Wölfelschneider, Jens; Hahn, Jonas; Rühle, Paul-Friedrich; Stillkrieg, Willy; Fuchs, Jana; Fietkau, Rainer; Frey, Benjamin; et al. (Frontiers in Immunology, 2018)
Inflammation and bone erosion are central in rheumatoid arthritis (RA). Even though effective medications for control and treatment of RA are available, remission is only seen in a subset of patients. Treatment with low-dose radiotherapy (LD-RT) which has been already successfully used for amelioration of symptoms in benign diseases should be a promising approach to reduce pain, inflammation, and particularly bone erosion in patients with RA. Even though anti-inflammatory effects of LD-RT are already described with non-linear dose response relationships, and pain-reducing effects have been clinically observed, the underlying mechanisms are widely unknown. Besides immune cells many other cell types, such as fibroblast-like synoviocytes (FLS), osteoclasts, and osteoblast are present in the affected joint and might be modulated by LD-RT. For this study, these cell types were obtained from human tumor necrosis factor-α transgenic (hTNF-α tg) mice and were consecutively exposed to different doses of ionizing radiation (0.1, 0.5, 1.0, and 2.0 Gy, respectively) in vitro. In order to study the in vivo effects of LD-RT within the arthritic joint, hind paws of arthritic hTNF-α tg mice were locally irradiated with 0.5 Gy, a single dose per fraction that is known for good clinical responses. Starting at a dose of 0.5 Gy, proliferation of FLS was reduced and apoptosis significantly enhanced with no changes in necrosis. Further, expression of RANK-L was slightly reduced following irradiation with particularly 0.5 Gy. Starting from 0.5 Gy, the numbers of differentiated osteoclasts were significantly reduced, and a lower bone resorbing activity of treated osteoclasts was also observed, as monitored via pit formation and Cross Laps presence. LD-RT had further a positive effect on osteoblast-induced mineralization in a discontinuous dose response relationship with 0.5 Gy being most efficient. An increase of the gene expression ratio of OPG/RANK-L at 0.1 and 0.5 Gy and of production of OPG at 0.5 and 1.0 Gy was observed. In vivo, LD-RT resulted in less severe arthritis in arthritic hTNF-α tg mice and in significant reduction of inflammatory and erosive area with reduced osteoclasts and neutrophils. Locally applied LD-RT can, therefore, induce a beneficial micro-environment within arthritic joints by predominantly positively impacting on bone metabolism.
EVALuna2:34663
Keywords: rheumatoid arthritis; inflammation; low-dose radiotherapy; bone metabolism; synovial-like fibroblasts; osteoclasts; osteoblasts

Low-Salt Diet Attenuates B-Cell- and Myeloid-Cell-Driven Experimental Arthritides by Affecting Innate as Well as Adaptive Immune Mechanisms - Sehnert, Bettina; Pohle, Sandy; Heuberger, Cornelia; Rzepka, Rita; Seidl, Maximilian; Nimmerjahn, Falk; Chevalier, Nina; Titze, Jens; Voll, Reinhard E. (Frontiers in Immunology, 2021)
A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.
CRIS-Team Scopus Importer:2021-12-31
Keywords: collagen-induced arthritis; cytokines; diet; serum transfer-induced arthritis; sodium chloride

Lung cell entry, cell-cell fusion capacity, and neutralisation sensitivity of omicron sublineage BA.2.75 - Arora, Prerna; Nehlmeier, Inga; Kempf, Amy; Cossmann, Anne; Schulz, Sebastian; Dopfer-Jablonka, Alexandra; Baier, Eva; Tampe, Björn; Moerer, Onnen; Dickel, Steffen; Winkler, Martin S.; Jäck, Hans-Martin; et al. (Lancet Infectious Diseases, 2022)
CRIS-Team Scopus Importer:2022-11-11

Lymph node and pulmonary tuberculosis during upadacitinib treatment in a psoriatic arthritis patient - Valor-Mendez, Larissa; Manger, Bernhard; Wacker, Jochen; Kleyer, Arnd; Schett, Georg (Rheumatology Advances in Practice, 2022)
CRIS-Team Scopus Importer:2022-07-22

Lysosome-targeting amplifiers of reactive oxygen species as anticancer prodrugs - Daum, Steffen; Reshetnikov, Viktor; Sisa, Miroslav; Dumych, Tetyana; Lootsik, Maxim D.; Bilyy, Rostyslav; Bila, Evgenia; Janko, Christina; Alexiou, Christoph; Herrmann, Martin; Sellner, Leopold; Mokhir, Andriy (Angewandte Chemie-International Edition, 2017)
Cancer cells produce elevated amounts of reactive oxygen species that has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, where a prodrug reacts with ROS. However, at low µM concentrations of the prodrugs and ROS the activation is usually inefficient. Herein we suggested and validated a potentially general approach for solving this intrinsic problem of ROS-dependent prodrugs. In particular, known 4-(N-ferrocenyl-N-benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted to its lysosome specific analogue. Since lysosomes contain the higher concentration of active ROS than cytoplasm, activation of the latter prodrug was facilitated with respect to the parent compound. In particular, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC50 3.5-7.2 µM) and in vivo (40 mg/kg, NK/Ly murine model), but remained weakly toxic towards non-malignant cells (IC50 15-30 µM).
EVALuna2:13450

