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@article{faucris.245489417,
abstract = {Eicosanoids are essential mediators of the inflammatory response and contribute both to the initiation and the resolution of inflammation. Leukocyte-type 12/15-lipoxygenase (12/15-LO) represents a major enzyme involved in the generation of a subclass of eicosanoids, including the anti-inflammatory lipoxin A4 (LXA4). Nevertheless, the impact of 12/15-LO on chronic inflammatory diseases such as arthritis has remained elusive. By using two experimental models of arthritis, the K/BxN serum-transfer and a TNF transgenic mouse model, we show that deletion of 12/15-LO leads to uncontrolled inflammation and tissue damage. Consistent with these findings, 12/15-LO-deficient mice showed enhanced inflammatory gene expression and decreased levels of LXA4 within their inflamed synovia. In isolated macrophages, the addition of 12/15-LO-derived eicosanoids blocked both phosphorylation of p38MAPK and expression of a subset of proinflammatory genes. Conversely, 12/15-LO-deficient macrophages displayed significantly reduced levels of LXA4, which correlated with increased activation of p38MAPK and an enhanced inflammatory gene expression after stimulation with TNF-α. Taken together, these results support an anti-inflammatory and tissue-protective role of 12/15-LO and its products during chronic inflammatory disorders such as arthritis. Copyright © 2009 by The American Association of Immunologists, Inc.},
author = {Krönke, Gerhard and Katzenbeisser, Julia and Uderhardt, Stefan and Zaiss, Mario and Scholtysek, Carina and Schabbauer, Gernot and Zarbock, Alexander and Koenders, Marije I. and Axmann, Roland and Zwerina, Jochen and Baenckler, Hans W. and Van Den Berg, Wim and Voll, Reinhard E. and Kuehn, Hartmut and Joosten, Leo A. B. and Schett, Georg},
doi = {10.4049/jimmunol.0900327},
faupublication = {yes},
journal = {Journal of Immunology},
note = {CRIS-Team Scopus Importer:2020-11-20},
pages = {3383-3389},
peerreviewed = {Yes},
title = {12/15-{Lipoxygenase} counteracts inflammation and tissue damage in arthritis},
volume = {183},
year = {2009}
}
@article{faucris.245487919,
abstract = {12/15-Lipoxygenase (12/15-LO) catalyzes the oxidation of free and esterified fatty acids thereby generating a whole spectrum of bioactive lipid mediators. This enzyme is involved in the regulation of various homeostatic processes as well as in the pathogenesis of multiple diseases. During the innate and adaptive immune response, 12/15-LO and its products exert both pro- and anti-inflammatory effects. Likewise, this enzyme has been implicated in the pathogenesis of autoimmune disease as well as in the maintenance of self-tolerance. This review will summarize our current knowledge about the role of 12/15-LO and will try to examine the two faces of this enzyme within the context of inflammation and immunity. © 2012 Springer-Verlag.},
author = {Uderhardt, Stefan and Krönke, Gerhard},
doi = {10.1007/s00109-012-0954-4},
faupublication = {yes},
journal = {Journal of Molecular Medicine},
keywords = {12/15-Lipoxygenase; Clearance of apoptotic cells; Immunity; Inflammation; Oxidized phospholipids; Resident macrophages; Resolution of inflammation; Self-tolerance},
note = {CRIS-Team Scopus Importer:2020-11-20},
pages = {1247-1256},
peerreviewed = {Yes},
title = {12/15-{Lipoxygenase} during the regulation of inflammation, immunity, and self-tolerance},
volume = {90},
year = {2012}
}
@article{faucris.121939664,
abstract = {DCs are able to undergo rapid maturation, which subsequently allows them to initiate and orchestrate T cell-driven immune responses. DC maturation must be tightly controlled in order to avoid random T cell activation and development of autoimmunity. Here, we determined that 12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates DC activation and fine-tunes consecutive T cell responses. Specifically, 12/15-LO activity determined the DC activation threshold via generation of phospholipid oxidation products that induced an antioxidative response dependent on the transcription factor NRF2. Deletion of the 12/15-LO-encoding gene or pharmacologic inhibition of 12/15-LO in murine or human DCs accelerated maturation and shifted the cytokine profile, thereby favoring the differentiation of Th17 cells. Exposure of 12/15-LO-deficient DCs to 12/15-LO-derived oxidized phospholipids attenuated both DC activation and the development of Th17 cells. Analysis of lymphatic tissues from 12/15-LO-deficient mice confirmed enhanced maturation of DCs as well as an increased differentiation of Th17 cells. Moreover, experimental autoimmune encephalomyelitis in mice lacking 12/15-LO resulted in an exacerbated Th17-driven autoimmune disease. Together, our data reveal that 12/15-LO controls maturation of DCs and implicate enzymatic lipid oxidation in shaping the adaptive immune response.},
author = {Rothe, Tobias and Gruber, Florian and Uderhardt, Stefan and Ipseiz, Natacha and Rössner, Susanne and Oskolkova, Olga and Blueml, Stephan and Leitinger, Norbert and Bicker, Wolfgang and Bochkov, Valery N. and Yamamoto, Masayuki and Steinkasserer, Alexander and Schett, Georg and Zinser, Elisabeth and Krönke, Gerhard},
doi = {10.1172/JCI78490},
faupublication = {yes},
journal = {Journal of Clinical Investigation},
note = {EVALuna2:13111},
pages = {1944-54},
peerreviewed = {Yes},
title = {12/15-{Lipoxygenase}-mediated enzymatic lipid oxidation regulates {DC} maturation and function},
volume = {125},
year = {2015}
}
@article{faucris.108399984,
abstract = {Noninflammatory clearance of apoptotic cells (ACs) is crucial to maintain self-tolerance. Here, we have reported a role for the enzyme 12/15-lipoxygenase (12/15-LO) as a central factor governing the sorting of ACs into differentially activated monocyte subpopulations. During inflammation, uptake of ACs was confined to a population of 12/15-LO-expressing, alternatively activated resident macrophages (resMΦ), which blocked uptake of ACs into freshly recruited inflammatory Ly6C(hi) monocytes in a 12/15-LO-dependent manner. ResMΦ exposed 12/15-LO-derived oxidation products of phosphatidylethanolamine (oxPE) on their plasma membranes and thereby generated a sink for distinct soluble receptors for ACs such as milk fat globule-EGF factor 8, which were essential for the uptake of ACs into inflammatory monocytes. Loss of 12/15-LO activity, in turn, resulted in an aberrant phagocytosis of ACs by inflammatory monocytes, subsequent antigen presentation of AC-derived antigens, and a lupus-like autoimmune disease. Our data reveal an unexpected key role for enzymatic lipid oxidation during the maintenance of self-tolerance.},
author = {Uderhardt, Stefan and Herrmann, Martin and Oskolkova, Olga V. and Aschermann, Susanne and Bicker, Wolfgang and Ipseiz, Natacha and Sarter-Zaiss, Kerstin and Frey, Benjamin and Rothe, Tobias and Voll, Reinhard and Nimmerjahn, Falk and Bochkov, Valery N. and Schett, Georg and Krönke, Gerhard},
doi = {10.1016/j.immuni.2012.03.010},
faupublication = {yes},
journal = {Immunity},
pages = {834-46},
peerreviewed = {Yes},
title = {12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance.},
volume = {36},
year = {2012}
}
@inproceedings{faucris.284537220,
address = {LONDON},
author = {Rech, Jürgen and Kleyer, Arnd and Ostergaard, M. and Hagen, Melanie and Valor, L. and Tascilar, Koray and Krönke, Gerhard and Schönau, Verena and Kleinert, Stefan and Baraliakos, X. and Braun, J. and Fleck, M. and Rubbert-Roth, A. and Behrens, F. and Feuchtenberger, M. and Zaenker, M. and Kofler, D. M. and Voll, R. and Glaser, C. and Hueber, A. and Feist, E. and Burmester, G. R. and Karberg, K. and Strunk, J. and Canete, J. D. D. and Senolt, L. and Naredo, E. and Schett, Georg},
booktitle = {ANNALS OF THE RHEUMATIC DISEASES},
doi = {10.1136/annrheumdis-2022-eular.1693},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2022-11-04},
pages = {526-527},
peerreviewed = {unknown},
publisher = {BMJ PUBLISHING GROUP},
title = {{ABATACEPT} {DELAYS} {THE} {DEVELOPMENT} {OF} {RA}-{CLINICAL} {RESULTS} {AFTER} 18 {MONTHS} {FROM} {THE} {RANDOMIZED}, {PLACEBO}-{CONTROLLED} {ARIAA} {STUDY} {IN} {RA}-{AT} {RISK} {PATIENTS}},
year = {2022}
}
@inproceedings{faucris.270698825,
address = {HOBOKEN},
author = {Rech, Jürgen and Hueber, Axel and Ostergaard, Mikkel and Tascilar, Koray and Hagen, Melanie and Mendez, Larissa Valor and Kleyer, Arnd and Krönke, Gerhard and Simon, David and Schönau, Verena and Hueber, Axel and Kleinert, Stefan and Baraliakos, Xenofon and Fleck, Martin and Rubbert-Roth, Andrea and Behrens, Frank and Kofler, David and Feuchtenberger, Martin and Zaenker, Michael and Voll, Reinhard and Glaser, Cornelia and Feist, Eugen and Burmester, Gerd and Karberg, Kirsten and Strunk, Johannes and Canete, Juan D. and Naredo, Esperanza and Filkova, Maria and Senolt, Ladislav and Schett, Georg},
booktitle = {ARTHRITIS & RHEUMATOLOGY},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2022-03-11},
pages = {939-941},
peerreviewed = {unknown},