Machine Learning Algorithms for Early Detection of Bone Metastases in an Experimental Rat Model - Ellmann, Stephan; Seyler, Lisa; Gillmann, Clarissa; Popp, Vanessa; Treutlein, Christoph; Bozec, Aline; Uder, Michael; Bäuerle, Tobias (Journal of Visualized Experiments, 2020)
Machine learning (ML) algorithms permit the integration of different features into a model to perform classification or regression tasks with an accuracy exceeding its constituents. This protocol describes the development of an ML algorithm to predict the growth of breast cancer bone macrometastases in a rat model before any abnormalities are observable with standard imaging methods. Such an algorithm can facilitate the detection of early metastatic disease (i.e., micrometastasis) that is regularly missed during staging examinations. The applied metastasis model is site-specific, meaning that the rats develop metastases exclusively in their right hind leg. The model's tumor-take rate is 60%-80%, with macrometastases becoming visible in magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) in a subset of animals 30 days after induction, whereas a second subset of animals exhibit no tumor growth. Starting from image examinations acquired at an earlier time point, this protocol describes the extraction of features that indicate tissue vascularization detected by MRI, glucose metabolism by PET/CT, and the subsequent determination of the most relevant features for the prediction of macrometastatic disease. These features are then fed into a model-averaged neural network (avNNet) to classify the animals into one of two groups: one that will develop metastases and the other that will not develop any tumors. The protocol also describes the calculation of standard diagnostic parameters, such as overall accuracy, sensitivity, specificity, negative/positive predictive values, likelihood ratios, and the development of a receiver operating characteristic. An advantage of the proposed protocol is its flexibility, as it can be easily adapted to train a plethora of different ML algorithms with adjustable combinations of an unlimited number of features. Moreover, it can be used to analyze different problems in oncology, infection, and inflammation.
CRIS-Team Scopus Importer:2020-09-11

Machine learning-based improvement of an online rheumatology referral and triage system - Knitza, Johannes; Janousek, Lena; Kluge, Felix; Von Der Decken, Cay Benedikt; Kleinert, Stefan; Vorbrueggen, Wolfgang; Kleyer, Arnd; Simon, David; Hueber, Axel; Muehlensiepen, Felix; Vuillerme, Nicolas; Schett, Georg; et al. (Frontiers in Medicine, 2022)
Introduction: Rheport is an online rheumatology referral system allowing automatic appointment triaging of new rheumatology patient referrals according to the respective probability of an inflammatory rheumatic disease (IRD). Previous research reported that Rheport was well accepted among IRD patients. Its accuracy was, however, limited, currently being based on an expert-based weighted sum score. This study aimed to evaluate whether machine learning (ML) models could improve this limited accuracy. Materials and methods: Data from a national rheumatology registry (RHADAR) was used to train and test nine different ML models to correctly classify IRD patients. Diagnostic performance was compared of ML models and the current algorithm was compared using the area under the receiver operating curve (AUROC). Feature importance was investigated using shapley additive explanation (SHAP). Results: A complete data set of 2265 patients was used to train and test ML models. 30.5% of patients were diagnosed with an IRD, 69.3% were female. The diagnostic accuracy of the current Rheport algorithm (AUROC of 0.534) could be improved with all ML models, (AUROC ranging between 0.630 and 0.737). Targeting a sensitivity of 90%, the logistic regression model could double current specificity (17% vs. 33%). Finger joint pain, inflammatory marker levels, psoriasis, symptom duration and female sex were the five most important features of the best performing logistic regression model for IRD classification. Conclusion: In summary, ML could improve the accuracy of a currently used rheumatology online referral system. Including further laboratory parameters and enabling individual feature importance adaption could increase accuracy and lead to broader usage.
CRIS-Team Scopus Importer:2022-08-19
Keywords: artificial intelligence; decision support system (DSS); digital health; machine learning; rheumatology; symptom checker; triage

Machine Learning Electronic Health Record Identification of Patients with Rheumatoid Arthritis: Algorithm Pipeline Development and Validation Study - Maarseveen, Tjardo D.; Meinderink, Timo; Reinders, Marcel J. T.; Knitza, Johannes; Huizinga, Tom W. J.; Kleyer, Arnd; Simon, David; Van Den Akker, Erik B.; Knevel, Rachel (JMIR Medical Informatics, 2020)
Background: Financial codes are often used to extract diagnoses from electronic health records. This approach is prone to false positives. Alternatively, queries are constructed, but these are highly center and language specific. A tantalizing alternative is the automatic identification of patients by employing machine learning on format-free text entries.
CRIS-Team WoS Importer:2021-01-15

Machine Learning Identifies an Association Between Pre-existing Radiographic Damage and Long-term Clinical Outcomes with Secukinumab Therapy in Patients with Psoriatic Arthritis - Mease, Philip; Van Der Heijde, Desiree; Kirkham, Bruce; Schett, Georg; Orbai, Ana-Maria; Ritchlin, Christopher; Merola, Joseph; Pricop, Luminita; Zhu, Xuan; James, Davida; Ligozio, Gregory (ARTHRITIS & RHEUMATOLOGY, 2020)
CRIS-Team WoS Importer:2021-01-15

Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever - Kohl, Lisa; Siddique, Md Nur A Alam; Bodendorfer, Barbara; Berger, Raffaela; Preikschat, Annica; Daniel, Christoph; Ölke, Martha; Liebler-Tenorio, Elisabeth; Schulze-Lührmann, Jan; Mauermeir, Michael; Yang, Kai-Ting; Hayek, Inaya; et al. (Embo Molecular Medicine, 2022)
Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis-aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1−/− mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1−/− mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1−/− mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.
CRIS-Team Scopus Importer:2022-12-16
Keywords: Cis-aconitate decarboxylase 1; Coxiella burnetii; Immune responsive gene 1; immunometabolism; itaconate

Magnetic drug targeting reduces the chemotherapeutic burden on circulating leukocytes - Janko, Christina; Dürr, Stephan; Munoz, Luis Enrique; Lyer, Stefan; Chaurio, Ricardo; Tietze, Rainer; Von Loehneysen, Sarah; Schorn, Christine; Herrmann, Martin; Alexiou, Christoph (International Journal of Molecular Sciences, 2013)
Magnetic drug targeting (MDT) improves the integrity of healthy tissues and cells during treatment with cytotoxic drugs. An anticancer drug is bound to superparamagnetic iron oxide nanoparticles (SPION), injected into the vascular supply of the tumor and directed into the tumor by means of an external magnetic field. In this study, we investigated the impact of SPION, mitoxantrone (MTO) and SPIONMTO on cell viability in vitro and the nonspecific uptake of MTO into circulating leukocytes in vivo. MDT was compared with conventional chemotherapy. MTO uptake and the impact on cell viability were assessed by flow cytometry in a Jurkat cell culture. In order to analyze MTO loading of circulating leukocytes in vivo, we treated tumor-bearing rabbits with MDT and conventional chemotherapy. In vitro experiments showed a dose-dependent MTO uptake and reduction in the viability and proliferation of Jurkat cells. MTO and SPIONMTO showed similar cytotoxic activity. Non-loaded SPION did not have any effect on cell viability in the concentrations tested. Compared with systemic administration in vivo, MDT employing SPIONMTO significantly decreased the chemotherapeutic load in circulating leukocytes. We demonstrated that MDT spares the immune system in comparison with conventional chemotherapy. © 2013 by the authors; licensee MDPI, Basel, Switzerland.
CRIS-Team Scopus Importer:2022-06-27
Keywords: Chemotherapy; Immune system; Iron oxide nanoparticles; Leukocytes; Magnetic drug targeting; Mitoxantrone

MAGNETIC RESONANCE IMAGING (MRI) OF HANDS OF PSORIASIS PATIENTS: HIGH INCIDENCE OF INFLAMMATION - Simon, David; Faustini, F.; Englbrechtl, M.; Kleyer, Arnd; Kocijan, R.; Haschka, J.; Kraus, S.; Hueber, Axel; Sticherling, Michael; Schell, G.; Rech, Jürgen (2014)
EVALuna2:12862

Magnetic resonance imaging techniques for the quantitative analysis of skeletal muscle: State of the art. - Engelke, Klaus; Chaudry, Oliver; Gast, Lena; Eldib, Mootaz AB; Wang, Ling; Laredo, Jean Denis; Schett, Georg; Nagel, Armin Michael (Journal of Orthopaedic Translation, 2023)
BACKGROUND: Magnetic resonance imaging (MRI) is the dominant 3D imaging modality to quantify muscle properties in skeletal muscle disorders, in inherited and acquired muscle diseases, and in sarcopenia, in cachexia and frailty. METHODS: This review covers T1 weighted and Dixon sequences, introduces T2 mapping, diffusion tensor imaging (DTI) and non-proton MRI. Technical concepts, strengths, limitations and translational aspects of these techniques are discussed in detail. Examples of clinical applications are outlined. For comparison 31P-and 13C-MR Spectroscopy are also addressed. RESULTS: MRI technology provides a rich toolset to assess muscle deterioration. In addition to classical measures such as muscle atrophy using T1 weighted imaging and fat infiltration using Dixon sequences, parameters characterizing inflammation from T2 maps, tissue sodium using non-proton MRI techniques or concentration or fiber architecture using diffusion tensor imaging may be useful for an even earlier diagnosis of the impairment of muscle quality. CONCLUSION: Quantitative MRI provides new options for muscle research and clinical applications. Current limitations that also impair its more widespread use in clinical trials are lack of standardization, ambiguity of image segmentation and analysis approaches, a multitude of outcome parameters without a clear strategy which ones to use and the lack of normal data.
EVALuna2:540329