publisher = {WILEY},
title = {{Abatacept} {Reverses} {Subclinical} {Arthritis} in {Patients} with {High}-risk to {Develop} {Rheumatoid} {Arthritis} -results from the {Randomized}, {Placebo}-controlled {ARIAA} {Study} in {RA}-at {Risk} {Patients}},
year = {2021}
}
@inproceedings{faucris.287490418,
address = {HOBOKEN},
author = {Rech, Jürgen and Kleyer, Arnd and Ostergaard, Mikkel and Hagen, Melanie and Mendez, Larissa Valor and Tascilar, Koray and Krönke, Gerhard and Schönau, Verena and Simon, David and Kleinert, Stefan and Baraliakos, Xenofon and Braun, Juergen and Hueber, Axel and Fleck, Martin and Rubbert-Roth, Andrea and Behrens, Frank and Feuchtenberger, Martin and Zaenker, M. and Voll, Reinhard and Glaser, Cornelia and Filkova, Maria and Feist, Eugen and Burmester, Gerd and Karberg, Kirsten and Strunk, Johannes and Canete, Juan and Senolt, Ladislav and Naredo, Esperanza and Schett, Georg},
booktitle = {ARTHRITIS & RHEUMATOLOGY},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2023-01-13},
pages = {1067-1069},
peerreviewed = {unknown},
publisher = {WILEY},
title = {{Abatacept} {Significantly} {Reduces} {Subclinical} {Inflammation} {During} {Treatment} (6 {Months}), {This} {Persists} {After} {Discontinuation} (12 {Months}), {Resulting} in a {Delay} in the {Clinical} {Development} of {RA} in {Patients} at {Risk} of {RA} ({The} {ARIAA} {Study})},
year = {2022}
}
@article{faucris.276703286,
abstract = {Background: Rheumatoid arthritis (RA) requires early diagnosis and tight surveillance of disease activity. Remote self-collection of blood for the analysis of inflammation markers and autoantibodies could improve the monitoring of RA and facilitate the identification of individuals at-risk for RA.},
author = {Knitza, Johannes and Tascilar, Koray and Vuillerme, Nicolas and Eimer, Ekaterina and Matusewicz, Paul and Corte, Giulia and Schuster, Louis and Aubourg, Timothee and Bendzuck, Gerlinde and Korinth, Marianne and Elling-Audersch, Corinna and Kleyer, Arnd and Böltz, Sebastian and Hueber, Axel and Krönke, Gerhard and Schett, Georg and Simon, David},
doi = {10.1186/s13075-022-02809-7},
faupublication = {yes},
journal = {Arthritis Research & Therapy},
keywords = {Self-sampling; Capillary blood; Rheumatoid arthritis; Disease activity},
note = {CRIS-Team WoS Importer:2022-06-10},
peerreviewed = {Yes},
title = {{Accuracy} and tolerability of self-sampling of capillary blood for analysis of inflammation and autoantibodies in rheumatoid arthritis patients-results from a randomized controlled trial},
volume = {24},
year = {2022}
}
@article{faucris.109064604,
abstract = {To investigate the role of liver X receptors (LXRs) in experimental skin fibrosis and evaluate their potential as novel antifibrotic targets.We studied the role of LXRs in bleomycin-induced skin fibrosis, in the model of sclerodermatous graft-versus-host disease (sclGvHD) and in tight skin-1 (Tsk-1) mice, reflecting different subtypes of fibrotic disease. We examined both LXR isoforms using LXR?-, LXR?- and LXR-?/?-double-knockout mice. Finally, we investigated the effects of LXRs on fibroblasts and macrophages to establish the antifibrotic mode of action of LXRs.LXR activation by the agonist T0901317 had antifibrotic effects in bleomycin-induced skin fibrosis, in the sclGvHD model and in Tsk-1 mice. The antifibrotic activity of LXRs was particularly prominent in the inflammation-driven bleomycin and sclGvHD models. LXR?-, LXR?- and LXR?/?-double-knockout mice showed a similar response to bleomycin as wildtype animals. Low levels of the LXR target gene ABCA-1 in the skin of bleomycin-challenged and control mice suggested a low baseline activation of the antifibrotic LXR signalling, which, however, could be specifically activated by T0901317. Fibroblasts were not the direct target cells of LXRs agonists, but LXR activation inhibited fibrosis by interfering with infiltration of macrophages and their release of the pro-fibrotic interleukin-6.We identified LXRs as novel targets for antifibrotic therapies, a yet unknown aspect of these nuclear receptors. Our data suggest that LXR activation might be particularly effective in patients with inflammatory disease subtypes. Activation of LXRs interfered with the release of interleukin-6 from macrophages and, thus, inhibited fibroblast activation and collagen release.},
author = {Beyer, Christian and Huang, Jingang and Beer, Juergen and Zhang, Yun and Palumbo-Zerr, Katrin and Zerr, Pawel and Distler, Alfiya and Dees, Clara and Maier, Christiane and Munoz, Louis and Krönke, Gerhard and Uderhardt, Stefan and Distler, Oliver and Jones, Simon and Rose-John, Stefan and Oravecz, Tamas and Schett, Georg and Distler, Jörg and Munoz Becerra, Luis},
doi = {10.1136/annrheumdis-2013-204401},
faupublication = {yes},
journal = {Annals of the Rheumatic Diseases},
note = {EVALuna2:12871},
pages = {1317-24},
peerreviewed = {Yes},
title = {{Activation} of liver {X} receptors inhibits experimental fibrosis by interfering with interleukin-6 release from macrophages},
volume = {74},
year = {2015}
}
@article{faucris.107394804,
abstract = {Adopted orphan nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs), have emerged as key regulators of inflammation and immunity and likewise control skeletal homeostasis. These properties render them attractive targets for the therapy of various inflammatory and autoimmune diseases affecting the musculoskeletal system. This review summarises the current knowledge on the role of these families of receptors during innate and adaptive immunity as well as during the control of bone turnover and discuss the potential use of targeting these molecules during the treatment of chronic diseases such as osteoarthritis, rheumatoid arthritis and osteoporosis.},
author = {Ipseiz, Natacha and Scholtysek, Carina and Culemann, Stephan and Krönke, Gerhard},
doi = {10.4414/smw.2014.14055},
faupublication = {yes},
journal = {Swiss Medical Weekly},
note = {EVALuna2:13065},
pages = {w14055},
peerreviewed = {Yes},
title = {{Adopted} orphans as regulators of inflammation, immunity and skeletal homeostasis},
volume = {144},
year = {2014}
}
@article{faucris.252085556,
abstract = {Background: Biological disease-modifying anti-rheumatic drugs (bDMARDs) can be tapered in some rheumatoid arthritis (RA) patients in sustained remission. The purpose of this study was to assess the feasibility of building a model to estimate the individual flare probability in RA patients tapering bDMARDs using machine learning methods. Methods: Longitudinal clinical data of RA patients on bDMARDs from a randomized controlled trial of treatment withdrawal (RETRO) were used to build a predictive model to estimate the probability of a flare. Four basic machine learning models were trained, and their predictions were additionally combined to train an ensemble learning method, a stacking meta-classifier model to predict the individual flare probability within 14 weeks after each visit. Prediction performance was estimated using nested cross-validation as the area under the receiver operating curve (AUROC). Predictor importance was estimated using the permutation importance approach. Results: Data of 135 visits from 41 patients were included. A model selection approach based on nested cross-validation was implemented to find the most suitable modeling formalism for the flare prediction task as well as the optimal model hyper-parameters. Moreover, an approach based on stacking different classifiers was successfully applied to create a powerful and flexible prediction model with the final measured AUROC of 0.81 (95%CI 0.73–0.89). The percent dose change of bDMARDs, clinical disease activity (DAS-28 ESR), disease duration, and inflammatory markers were the most important predictors of a flare. Conclusion: Machine learning methods were deemed feasible to predict flares after tapering bDMARDs in RA patients in sustained remission.},
author = {Vodencarevic, Asmir and Tascilar, Koray and Reiser, Michaela and Hueber, Axel and Haschka, Judith and Bayat, Sara and Meinderink, Timo and Knitza, Johannes and Mendez, Larissa and Hagen, Melanie and Krönke, Gerhard and Rech, Jürgen and Manger, Bernhard and Kleyer, Arnd and Zimmermann-Rittereiser, Marcus and Schett, Georg and Simon, David and Hartmann, Fabian},
doi = {10.1186/s13075-021-02439-5},
faupublication = {yes},
journal = {Arthritis Research & Therapy},
keywords = {Flare prediction; Machine learning; Rheumatoid arthritis},
note = {CRIS-Team Scopus Importer:2021-03-19},
peerreviewed = {Yes},
title = {{Advanced} machine learning for predicting individual risk of flares in rheumatoid arthritis patients tapering biologic drugs},
volume = {23},
year = {2021}
}
@article{faucris.271470331,
abstract = {Objectives: To evaluate whether neural networks
can distinguish between seropositive rheumatoid arthritis (RA),
seronegative RA and psoriatic arthritis (PsA) based on inflammatory
patterns from hand MRI and to test how psoriasis patients with
subclinical inflammation fit into such patterns.