Maintained Benefit in Health-Related Quality of Life of Patients with Giant Cell Arteritis Treated with Tocilizumab Plus Prednisone Tapering: Results from the Open-Label, Long-Term Extension of a Phase 3 Randomized Controlled Trial - Stone, John; Han, Jian; 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

Management of Peripheral Arthritis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations - Leung, Ying Ying; Korotaeva, Tatiana V.; Candia, Liliana; Pedersen, Susanne Juhl; Molano, Wilson Bautista; Ruderman, Eric M.; Bisoendial, Radjesh; Perez-Alamino, Rodolfo; Olsder, Wendy; Möller, Burkhard; Grazio, Simeon; Gudu, Tania; et al. (Journal of Rheumatology, 2023)
OBJECTIVE: We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations. METHODS: A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings. RESULTS: The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain. CONCLUSION: Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations.
CRIS-Team Scopus Importer:2023-01-13
Keywords: GRAPPA; peripheral arthritis; practice guideline; psoriasis; psoriatic arthritis; systematic literature review

MANAGEMENT OF REFERRALS, TREATMENT STRATEGY, AND RESEARCH CHALLENGES IN POLYMYALGIA RHEUMATICA AMONGST RHEUMATOLOGISTS WORLDWIDE: A QUESTIONNAIRE BASED STUDY - Donskov, A. Overgaard; Mackie, S.; Hauge, E. M.; Gutierrez, C. Toro; Hansen, I.; Hemmig, A.; Van Der Maas, A.; Gheita, T. A.; Nielsen, B. Dalsgaard; Douglas, K.; Conway, R.; Rezus, E.; et al. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

Mapping and predicting mortality from systemic sclerosis - Elhai, Muriel; Meune, Christophe; Boubaya, Marouane; Avouac, Jerome; Hachulla, Eric; Balbir-Gurman, Alexandra; Riemekasten, Gabriela; Airo, Paolo; Joven, Beatriz; Vettori, Serena; Cozzi, Franco; Ullman, Susanne; et al. (Annals of the Rheumatic Diseases, 2017)
To determine the causes of death and risk factors in systemic sclerosis (SSc).Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation.We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile.Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.
EVALuna2:13444

Markerless RGB-D Hand Pose Estimation for Activity Monitoring of Musculoskeletal Diseases - Wirth, Vanessa; Liphardt, Anna-Maria; Coppers, Birte; Bräunig, Johanna; Heinrich, Simon; Leyendecker, Sigrid; Kleyer, Arnd; Schett, Georg; Vossiek, Martin; Egger, Bernhard; Stamminger, Marc (IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI’23), 2023)

Marker position uncertainty in joint angle analysis for normal human gait — A new error-modelling approach - Scheiterer, Eduard; Heinrich, Simon; Liphardt, Anna-Maria; Leyendecker, Sigrid (Biomedical Signal Processing and Control, 2024)

Massive nodulous lesions on hands and feet in a RA patient and improvement under baricitinib treatment - Valor-Méndez, Larissa; Hagen, Melanie; Kleyer, Arnd; Manger, Bernhard; Schett, Georg (RMD Open, 2020)
CRIS-Team Scopus Importer:2020-12-04
Keywords: Arthritis; Methotrexate; Rheumatoid; Therapeutics

Mass Spectrometry–Based Lipidomics of Oral Squamous Cell Carcinoma Tissue Reveals Aberrant Cholesterol and Glycerophospholipid Metabolism — A Pilot Study - Dickinson, Amy; Saraswat, Mayank; Joenväärä, Sakari; Agarwal, Rahul; Jyllikoski, Daniel; Wilkman, Tommy; Mäkitie, Antti; Silén, Suvi (Translational Oncology, 2020)
Lipid metabolic reprogramming is one hallmark of cancer. Lipid metabolism is regulated by numerous enzymes, many of which are targeted by several drugs on the market. We aimed to characterize the lipid alterations in oral squamous cell carcinoma (OSCC) as a basis for understanding its lipid metabolism, thus identifying potential therapeutic targets. We compared lipid species, classes, and glycerophospholipid (GPL) fatty acid species between paired tumor tissue and healthy oral tongue mucosa samples from 10 OSCC patients using a QExactive mass spectrometer. After filtering the 1370 lipid species identified, we analyzed 349 species: 71 were significantly increased in OSCC. The GPL metabolism pathway was most represented by the lipids differing in OSCC (P =.005). Cholesterol and the GPLs phosphatidylcholines, phosphatidylethanolamines, and phosphatidylinositols were most significantly increased in OSCC tissue (FC 1.8, 2.0, 2.1, and 2.3 and, P =.003, P =.005, P =.002, P =.007). In conclusion, we have demonstrated a shift in the lipid metabolism in these OSCC samples by characterizing the detailed landscape. Predominantly, cholesterol and GPL metabolism were altered, suggesting that interactions with sterol regulatory binding proteins may be involved. The FA composition changes of the GPLs suggest increased de novo lipogenesis.
CRIS-Team Scopus Importer:2020-06-23

Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production - Rivellese, Felice; Mauro, Daniele; Nerviani, Alessandra; Pagani, Sara; Fossati-Jimack, Liliane; Messemaker, Tobias; Kurreeman, Fina A.S.; Toes, René E.M.; Rauber, Simon; Schett, Georg; Jones, Gareth W.; Jones, Simon A.; et al. (Annals of the Rheumatic Diseases, 2018)
OBJECTIVES: Mast cells (MCs) are involved in the pathogenesis of rheumatoid arthritis (RA). However, their contribution remains controversial. To establish their role in RA, we analysed their presence in the synovium of treatment-naïve patients with early RA and their association and functional relationship with histological features of synovitis. METHODS: Synovial tissue was obtained by ultrasound-guided biopsy from treatment-naïve patients with early RA (n=99). Immune cells (CD3/CD20/CD138/CD68) and their relationship with CD117+MCs in synovial tissue were analysed by immunohistochemistry (IHC) and immunofluorescence (IF). The functional involvement of MCs in ectopic lymphoid structures (ELS) was investigated in vitro, by coculturing MCs with naïve B cells and anticitrullinated protein antibodies (ACPA)-producing B cell clones, and in vivo in interleukin-27 receptor alpha (IL27ra)-deficient and control mice during antigen-induced arthritis (AIA). RESULTS: High synovial MC counts are associated with local and systemic inflammation, autoantibody positivity and high disease activity. IHC/IF showed that MCs reside at the outer border of lymphoid aggregates. Furthermore, human MCs promote the activation and differentiation of naïve B cells and induce the production of ACPA, mainly via contact-dependent interactions. In AIA, synovial MC numbers increase in IL27ra deficient mice, in association with ELS and worse disease activity. CONCLUSIONS: Synovial MCs identify early RA patients with a severe clinical form of synovitis characterised by the presence of ELS.
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Maternal SARS-CoV-2 infection during pregnancy: possible impact on the infant - Morhart, Patrick; Mardin, Christian; Rauh, Manfred; Juengert, Joerg; Hammersen, Johanna; Kehl, Sven; Schuh, Wolfgang; Maier-Wohlfart, Sigrun; Hermes, Katharina; Neubert, Antje; Schneider, Michael; Hein, Alexander; et al. (European Journal of Pediatrics, 2021)
The risk and potential consequences of mother-to-child transmission of severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) during pregnancy are still a matter of debate. We studied the impact of SARS-CoV-2 infection on 56 complete households, including 27 newborns whose mothers were pregnant when exposed to the virus. Two PCR-confirmed perinatal SARS-CoV-2 transmissions with mild symptoms in affected neonates were recorded. In addition, we observed a severe eye malformation (unilateral microphthalmia, optic nerve hypoplasia, and congenital retinopathy) associated with maternal SARS-CoV-2 infection in weeks 5 and 6 of embryonic development. This embryopathy could not be explained by other infectious agents, genetic factors, drug use, or maternal disease during pregnancy. Eight other women with a history of SARS-CoV-2 infection prior to gestational week 12, however, delivered healthy infants. Conclusion: The repeated occurrence of mother-to-child transmission in our cohort with risks that remain incompletely understood, such as long-term effects and the possibility of an embryopathy, should sensitize researchers and stimulate further studies as well as support COVID-19 vaccination recommendations for pregnant women. Trial registration number: NCT04741412. Date of registration: November 18, 2020What is Known:•Materno-fetal transmission of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) during pregnancy has rarely been reported so far, but was demonstrated in isolated cases.What is New:•In a study of complete households with documented SARS-CoV-2 infection, including a cohort of pregnant women, we observed perinatal coronavirus transmission at a higher frequency than expected.•We also describe a newborn boy with an eye malformation reminiscent of rubella embryopathy but associated with early gestation SARS-CoV-2 infection of his mother.•A coronavirus-related embryopathy, reported here for the first time, is a finding that requires further investigation.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Case report; Coronavirus; Embryopathy; Malformation; Materno-fetal transmission

McLabel: A Local Thresholding Tool for Efficient Semi-automatic Labelling of Cells in Fluorescence Microscopy - Utz, Jonas; Schlereth, Maja; Qiu, Jingna; Thies, Mareike; Wagner, Fabian; Brahim, Oumaima B.; Gu, Mingxuan; Uderhardt, Stefan; Breininger, Katharina (Informatik aktuell, 2023)
In this work, we present a semi-automatic labelling tool for the annotation of complex cellular structures such as macrophages in fluorescence microscopy images. We present McLabel, a napari plugin that allows users to label structures of interest by simply scribbling outlines around the area of interest, using the triangle thresholding method with post-processing to identify the desired structure. Additionally, manual adaption of the threshold allows for quick and fine-grained local correction of the segmentation. The tool is evaluated in a user study with five experts, who annotated images both with and without the tool. The results show that variability in annotations between experts is reduced when the labelling tool is used and annotation time is reduced by a factor of five on average1.
CRIS-Team Scopus Importer:2023-09-29

Measuring treatment effect on psoriatic arthritis-related domains: insights from the SPIRIT-H2H study at weeks 24 and 52 - Behrens, Frank; Leage, Soyi Liu; Sapin, Christophe; El Baou, Celine; De La Torre, Inmaculada; Meszaros, Gabriella; Schett, Georg; Combe, Bernard; Van Den Bosch, Filip; Gossec, Laure (Clinical Rheumatology, 2021)
Introduction Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA).
CRIS-Team WoS Importer:2021-09-24

MECHANICAL LOADING-INDUCED BHLHE40 PROMOTES INFLAMMATORY ARTHRITIS - Gracey, E.; Cambre, I.; Gilis, E.; Stappers, F.; Planckaert, G.; Bozec, Aline; Elewaut, D. (ANNALS OF THE RHEUMATIC DISEASES, 2022)
CRIS-Team WoS Importer:2022-11-04

MECHANICAL STRAIN DETERMINES THE SITE-SPECIFIC DIRECTION OF INFLAMMATION AND TISSUE DAMAGE IN ARTHRITIS - Cambre, I.; Gaublomme, D.; Burssens, A.; Jacques, P.; Elewaut, D.; Lories, R.; Schett, Georg; Kollias, G.; De Muynck, A.; Meuris, L.; Callewaert, N.; Lambrecht, S.; et al. (2018)
EVALuna2:34153

Mechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis. - Cambre, Isabelle; Gaublomme, Djoere; Burssens, Arne; Jacques, Peggy; Schryvers, Nadia; De Muynck, Amelie; Meuris, Leander; Lambrecht, Stijn; Carter, Shea; De Bleser, Pieter; Saeys, Yvan; Van Hoorebeke, Luc; et al. (Nature Communications, 2018)
Many pro-inflammatory pathways leading to arthritis have global effects on the immune system rather than only acting locally in joints. The reason behind the regional and patchy distribution of arthritis represents a longstanding paradox. Here we show that biomechanical loading acts as a decisive factor in the transition from systemic autoimmunity to joint inflammation. Distribution of inflammation and erosive disease is confined to mechano-sensitive regions with a unique microanatomy. Curiously, this pathway relies on stromal cells but not adaptive immunity. Mechano-stimulation of mesenchymal cells induces CXCL1 and CCL2 for the recruitment of classical monocytes, which can differentiate into bone-resorbing osteoclasts. Genetic ablation of CCL2 or pharmacologic targeting of its receptor CCR2 abates mechanically-induced exacerbation of arthritis, indicating that stress-induced chemokine release by mesenchymal cells and chemo-attraction of monocytes determines preferential homing of arthritis to certain hot spots. Thus, mechanical strain controls the site-specific localisation of inflammation and tissue damage in arthritis.
EVALuna2:34951

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis - Bozec, Aline; Hannemann, Nicole (Journal of Visualized Experiments, 2016)
Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1? protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes.
EVALuna2:13294

Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis - Catrina, Anca I.; Svensson, Camilla I.; Malmstrom, Vivianne; Schett, Georg; Klareskog, Lars (Nature Reviews Rheumatology, 2016)
A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation. In patients with seropositive RA (that is, characterized by the presence of autoantibodies) evidence is accumulating that immunity against post-translationally modified (such as citrullinated) autoantigens might be triggered in mucosal organs, such as the lung, long before the first signs of inflammation are seen in the joints. However, the mechanism by which systemic autoimmunity specifically homes to the joint and bone compartment, thereby triggering inflammation, remains elusive. This Review summarizes potential pathways involved in this joint-homing mechanism, focusing particularly on osteoclasts as the primary targets of anti-citrullinated protein antibodies (ACPAs) in the bone and joint compartment. Osteoclasts are dependent on citrullinating enzymes for their normal differentiation and are unique in displaying citrullinated antigens on their cell surface in a non-inflamed state. The binding of ACPAs to osteoclasts releases the chemokine IL-8, leading to bone erosion and pain. This process initiates a chain of events that could lead to attraction and activation of neutrophils, resulting in a complex series of proinflammatory processes in the synovium, eventually leading to RA.
EVALuna2:13384