Methods: ResNet
neural networks were utilized to compare (i) seropositive RA vs. PsA,
(ii) seronegative RA vs. PsA and (iii) seropositive vs. seronegative RA
with respect to hand MRI data. Results from T1 coronal, T2 coronal, T1
coronal and axial fat suppressed contrast-enhanced (CE) and T2 fat
suppressed axial sequences were used. The performance of such trained
networks was analyzed by the
area-under-the-receiver-operating-characteristic curve (AUROC) with and
without presentation of demographic and clinical parameters.
Additionally, the trained networks were applied to psoriasis patients
without clinical arthritis.
Results: MRI scans from 649 patients
(135 seronegative RA, 190 seropositive RA, 177 PsA, 147 psoriasis) were
fed into ResNet neural networks. AUROC was 75% for seropositive RA vs.
PsA, 74% for seronegative RA vs. PsA and 67% for seropositive vs.
seronegative RA. All MRI sequences were relevant for classification,
however, when deleting contrast agent-based sequences the loss of
performance was only marginal. The addition of demographic and clinical
data to the networks did not provide significant improvements for
classification. Psoriasis patients were mostly assigned to PsA by the
neural networks, suggesting that a PsA-like MRI pattern may be present
early in the course of psoriatic disease.
Conclusion: Neural
networks can be successfully trained to distinguish MRI inflammation
related to seropositive RA, seronegative RA, and PsA.},
author = {Folle, Lukas and Bayat, Sara and Kleyer, Arnd and Fagni, Filippo and Kapsner, Lorenz and Schlereth, Maja and Meinderink, Timo and Breininger, Katharina and Tascilar, Koray and Krönke, Gerhard and Uder, Michael and Sticherling, Michael and Bickelhaupt, Sebastian and Schett, Georg and Maier, Andreas and Roemer, Frank and Simon, David},
doi = {10.1093/rheumatology/keac197},
faupublication = {yes},
journal = {Rheumatology},
keywords = {Rheumatoid arthritis; Psoriatic arthritis; neural networks; deep learning},
peerreviewed = {Yes},
title = {{Advanced} neural networks for classification of {MRI} in psoriatic arthritis, seronegative, and seropositive rheumatoid arthritis},
year = {2022}
}
@article{faucris.248101983,
abstract = {Rationale: Structural remodeling or damage as a result of disease or injury is often not evenly distributed throughout a tissue but strongly depends on localization and extent of damaging stimuli. Skeletal muscle as a mechanically active organ can express signs of local or even systemic myopathic damage, necrosis, or repair. Conventionally, muscle biopsies (patients) or whole muscles (animal models) are mechanically sliced and stained to assess structural alterations histologically. Three-dimensional tissue information can be obtained by applying deep imaging modalities, e.g. multiphoton or light-sheet microscopy. Chemical clearing approaches reduce scattering, e.g. through matching refractive tissue indices, to overcome optical penetration depth limits in thick tissues.},
author = {Schneidereit, Dominik and Broellochs, Anita and Ritter, Paul and Kreiß, Lucas and Mokhtari, Zeinab and Beilhack, Andreas and Krönke, Gerhard and Ackermann, Jochen and Faas, Maria and Grüneboom, Anika and Schürmann, Sebastian and Friedrich, Oliver},
doi = {10.7150/thno.51558},
faupublication = {yes},
journal = {Theranostics},
month = {Jan},
note = {CRIS-Team WoS Importer:2021-01-22},
pages = {2876-2891},
peerreviewed = {Yes},
title = {{An} advanced optical clearing protocol allows label-free detection of tissue necrosis via multiphoton microscopy in injured whole muscle},
volume = {11},
year = {2021}
}
@article{faucris.282419491,
abstract = {Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA autoantibodies and organ inflammation. Five patients with SLE (four women and one man) with a median (range) age of 22 (6) years, median (range) disease duration of 4 (8) years and active disease (median (range) SLE disease activity index Systemic Lupus Erythematosus Disease Activity Index: 16 (8)) refractory to several immunosuppressive drug treatments were enrolled in a compassionate-use chimeric antigen receptor (CAR) T cell program. Autologous T cells from patients with SLE were transduced with a lentiviral anti-CD19 CAR vector, expanded and reinfused at a dose of 1 × 106 CAR T cells per kg body weight into the patients after lymphodepletion with fludarabine and cyclophosphamide. CAR T cells expanded in vivo, led to deep depletion of B cells, improvement of clinical symptoms and normalization of laboratory parameters including seroconversion of anti-double-stranded DNA antibodies. Remission of SLE according to DORIS criteria was achieved in all five patients after 3 months and the median (range) Systemic Lupus Erythematosus Disease Activity Index score after 3 months was 0 (2). Drug-free remission was maintained during longer follow-up (median (range) of 8 (12) months after CAR T cell administration) and even after the reappearance of B cells, which was observed after a mean (±s.d.) of 110 ± 32 d after CAR T cell treatment. Reappearing B cells were naïve and showed non-class-switched B cell receptors. CAR T cell treatment was well tolerated with only mild cytokine-release syndrome. These data suggest that CD19 CAR T cell transfer is feasible, tolerable and highly effective in SLE.},
author = {Mackensen, Andreas and Müller, Fabian and Mougiakakos, Dimitrios and Böltz, Sebastian and Wilhelm, Artur and Aigner, Michael and Völkl, Simon and Simon, David and Kleyer, Arnd and Munoz, Luis Enrique and Kretschmann, Sascha and Kharboutli, Soraya and Gary, Regina and Reimann, Hannah and Rösler, Wolf and Uderhardt, Stefan and Bang, Holger and Herrmann, Martin and Ekici, Arif Bülent and Büttner, Christian and Habenicht, Katharina Marie and Winkler, Thomas and Krönke, Gerhard and Schett, Georg},
doi = {10.1038/s41591-022-02017-5},
faupublication = {yes},
journal = {Nature Medicine},
note = {CRIS-Team Scopus Importer:2022-09-30},
peerreviewed = {Yes},
title = {{Anti}-{CD19} {CAR} {T} cell therapy for refractory systemic lupus erythematosus},
year = {2022}
}
@article{faucris.121879384,