Mechanisms of fibrosis and their translation into clinical aspects - Beyer, Christian; Distler, J. H. W. (Zeitschrift für Rheumatologie, 2014)
EVALuna2:12969

MECHANOSENSITIVE BLOOD MARKERS AND THEIR INTERRELATION IN PATIENTS WITH MEDIAL COMPARTMENT KNEE OSTEOARTHRITIS - Muendermann, A.; Nueesch, C.; Chammartin, F.; Simon, H.; Liphardt, Anna-Maria; Egloff, C. (OSTEOARTHRITIS AND CARTILAGE, 2021)
CRIS-Team WoS Importer:2021-05-21

Ménage-à-Trois: The Ratio of Bicarbonate to CO2 and the pH Regulate the Capacity of Neutrophils to Form NETs - Maueröder, Christian; Mahajan, Aparna; Paulus, Susanne; Goesswein, Stefanie; Hahn, Jonas; Kienhoefer, Deborah; Biermann, Mona H.; Tripal, Philipp; Friedrich, Ralf P.; Munoz Becerra, Luis; Neurath, Markus; Becker, Christoph; et al. (Frontiers in Immunology, 2016)
In this study, we identified and characterized the potential of a high ratio of bicarbonate to CO2 and a moderately alkaline pH to render neutrophils prone to undergo neutrophil extracellular trap (NET) formation. Both experimental settings increased the rate of spontaneous NET release and potentiated the NET-inducing capacity of phorbol esters (phorbol-2-myristate-13-acetate), ionomycin, monosodium urate, and LPS. In contrast, an acidic environment impaired NET formation both spontaneous and induced. Our findings indicate that intracellular alkalinization of neutrophils in response to an alkaline environment leads to an increase of intracellular calcium and neutrophil activation. We further found that the anion channel blocker DIDS strongly reduced NET formation induced by bicarbonate. This finding suggests that the effects observed are due to a molecular program that renders neutrophils susceptible to NET formation. Inflammatory foci may be characterized by an acidic environment. Our data indicate that NET formation is favored by the higher pH at the border regions of inflamed areas. Moreover, our findings highlight the necessity for strict pH control during assays of NET formation.
EVALuna2:2182

Metabolic and molecular imaging in inflammatory arthritis - de Sousa, Rita Noversa; Tascilar, Koray; Corte, Giulia; Atzinger, Armin; Minopoulou, Ioanna; Ohrndorf, Sarah; Waldner, Maximilian; Schmidkonz, Christian; Kuwert, Torsten; Knieling, Ferdinand; Kleyer, Arnd; Ramming, Andreas; et al. (RMD Open, 2024)
It is known that metabolic shifts and tissue remodelling precede the development of visible inflammation and structural organ damage in inflammatory rheumatic diseases such as the inflammatory arthritides. As such, visualising and measuring metabolic tissue activity could be useful to identify biomarkers of disease activity already in a very early phase. Recent advances in imaging have led to the development of so-called ‘metabolic imaging’ tools that can detect these changes in metabolism in an increasingly accurate manner and non-invasively. Nuclear imaging techniques such as 18F-D-glucose and fibroblast activation protein inhibitor-labelled positron emission tomography are increasingly used and have yielded impressing results in the visualisation (including whole-body staging) of inflammatory changes in both early and established arthritis. Furthermore, optical imaging-based bedside techniques such as multispectral optoacoustic tomography and fluorescence optical imaging are advancing our understanding of arthritis by identifying intra-articular metabolic changes that correlate with the onset of inflammation with high precision and without the need of ionising radiation. Metabolic imaging holds great potential for improving the management of patients with inflammatory arthritis by contributing to early disease interception and improving diagnostic accuracy, thereby paving the way for a more personalised approach to therapy strategies including preventive strategies. In this narrative review, we discuss state-of-the-art metabolic imaging methods used in the assessment of arthritis and inflammation, and we advocate for more extensive research endeavours to elucidate their full field of application in rheumatology.
CRIS-Team Scopus Importer:2024-02-23