abstract = {Objective: To investigate the factors associated with cartilage proteoglycan content in patients with rheumatoid arthritis (RA) Methods: 32 RA patients received high-field 3 Tesla Gadolinium-Enhanced MRI of Cartilage (dGEMRIC) for determining cartilage proteoglycan content. Measurements were performed in three individual cartilage regions (medial, central, lateral) of the metacarpophalangeal joints 2 and 3. dGEMRIC values were then related to disease duration, disease activity, anti-citrullinated protein antibody (ACPA) status, rheumatoid factor status and C-reactive protein level. Results: dGEMRIC values were not significantly different between the MCP2 and MCP3 joint. Inter-class correlations were high (>0.92) for all three (medial, central and lateral) cartilage compartments. dGEMRIC values were significantly lower in RA patients with longer disease duration (>=3 years) and those with ACPA positivity than those with a short disease duration (<3 years)(p=0.034) or negative ACPA (p=0.0002), respectively. In contrast, no association between cartilage proteoglycan content and disease activity, C-reactive protein level and rheumatoid factor status was found. Conclusion: Decreased cartilage proteoglycan content in RA patients is associated with disease duration and ACPA positivity but not with the actual disease activity, CRP level or rheumatoid factor status. These data suggest that the cumulative burden of inflammation as well as ACPA are the determinants for cartilage damage in RA.},
author = {Renner, Nina and Krönke, Gerhard and Rech, Jürgen and Uder, Michael and Janka, Rolf Matthias and Lauer, Lars and Paul, Dominik and Herz, Barbara and Schlechtweg, Philipp and Hennig, Friedrich and Schett, Georg and Welsch, Götz},
doi = {10.1002/art.38862},
faupublication = {yes},
journal = {Arthritis and Rheumatology},
note = {EVALuna2:12983},
pages = {3283-8},
peerreviewed = {Yes},
title = {{Anti}-citrullinated protein antibody positivity correlates with cartilage damage and proteoglycan levels in patients with rheumatoid arthritis in the hand joints},
volume = {66},
year = {2014}
}
@inproceedings{faucris.234061647,
address = {HOBOKEN},
author = {Schett, Georg and Simon, David and Hueber, Axel and Bang, Holger and Rech, Jürgen and Krönke, Gerhard and Kleyer, Arnd},
booktitle = {ARTHRITIS & RHEUMATOLOGY},
faupublication = {yes},
note = {CRIS-Team WoS Importer:2020-02-11},
peerreviewed = {unknown},
publisher = {WILEY},
title = {{Anti}-citrullinated {Vimentin} {Antibodies} {Are} {Associated} to {Early} {Deterioration} of {Cortical} {Bone} and {Volumetric} {Bone} {Mineral} {Density} in {Finger} {Joints} in {RA}-at-risk {Patients}},
year = {2019}
}
@article{faucris.124251864,
abstract = {Resolution of inflammation is an active counter-regulatory mechanism involving polyunsaturated fatty acid-derived proresolving lipid mediators. Postoperative intestinal motility disturbances, clinically known as postoperative ileus, occur frequently after abdominal surgery and are mediated by a complex inflammation of the intestinal muscularis externa. Herein, we tested the hypothesis that proresolving lipid mediators are involved in the resolution of postoperative ileus. In a standardized experimental model of postoperative ileus, we detected strong expression of 12/15-lipoxygenase within the postoperative muscularis externa of C57BL/6 mice, predominately located within CX3CR1(+)/Ly6C(+) infiltrating monocytes rather than Ly6G(+) neutrophils. Mass spectrometry analyses demonstrated that a 12/15-lipoxygenase increase was accompanied by production of docosahexaenoic acid-derived lipid mediators, particularly protectin DX and resolvin D2, and their common precursor 17-hydroxy docosahexaenoic acid. Perioperative administration of protectin DX, but not resolvin D2 diminished blood-derived leukocyte infiltration into the surgically manipulated muscularis externa and improved the gastrointestinal motility. Flow cytometry analyses showed impaired Ly6G(+)/Ly6C(+) neutrophil extravasation after protectin DX treatment, whereas Ly6G(-)/Ly6C(+) monocyte numbers were not affected. 12/15-lipoxygenase-deficient mice, lacking endogenous protectin DX synthesis, demonstrated increased postoperative leukocyte levels. Preoperative intravenous administration of a docosahexaenoic acid-rich lipid emulsion reduced postoperative leukocyte infiltration in wild-type mice but failed in 12/15-lipoxygenase-deficient mice mice. Protectin DX application reduced leukocyte influx and rescued 12/15-lipoxygenase-deficient mice mice from postoperative ileus. In conclusion, our results show that 12/15-lipoxygenase mediates postoperative ileus resolution via production of proresolving docosahexaenoic acid-derived protectin DX. Perioperative, parenteral protectin DX or docosahexaenoic acid supplementation, as well as modulation of the 12/15-lipoxygenase pathway, may be instrumental in prevention of postoperative ileus.},
author = {Stein, Kathy and Stoffels, Melissa and Lysson, Mariola and Schneiker, Bianca and Dewald, Oliver and Krönke, Gerhard and Kalff, Joerg C. and Wehner, Sven},
doi = {10.1189/jlb.3HI0515-189R},
faupublication = {yes},
journal = {Journal of Leukocyte Biology},
note = {EVALuna2:13152},
pages = {231-9},
peerreviewed = {Yes},
title = {{A} role for 12/15-lipoxygenase-derived proresolving mediators in postoperative ileus: protectin {DX}-regulated neutrophil extravasation},
volume = {99},
year = {2016}
}
@article{faucris.288830677,
abstract = {BACKGROUND: The goal of the study was to investigate patients' with systemic rheumatic diseases and healthcare professionals' experiences and preferences regarding self-sampling of capillary blood in rheumatology care.
METHODS: Patients performed a supervised and consecutive unsupervised capillary blood self-collection using an upper arm based device. Subsequently, patients (n = 15) and their attending health care professionals (n = 5) participated in an explorative, qualitative study using problem-centered, telephone interviews. Interview data were analyzed using structured qualitative content analysis.
RESULTS: Interviewed patients reported easy application and high usability. Patients and health care professionals alike reported time and cost savings, increased independence and flexibility, improved monitoring and reduction of risk of infection during Covid-19 as benefits. Reported drawbacks include limited blood volume, limited usability in case of functional restrictions, and environmental concerns. Older, immobile patients with long journeys to traditional blood collection sites and young patients with little time to spare for traditional blood collection appointments could be user groups, likely to benefit from self-sampling services.
CONCLUSIONS: At-home blood self-sampling could effectively complement current rheumatology telehealth care. Appropriateness and value of this service needs to be carefully discussed with patients on an individual basis.
TRIAL REGISTRATION: WHO International Clinical Trials Registry: DRKS00024925. Registered on 15/04/2021.},
author = {Muehlensiepen, Felix and May, Susann and Zarbl, Joshua and Vogt, Ekaterina and Boy, Katharina and Heinze, Martin and Böltz, Sebastian and Labinsky, Hannah and Bendzuck, Gerlinde and Korinth, Marianne and Elling-Audersch, Corinna and Vuillerme, Nicolas and Schett, Georg and Krönke, Gerhard and Knitza, Johannes},
doi = {10.1186/s12913-022-08787-5},
faupublication = {yes},
journal = {BMC Health Services Research},
note = {EVALuna2:520656},
peerreviewed = {Yes},
title = {{At}-home blood self-sampling in rheumatology: a qualitative study with patients and health care professionals.},
volume = {22},
year = {2022}
}
@article{faucris.206764878,
abstract = {Deficient clearance of apoptotic cells reportedly contributes to the etiopathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Based on this knowledge, we developed a highly specific and sensitive test for the detection of SLE autoantibodies (AAb) utilizing secondary NEcrotic cell (SNEC)-derived material as a substrate. The goal of the present study was to validate the use of SNEC as an appropriate antigen for the diagnosis of SLE in large cohort of patients. We confirmed the presence of apoptotically modified autoantigens on SNEC (dsDNA, high mobility group box 1 protein, apoptosis-associated chromatin modifications, e.g., histones H3-K27-me3; H2A/H4 AcK8,12,16; and H2B-AcK12). Anti-SNEC AAb were measured in the serum of 155 patients with SLE, 89 normal healthy donors (NHD), and 169 patients with other autoimmune connective tissue diseases employing SNEC-based indirect enzyme-linked immunosorbent assay (SNEC ELISA). We compared the test performance of SNEC ELISA with the routine diagnostic tests dsDNA Farr radioimmunoassay (RIA) and nucleosome-based ELISA (anti-dsDNA-NcX-ELISA). SNEC ELISA distinguished patients with SLE with a specificity of 98.9% and a sensitivity of 70.6% from NHD clearly surpassing RIA and anti-dsDNA-NcX-ELISA. In contrast to the other tests, SNEC ELISA significantly discriminated patients with SLE from patients with rheumatoid arthritis, primary anti-phospholipid syndrome, spondyloarthropathy, psoriatic arthritis, and systemic sclerosis. A positive test result in SNEC ELISA significantly correlated with serological variables and reflected the uptake of opsonized SNEC by neutrophils. This stresses the relevance of SNECs in the pathogenesis of SLE. We conclude that SNEC ELISA allows for the sensitive detection of pathologically relevant AAb, enabling its diagnostic usage. A positive SNEC test reflects the opsonization of cell remnants by AAb, the neutrophil recruitment to tissues, and the enhancement of local and systemic inflammatory responses.},
author = {Biermann, Mona and Boeltz, Sebastian and Pieterse, Elmar and Knopf, Jasmin and Rech, Jürgen and Bilyy, Rostyslav and Van Der Vlag, Johan and Tincani, Angela and Distler, Jörg and Krönke, Gerhard and Schett, Georg and Herrmann, Martin and Munoz, Luis Enrique},
doi = {10.3389/fimmu.2018.00989},
faupublication = {yes},
journal = {Frontiers in Immunology},
note = {EVALuna2:34144},
peerreviewed = {Yes},
title = {{Autoantibodies} {Recognizing} {Secondary} {NEcrotic} {Cells} {Promote} {Neutrophilic} {Phagocytosis} and {Identify} {Patients} {With} {Systemic} {Lupus} {Erythematosus}},
volume = {9},
year = {2018}
}
@inproceedings{faucris.276966811,
abstract = {
The segmentation network was trained using 541 HR-pQCT patient scans (RA, PsA, and OA patients with motion grades up to 3) as input and the corresponding expert segmentation of the second metacarpal bone as reference. To optimize the parameters of the network, the current prediction was compared with the expert segmentation using the Dice coefficient. Pre-processing steps included resizing, flipping of left hands, and intensity normalization. The architecture of the segmentation network is based on the 2D U-Net, which was pre-trained on ImageNet. The predictions were resized to the original resolution and converted to the scanner-specific data format as post-processing steps. The scanner then calculated the average bone-mineral density (D100) based on the scan and the corresponding network-generated segmentation. The scans were split into training, validation, and testing with ratios of 70%, 20%, and 10% respectively.
The bone segmentation using the neural network on the test set reached a Dice coefficient of 97.2%. A quantitative comparison of the network prediction (blue) and the expert annotation (red) is presented in figure 2. The deviation of the expert annotation from the bone contour is likely due to the shift of the scan when exceeding the specified maximum number of slices of the scanner. Since the neural network operates on a slice level, such deviations are implicitly accounted for.
The results of the vBMD analysis are summarized in figure 3. Significant Pearson correlation with 0.999 (p<.001) was achieved for the D100 on the test set. Still, a slight offset is present in the predictions, which might lead to underestimating the D100. However, this could be eliminated in a calibration step beforehand.
Neural networks can be used to generate accurate segmentations of the MCP2 head even with erosions present and can be integrated into the clinical workflow with a performance on par with expert annotators and save time through the automation of the annotation process.
<}, author = {Folle, Lukas and Meinderink, Timo and Simon, David and Liphardt, Anna-Maria and Thies, Mareike and Krönke, Gerhard and Schett, Georg and Kleyer, Arnd and Maier, Andreas}, booktitle = {23}, date = {2022-06-12/2022-06-17}, editor = {Bert van Rietbergen, Harry van Lenthe, Quentin Grimal}, faupublication = {yes}, keywords = {deep learning, bone imaging, segmentation}, pages = {O55}, peerreviewed = {Yes}, series = {International Workshop on quantitative musculoskeletal imaging (QMSKI)}, title = {{Automated} {Bone} {Density} {Measurements} using {Deep} {Learning}}, venue = {Nordwijk}, volume = {23}, year = {2022} } @article{faucris.245487670, abstract = {Objectives: Autophagy is a homeostatic process to recycle dispensable and damaged cell organelles. Dysregulation of autophagic pathways has recently been implicated in the pathogenesis of various diseases. Here, we investigated the role of autophagy during joint destruction in arthritis. Methods: Autophagy in osteoclasts was analysed in vitro and ex vivo by transmission electron microscopy, Western blotting and immunohistochemistry for Beclin1 and Atg7. Small molecule inhibitors, LysMCre-mediated knockout of Atg7 and lentiviral overexpression of Beclin1 were used to modulate autophagy in vitro and in vivo. Osteoclast differentiation markers were quantified by realtime PCR. The extent of bone and cartilage destruction was analysed in human tumour necrosis factor α transgenic (hTNFα tg) mice after adoptive transfer with myeloid specific Atg7-deficient bone marrow. Results: Autophagy was activated in osteoclasts of human rheumatoid arthritis (RA) showing increased expression of Beclin1 and Atg7. TNFα potently induced the expression of autophagy-related genes and activated autophagy in vitro and in vivo. Activation of autophagy by overexpression of Beclin1-induced osteoclastogenesis and enhanced the resorptive capacity of cultured osteoclasts, whereas pharmacologic or genetic inactivation of autophagy prevented osteoclast differentiation. Arthritic hTNFα tg mice transplanted with Atg7fl/fl×LysMCre+ bone marrow cells (BMC) showed reduced numbers of osteoclasts and were protected from TNFα-induced bone erosion, proteoglycan loss and chondrocyte death. Conclusions: These findings demonstrate that autophagy is activated in RA in a TNFα-dependent manner and regulates osteoclast differentiation and bone resorption. We thus provide evidence for a central role of autophagy in joint destruction in RA.