Metabolic impairment of non-small cell lung cancers by mitochondrial HSPD1 targeting - Parma, Beatrice; Ramesh, Vignesh; Gollavilli, Paradesi Naidu; Siddiqui, Aarif; Pinna, Luisa; Schwab, Annemarie; Marschall, Sabine; Zhang, Shuman; Pilarsky, Christian; Napoli, Francesca; Volante, Marco; Urbanczyk, Sophia; et al. (Journal of Experimental & Clinical Cancer Research, 2021)
Background The identification of novel targets is of paramount importance to develop more effective drugs and improve the treatment of non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths worldwide. Since cells alter their metabolic rewiring during tumorigenesis and along cancer progression, targeting key metabolic players and metabolism-associated proteins represents a valuable approach with a high therapeutic potential. Metabolic fitness relies on the functionality of heat shock proteins (HSPs), molecular chaperones that facilitate the correct folding of metabolism enzymes and their assembly in macromolecular structures. Methods Gene fitness was determined by bioinformatics analysis from available datasets from genetic screenings. HSPD1 expression was evaluated by immunohistochemistry from formalin-fixed paraffin-embedded tissues from NSCLC patients. Real-time proliferation assays with and without cytotoxicity reagents, colony formation assays and cell cycle analyses were used to monitor growth and drug sensitivity of different NSCLC cells in vitro. In vivo growth was monitored with subcutaneous injections in immune-deficient mice. Cell metabolic activity was analyzed through extracellular metabolic flux analysis. Specific knockouts were introduced by CRISPR/Cas9. Results We show heat shock protein family D member 1 (HSPD1 or HSP60) as a survival gene ubiquitously expressed in NSCLC and associated with poor patients' prognosis. HSPD1 knockdown or its chemical disruption by the small molecule KHS101 induces a drastic breakdown of oxidative phosphorylation, and suppresses cell proliferation both in vitro and in vivo. By combining drug profiling with transcriptomics and through a whole-genome CRISPR/Cas9 screen, we demonstrate that HSPD1-targeted anti-cancer effects are dependent on oxidative phosphorylation and validated molecular determinants of KHS101 sensitivity, in particular, the creatine-transporter SLC6A8 and the subunit of the cytochrome c oxidase complex COX5B. Conclusions These results highlight mitochondrial metabolism as an attractive target and HSPD1 as a potential theranostic marker for developing therapies to combat NSCLC.
CRIS-Team WoS Importer:2021-08-20

Metabolic regulation of plasma cell generation in germinal centers through EFhd2 - Weckwerth, Leonie; Gottwald, A.; Mielenz, Dirk (EUROPEAN JOURNAL OF IMMUNOLOGY, 2022)
CRIS-Team WoS Importer:2023-01-27

Metabolic reprogramming of osteoclasts represents a therapeutic target during the treatment of osteoporosis - Taubmann, Jule; Krishnacoumar, Brenda; Böhm, Christina; Faas, Maria; Müller, Dorothea; Adam, Susanne; Stoll, Cornelia; Böttcher, Martin; Mougiakakos, Dimitrios; Sonnewald, Uwe; Hofmann, Jörg; Schett, Georg; et al. (Scientific Reports, 2020)
Osteoclasts are specialised bone resorbing cells that control both physiological and pathological bone turnover. Functional changes in the differentiation and activity of osteoclasts are accompanied by active metabolic reprogramming. However, the biological significance and the in vivo relevance of these events has remained unclear. Here we show that bone resorption of differentiated osteoclasts heavily relies on increased aerobic glycolysis and glycolysis-derived lactate production. While pharmacological inhibition of glycolysis did not affect osteoclast differentiation or viability, it efficiently blocked bone resorption in vitro and in vivo and consequently ameliorated ovariectomy-induced bone loss. Our experiments thus highlight the therapeutic potential of interfering with osteoclast-intrinsic metabolic pathways as possible strategy for the treatment of diseases characterized by accelerated bone loss.
CRIS-Team Scopus Importer:2020-12-11

Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids - Auger, Jean-Philippe; Zimmermann, Max; Faas, Maria; Stifel, Ulrich; Chambers, David; Krishnacoumar, Brenda; Taudte, R. Verena; Grund, Charlotte; Erdmann, Gitta; Scholtysek, Carina; Uderhardt, Stefan; Ben Brahim, Oumaima; et al. (Nature, 2024)
Glucocorticoids represent the mainstay of therapy for a broad spectrum of immune-mediated inflammatory diseases. However, the molecular mechanisms underlying their anti-inflammatory mode of action have remained incompletely understood1. Here we show that the anti-inflammatory properties of glucocorticoids involve reprogramming of the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and consequent inhibition of the inflammatory response. The glucocorticoid receptor interacts with parts of the pyruvate dehydrogenase complex whereby glucocorticoids provoke an increase in activity and enable an accelerated and paradoxical flux of the tricarboxylic acid (TCA) cycle in otherwise pro-inflammatory macrophages. This glucocorticoid-mediated rewiring of mitochondrial metabolism potentiates TCA-cycle-dependent production of itaconate throughout the inflammatory response, thereby interfering with the production of pro-inflammatory cytokines. By contrast, artificial blocking of the TCA cycle or genetic deficiency in aconitate decarboxylase 1, the rate-limiting enzyme of itaconate synthesis, interferes with the anti-inflammatory effects of glucocorticoids and, accordingly, abrogates their beneficial effects during a diverse range of preclinical models of immune-mediated inflammatory diseases. Our findings provide important insights into the anti-inflammatory properties of glucocorticoids and have substantial implications for the design of new classes of anti-inflammatory drugs.
CRIS-Team Scopus Importer:2024-04-19

Metabolische Arthritiden, seltene Erkrankungen - Manger, Bernhard (Zeitschrift für Rheumatologie, 2019)
CRIS-Team WoS Importer:2019-08-20