}, author = {Lin, Neng-Yu and Beyer, Christian and Gießl, Andreas and Kireva, Trayana and Scholtysek, Carina and Uderhardt, Stefan and Munoz, Luis Enrique and Dees, Clara and Distler, Alfiya and Wirtz, Stefan and Krönke, Gerhard and Spencer, Brian and Distler, Oliver and Schett, Georg and Distler, Jörg}, doi = {10.1136/annrheumdis-2012-201671}, faupublication = {yes}, journal = {Annals of the Rheumatic Diseases}, note = {CRIS-Team Scopus Importer:2020-11-20}, pages = {761-768}, peerreviewed = {Yes}, title = {{Autophagy} regulates {TNFα}-mediated joint destruction in experimental arthritis}, volume = {72}, year = {2013} } @inproceedings{faucris.287478378, address = {HOBOKEN}, author = {Kemenes, Stephan and Hartmann, Fabian and Tascilar, Koray and Simon, David and Bayat, Sara and Krönke, Gerhard and Mendez, Larissa Valor and Schuster, Louis and Liphardt, Anna-Maria and Schett, Georg and Kleyer, Arnd}, booktitle = {ARTHRITIS & RHEUMATOLOGY}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2023-01-13}, pages = {3931-3933}, peerreviewed = {unknown}, publisher = {WILEY}, title = {{Baricitinib} {Improves} {Bone} {Biomechanical} {Properties} in {Rheumatoid} {Arthritis} ({RA}) - {Results} of a {Prospective} {Interventional} {Study}}, year = {2022} } @inproceedings{faucris.284517024, address = {LONDON}, author = {Kemenes, S. and Bayat, Sara and Simon, David and Krönke, Gerhard and Bohr, D. and Valor, L. and Hartmann, F. and Schuster, Louis and Tascilar, Koray and Schett, Georg and Kleyer, Arnd}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, doi = {10.1136/annrheumdis-2022-eular.476}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2022-11-04}, pages = {1320-1321}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{BARICITINIB} {LEADS} {TO} {RAPID} {AND} {PERSISTENT} {RESOLUTION} {OF} {SYNOVITIS} {AS} {MEASURED} {BY} {HAND} {MRI} {IN} {PATIENTS} {WITH} {ACTIVE} {RHEUMATOID} {ARTHRITIS} ({RA}) {FAILING} {CS}/{BDMARD} {THERAPY}}, year = {2022} } @article{faucris.245488668, abstract = {Objective: To study whether Dickkopf (DKK)-1, an inhibitor of wingless (Wnt) signalling, is involved in the fusion of sacroiliac joints. Methods: Mice transgenic for tumour necrosis factor (TNFtg mice), which develop bilateral sacroiliitis, were treated with vehicle, anti-TNF antibody or anti-DKK1 antibody. Sacroiliac joints were analysed for histological signs of inflammation, bone erosion, osteoclast formation and ankylosis. Moreover, expression of collagen type X, β-catenin and DKK-1 was assessed by immunohistochemistry. Results: There were no signs of spontaneous ankylosis of the sacroiliac joints in TNFtg mice. TNF blockade effectively reduced inflammation, bone erosion and osteoclast numbers in the sacroiliac joints, but did not lead to ankylosis. Blockade of DKK1 had no effect on inflammatory signs of sacroiliitis, but significantly reduced bone erosions and osteoclast counts. Moreover, DKK1 blockade promoted expression of collagen type X, the formation of hypertrophic chondrocytes and ankylosis of sacroiliac joints. Conclusion: DKK1 influences inflammatory remodelling of sacroiliac joints by prevention of joint ankylosis. This may indicate an important role of the Wnt signalling pathway in the structural bone changes of axial joint disease. Although this model does not reflect the entire spectrum of ankylosing spondylitis in humans, it helps to explain the pathophysiological processes of sacroiliac joint ankylosis, which is a hallmark of the spondyloarthritides.}, author = {Uderhardt, Stefan and Diarra, Danielle and Katzenbeisser, J. and David, Jean-Pierre and Zwerina, J. and Richards, W. and Krönke, Gerhard and Schett, Georg}, doi = {10.1136/ard.2008.102046}, faupublication = {yes}, journal = {Annals of the Rheumatic Diseases}, note = {CRIS-Team Scopus Importer:2020-11-20}, pages = {592-597}, peerreviewed = {Yes}, title = {{Blockade} of {Dickkopf} ({DKK})-1 induces fusion of sacroiliac joints}, volume = {69}, year = {2010} } @inproceedings{faucris.287482636, address = {HOBOKEN}, author = {Schett, Georg and Böltz, Sebastian and Müller, Fabian and Kleyer, Arnd and Völkl, Simon and Aigner, Michael and Gary, Regina and Kretschmann, Sascha and Simon, David and Kharboutli, Soraya and Mougiakakos, Dimitrios and Krönke, Gerhard and Mackensen, Andreas}, booktitle = {ARTHRITIS & RHEUMATOLOGY}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2023-01-13}, pages = {3284-3285}, peerreviewed = {unknown}, publisher = {WILEY}, title = {{CAR} {T} {Cell} {Treatment} of {Refractory} {Systemic} {Lupus} {Erythematosus}}, year = {2022} } @inproceedings{faucris.284521020, address = {LONDON}, author = {Schett, Georg and Böltz, Sebastian and Müller, Fabian and Kleyer, Arnd and Völkl, Simon and Aigner, Michael and Gary, Regina and Kretschmann, S. and Simon, David and Kharboutli, Soraya and Mougiakakos, D. and Krönke, Gerhard and Andreas, M.}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, doi = {10.1136/annrheumdis-2022-eular.1120}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2022-11-04}, pages = {185-185}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{CAR}-{T} {CELL} {TREATMENT} {OF} {REFRACTORY} {SYSTEMIC} {LUPUS} {ERYTHEMATOSUS}- {SAFETY} {AND} {PRELIMINARY} {EFFICACY} {DATA} {FROM} {THE} {FIRST} {FOUR} {PATIENTS}}, year = {2022} } @inproceedings{faucris.209039052, author = {Renner, Nina and Kleyer, Arnd and Krönke, Gerhard and Simon, David and Rech, Jürgen and Schett, Georg and Welsch, G. and Pachowsky, Milena}, doi = {10.1136/annrheumdis-2018-eular.2849}, faupublication = {yes}, note = {EVALuna2:35002}, pages = {1181-1181}, peerreviewed = {Yes}, title = {{CARTILAGE} {DAMAGE} {QUANTITATIVELY} {ASSESSED} {BY} {MRI} {USING} {T2} {MAPPING} {IN} {CCP}-{POSITIVE} {RA} {PATIENTS}}, volume = {77}, year = {2018} } @inproceedings{faucris.235494187, author = {Puchner, A. and Saferding, V. and Bonelli, M. and Leiss, H. and Pfeifle, René and Krönke, Gerhard and Smolen, J. and Redlich, K. and Blueml, S.}, doi = {10.1136/annrheumdis-2018-eular.7320}, faupublication = {yes}, note = {EVALuna2:213263}, pages = {256-256}, peerreviewed = {Yes}, title = {{CD11C}+{DENDTRITIC} {CELLS} {IN} {INFLAMMATORY} {ARTHRITIS}}, volume = {77}, year = {2018} } @article{faucris.293805153, author = {Müller, Fabian and Böltz, Sebastian and Knitza, Johannes and Aigner, Michael and Völkl, Simon and Kharboutli, Soraya and Reimann, Hannah and Taubmann, Jule and Kretschmann, Sascha and Rösler, Wolf and Manger, Bernhard and Wacker, Jochen and Mougiakakos, Dimitrios and Jabari, Samir and Schröder, Rolf and Uder, Michael and Roemer, Frank and Krönke, Gerhard and Mackensen, Andreas and Schett, Georg}, doi = {10.1016/S0140-6736(23)00023-5}, faupublication = {yes}, journal = {Lancet}, note = {CRIS-Team Scopus Importer:2023-03-24}, pages = {815-818}, peerreviewed = {Yes}, title = {{CD19}-targeted {CAR} {T} cells in refractory antisynthetase syndrome}, volume = {401}, year = {2023} } @article{faucris.262967721, author = {Mougiakakos, Dimitrios and Krönke, Gerhard and Völkl, Simon and Kretschmann, Sascha and Aigner, Michael and Kharboutli, Soraya and Böltz, Sebastian and Manger, Bernhard and Mackensen, Andreas and Schett, Georg}, doi = {10.1056/NEJMc2107725}, faupublication = {yes}, journal = {New England Journal of Medicine}, note = {CRIS-Team Scopus Importer:2021-08-20}, pages = {567-569}, peerreviewed = {Yes}, title = {{CD19}-targeted {CAR} {T} cells in refractory systemic lupus erythematosus}, volume = {385}, year = {2021} } @inproceedings{faucris.291595199, address = {WASHINGTON}, author = {Müller, Fabian and Völkl, Simon and Mougiakakos, Dimitrios and Böltz, Sebastian and Aigner, Michael and Gary, Regina and Kretschmann, Sascha and Kharboutli, Soraya and Kleyer, Arnd and Simon, David and Rösler, Wolf and Habenicht, Katharina Marie and Winkler, Thomas and Krönke, Gerhard and Schett, Georg and Mackensen, Andreas}, booktitle = {BLOOD}, doi = {10.1182/blood-2022-165077}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2023-03-10}, pages = {4562-4563}, peerreviewed = {unknown}, publisher = {AMER SOC HEMATOLOGY}, title = {{CD19}-{Targeted} {CAR}-{T} {Cells} in {Refractory} {Systemic} {Lupus} {Erythematosus}: {Safety}, {Efficacy}, and {Mechanistic} {Insights} from the {First} {Five} {Patients}}, venue = {New Orleans, LA}, year = {2022} } @article{faucris.299984487, author = {Reimann, Hannah and Kremer, Anita and Blumenberg, Viktoria and Schmidt, Katja and Aigner, Michael and Jacobs, Benedikt and Eisenhauer, Nina and Kämpf, Alina and Rösler, Wolf and Kharboutli, Soraya and Mougiakakos, Dimitrios and Lang, Vanessa and Lischer, Christopher and Irrgang, Pascal and Leppkes, Moritz and Vera González, Julio and Krönke, Gerhard and Kremer, Andreas and Tenbusch, Matthias and Bruns, Heiko and Harrer, Thomas and Müller, Fabian and Schett, Georg and Mackensen, Andreas and Subklewe, Marion and Völkl, Simon}, doi = {10.1182/bloodadvances.2022007806}, faupublication = {yes}, journal = {Blood Advances}, note = {EVALuna2:512817}, pages = {2066-2069}, peerreviewed = {Yes}, title = {{Cellular} and humoral immune responses to {SARS}-{CoV}-2 vaccination in patients after {CD19}.{CAR} {T}-cell therapy}, volume = {7}, year = {2023} } @article{faucris.236670661, abstract = {Systemic immune dysregulation contributes to the development of neuropsychiatric and neurodegenerative diseases. The precise effect of chronic peripheral immune stimulation on myeloid cells across anatomical brain regions is unclear. Here, we demonstrate brain-region-specific differences in myeloid responses induced by chronic peripheral inflammation. This shift in the myeloid compartment is associated with the appearance of an inflammatory myeloid subpopulation in the cortex, striatum, and thalamus accompanied by regional transcriptomic fingerprints that include induction of chemokines, complement factors, and endothelial adhesion molecules. In contrast, myeloid immune responses within the hippocampus and cerebellum are subtle or absent. Treatment with the anti-tumor necrosis factor α (anti-TNF-α) antibody infliximab ablates the region-specific inflammatory response. A region-specific myeloid cell response to chronic peripheral inflammation is observed in postmortem brains from individuals with rheumatoid arthritis. Our data suggest that chronic peripheral inflammation has heterogeneous effects on the brain, as evidenced by the spectrum of myeloid cell responses observed across brain regions.}, author = {Süß, Patrick and Hoffmann, Alana and Rothe, Tobias and Ouyang, Zhengyu and Baum, Wolfgang and Staszewski, Ori and Schett, Georg and Prinz, Marco and Krönke, Gerhard and Glass, Christopher K. and Winkler, Jürgen and Schlachetzki, Johannes}, doi = {10.1016/j.celrep.2020.02.109}, faupublication = {yes}, journal = {Cell Reports}, keywords = {blood-brain barrier; brain regions; chronic peripheral inflammation; CNS myeloid cells; human rheumatoid arthritis; microglia}, note = {CRIS-Team Scopus Importer:2020-03-31}, pages = {4082-4095.e6}, peerreviewed = {Yes}, title = {{Chronic} {Peripheral} {Inflammation} {Causes} a {Region}-{Specific} {Myeloid} {Response} in the {Central} {Nervous} {System}}, volume = {30}, year = {2020} } @inproceedings{faucris.276622806, abstract = {Background: While MRI evaluation of joints has been primarily used to quantify inflammation at a cross-sectional and longitudinal level, less is known about the potential of MRI in distinguishing different patterns of inflammation in the various forms of arthritis.Objectives: To evaluate (i) whether deep learning using neural networks can be trained to distinguish between seropositive rheumatoid arthritis (RA+), seronegative RA (RA-), and psoriatic arthritis (PsA) based on structural inflammatory patterns on hand magnetic resonance imaging and (ii) to assess if psoriasis patients with subclinical inflammation fit into such patterns.
Methods: ResNet 3D [1] neural networks were trained to
distinguish (i) RA+ vs. PsA, (ii) RA- vs. PsA and (iii) RA+ vs. RA- with
respect to hand MRI data. Diagnosis of patients was determined using
the following guidelines: ACR/EULAR 2010 [2] for RA and CASPAR [3] for
PsA. Results from T1 coronal, T2 coronal, T1 coronal and axial fat
suppressed contrast-enhanced (CE) and T2 fat suppressed axial sequences
were used. The performance of such trained networks was analyzed by the
area-under-the-receiver-operating-characteristic curve (AUROC) with and
without imputation of demographic and clinical parameters (
Figure 1A
). Additionally, the trained networks were applied to psoriasis patients without clinical signs of PsA.
Results: MRI scans from 649 patients (135 RA-, 190 RA+, 177 PsA, 147 psoriasis) were included (
Table 1
). The AUROC for differentiation between disease entities was 75%
(SD 3%) for RA+ vs. PsA, 74% (SD 8%) for RA- vs. PsA, and 67% (6%) for
RA+ vs. RA-. All MRI sequences were relevant for classification,
however, when deleting CE sequences, the loss of performance was only
marginal. The addition of patient-specific data to the networks did not
provide significant improvements. Increasing amounts of training data
demonstrated improved performance of the networks (
Figure 1B
). Psoriasis patients were mostly assigned to PsA by the neural
networks, suggesting that PsA-like MRI pattern may be present early in
the course of psoriatic disease.
Conclusion: Deep learning can be successfully applied to differentiate MRI inflammatory patterns related to RA+, RA-, and PsA. Early changes in psoriasis patients can be recognized by neural networks and are characterized by a pattern that allowed the networks to classify them as PsA.
<}, author = {Folle, Lukas and Bayat, Sara and Kleyer, Arnd and Fagni, Filippo and Kapsner, Lorenz and Schlereth, Maja and Meinderink, Timo and Breininger, Katharina and Tascilar, Koray and Krönke, Gerhard and Uder, Michael and Sticherling, Michael and Bickelhaupt, Sebastian and Maier, Andreas and Roemer, Frank and Simon, David and Schett, Georg}, booktitle = {Supplement 1}, date = {2022-06-01/2022-06-04}, doi = {10.1136/annrheumdis-2022-eular.966}, editor = {Prof Josef Smolen}, faupublication = {yes}, keywords = {Rheumatoid arthritis, deep learning, neural networks}, pages = {194}, peerreviewed = {Yes}, publisher = {BMJ Publishing Group}, series = {Annals of Rheumatic Disease}, title = {{CLASSIFICATION} {OF} {PSORIATIC} {ARTHRITIS}, {SERONEGATIVE} {RHEUMATOID} {ARTHRITIS}, {AND} {SEROPOSITIVE} {RHEUMATOID} {ARTHRITIS} {USING} {DEEP} {LEARNING} {ON} {MAGNETIC} {RESONANCE} {IMAGING}}, url = {https://ard.bmj.com/content/81/Suppl{\_}1/194.2}, venue = {Kopenhagen}, volume = {81}, year = {2022} } @article{faucris.111097184, author = {Stock, Michael and Distler, A. and Distler, Jörg and Beyer, Christian and Ruiz-Heiland, G. and Ipseiz, Natacha and Seeling, Michaela and Krönke, Gerhard and Nimmerjahn, Falk and Schett, Georg}, doi = {10.1016/j.joca.2016.11.003}, faupublication = {yes}, journal = {Osteoarthritis and Cartilage}, note = {EVALuna2:13371}, peerreviewed = {No}, title = {{Corrigendum} to "{Fc}-gamma receptors are not involved in cartilage damage during experimental osteoarthritis" [{Osteoarthritis} {Cartilage} 23 (2015) 1221-1225]}, year = {2016} } @article{faucris.270874176, author = {Folle, Lukas and Simon, David and Tascilar, Koray and Krönke, Gerhard and Liphardt, Anna-Maria and Maier, Andreas and Schett, Georg and Kleyer, Arnd}, doi = {10.3389/fmed.2022.850552}, faupublication = {yes}, journal = {Frontiers in Medicine}, keywords = {artificial intelligence; arthritis; joint; bone; deep learning}, peerreviewed = {Yes}, title = {{Deep} {Learning}-{Based} {Classification} of {Inflammatory} {Arthritis} by {Identification} of {Joint} {Shape} {Patterns}—{How} {Neural} {Networks} {Can} {Tell} {Us} {Where} to “{Deep} {Dive}” {Clinically}}, volume = {9}, year = {2022} } @article{faucris.257666719, abstract = {Arthritis patients develop hand bone loss, which leads to destruction and functional impairment of the affected joints. High resolution peripheral quantitative computed tomography (HR-pQCT) allows the quantification of volumetric bone mineral density (vBMD) and bone microstructure in vivo with an isotropic voxel size of 82 micrometres. However, image-processing to obtain bone characteristics is a time-consuming process as it requires semi-automatic segmentation of the bone. In this work, a fully automatic vBMD measurement pipeline for the metacarpal (MC) bone using deep learning methods is introduced. Based on a dataset of HR-pQCT volumes with MC measurements for 541 patients with arthritis, a segmentation network is trained. The best network achieves an intersection over union as high as 0.94 and a Dice similarity coefficient of 0.97 while taking only 33 s to process a whole patient yielding a speedup between 2.5 and 4.0 for the whole workflow. Strong correlation between the vBMD measurements of the expert and of the automatic pipeline are achieved for the average bone density with 0.999 (Pearson) and 0.996 (Spearman’s rank) with $$p < 0.001$$for all correlations. A qualitative assessment of the network predictions and the manual annotations yields a 65.9% probability that the expert favors the network predictions. Further, the steps to integrate the pipeline into the clinical workflow are shown. In order to make these workflow improvements available to others, we openly share the code of this work.}, author = {Folle, Lukas and Meinderink, Timo and Simon, David and Liphardt, Anna-Maria and Krönke, Gerhard and Schett, Georg and Kleyer, Arnd and Maier, Andreas}, doi = {10.1038/s41598-021-89111-9}, faupublication = {yes}, journal = {Scientific Reports}, keywords = {Rheumatic diseases, segmentation, deep learning}, pages = {9697}, peerreviewed = {Yes}, title = {{Deep} learning methods allow fully automated segmentation of metacarpal bones to quantify volumetric bone mineral density}, volume = {11}, year = {2021} } @article{faucris.111332364, abstract = {Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) result in severe joint destruction and functional disability if left untreated. We aim to develop tools that help patients with RA and PsA to understand and experience the impact of inflammatory joint disease on the integrity of their (juxta-articular) bone and increase adherence to medical treatment. In this study, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to develop 3D prototypes of patients' finger joints.HR-pQCT (XtremeCT, Scanco) measurements were performed in healthy individuals and patients with inflammatory joint disease, followed by a 3D print using the objet30 printer. Healthy participants (n = 10), and patients (n = 15 with RA and 15 with PsA) underwent a detailed, standardized interview with demonstration of printed joints.Utilizing HR-pQCT images of metacarpophalangeal (MCP) heads, high quality and exact 3D prints as prototypes were created. Erosions in different sizes and the trabecular network printed in detail were visualized, demonstrating structural reduction in arthritic vs. healthy bone. After demonstration of 3D prints (healthy vs. erosive joint, visual and haptic) 26/39 (66%) participants (including healthy volunteers) were deeply affected, often quoting "shock". Of the patients with RA and PsA, 13/15 (86%) and 11/15 (73%), respectively, stated that they would rethink their attitude to medication adherence. More importantly, 21/24 patients with RA or PsA (87.5%) expressed that they would have wished to see such 3D prints during their first disease-specific conversations.Using arthro-haptic 3D printed prototypes of joints may help to better understand the impact of inflammatory arthritides on bone integrity and long-term damage.}, author = {Kleyer, Arnd and Beyer, Laura and Simon, Christoph and Stemmler, Fabian and Englbrecht, Matthias and Beyer, Christian and Rech, Juergen and Manger, Bernhard and Krönke, Gerhard and Schett, Georg and Hueber, Axel}, doi = {10.1186/s13075-017-1234-z}, faupublication = {yes}, journal = {Arthritis Research & Therapy}, note = {EVALuna2:13404}, pages = {34}, peerreviewed = {Yes}, title = {{Development} of three-dimensional prints of arthritic joints for supporting patients' awareness to structural damage}, volume = {19}, year = {2017} } @inproceedings{faucris.259167152, author = {Folle, Lukas and Liu, Chang and Simon, David and Meinderink, Timo and Liphardt, Anna-Maria and Krönke, Gerhard and Schett, Georg and Maier, Andreas and Kleyer, Arnd}, booktitle = {Annals of the Rheumatic Diseases 2021}, date = {2021-06-02/2021-06-05}, doi = {10.1136/annrheumdis-2021-eular.383}, faupublication = {yes}, keywords = {Deep Learning; Rheumatoid arthritis; psoriatic arthritis}, pages = {86-87}, peerreviewed = {Yes}, publisher = {BMJ Publishing group}, series = {Annals of the Rheumatic Diseases}, title = {{Differential} diagnosis of {RA} and {PsA} using neural networks on {3D} bone shape of finger joints}, url = {https://ard.bmj.com/content/80/Suppl{\_}1/86}, venue = {Paris}, volume = {80}, year = {2021} } @article{faucris.284138083, abstract = {Patient-reported outcomes (PRO) represent a cornerstone in the management of patients with rheumatoid arthritis (RA). However, PRO are currently recorded mainly on paper and only during on-site appointments. Electronic PRO (ePRO) enable continuous remote monitoring and could improve shared decision-making (SDM) and implementation of a treat-to-target (T2T) approach. This study aims to investigate patient and physician experiences, perceived drawbacks and benefits of using an ePRO web-app (ABATON RA) to digitally support SDM and T2T. A qualitative study embedded in a multicenter randomized controlled trial (RCT) consisting of interviews with RA patients and physicians that were subsequently analyzed using deductive-inductive qualitative content analysis. Between August 2021 and May 2022, interviews with ten RA patients and five physicians were completed. Three key themes emerged in the analysis: (i) App user experiences; (ii) perceived drawbacks of app-supported rheumatology care; and (iii) perceived benefits of app-supported rheumatology care. Continuous ePRO collection and a high level of standardization strained some RA patients. Certain ePRO seemed outdated and were hard to understand. Patients and physicians appreciated having an improved overview of disease activity, capturing disease flares and continuous remote monitoring. Paper- and time-saving were associated with using ePRO. Physicians feared to become too focused on ePRO data, stressed the lack of ePRO monitoring reimbursement and app interoperability. For RA patients and physicians, benefits seemed to outweigh observed drawbacks of the digitally supported SDM using ePRO. The software was easy to use and could lead to a better understanding of the individual disease course, resource allocation and treatment of rheumatoid arthritis.}, author = {Muehlensiepen, Felix and May, Susann and Hadaschik, Katharina and Vuillerme, Nicolas and Heinze, Martin and Grahammer, Manuel and Labinsky, Hannah and Böltz, Sebastian and Detert, Jacqueline and Petersen, Jana and Krönke, Gerhard and Schett, Georg and Knitza, Johannes}, doi = {10.1007/s00296-022-05224-y}, faupublication = {yes}, journal = {Rheumatology International}, keywords = {ePRO; Health Services Research; mHealth; Qualitative research; Rheumatology; SDM}, note = {CRIS-Team Scopus Importer:2022-10-28}, peerreviewed = {Yes}, title = {{Digitally} supported shared decision-making and treat-to-target in rheumatology: a qualitative study embedded in a multicenter randomized controlled trial}, year = {2022} } @article{faucris.280960939, author = {Yalcin Mutlu, Melek and Wacker, Jochen and Tascilar, Koray and Taubmann, Jule and Manger, Bernhard and Krönke, Gerhard and Schett, Georg and Simon, David}, doi = {10.1093/rheumatology/keac393}, faupublication = {yes}, journal = {Rheumatology}, note = {CRIS-Team WoS Importer:2022-08-26}, peerreviewed = {No}, title = {{Effective} and safe treatment of anti-{CD38} therapy in systemic lupus erythematosus-associated refractory cerebral vasculitis induces immune tolerance}, year = {2022} } @article{faucris.286183521, abstract = {BACKGROUND: Baricitinib (BARI) is approved for the treatment of rheumatoid arthritis (RA) after failure of conventional synthetic and biologic disease modifying anti-rheumatic drugs (cs/bDMARDs) in combination with methotrexate (MTX) or as monotherapy. However, real-world data are scarce regarding efficacy and drug persistence for BARI monotherapy (BARI-mono) versus its combination with MTX (BARI-combo). OBJECTIVE: To evaluate efficacy and drug persistence of BARImono compared with BARI-combo in routine clinical practice METHODS: Patients with RA who were switched to BARI were included in a prospective, monocentric cohort. Demographics, clinical outcomes, adverse events and medication were prospectively recorded every 3 months. Clinical efficacy was measured by DAS-28 ESR while drug persistence was measured as the time on drug. We estimated least-square mean DAS-28 scores over time using linear mixed effects models including time-group interactions. Kaplan-Meier method was used to estimate BARI survival and probability of remission over time. RESULTS: 139 patients (98 women; aged 58.4 (12.8) years; mean disease duration of 9.7 years) were included between 2017 and 2021. 46 patients received BARI-combo, 93 patients received BARI-mono. Mean DAS-28 ESR were not significantly but only numerically different between both groups at baseline and multiple timepoints over follow-up. DAS-28 ESR remission was attained at least once upto 48 weeks in 62% and 51% patients in BARI-combo versus BARI-mono group (log-rank p=0.64). Drug persistence was high (69 vs 67% at 48 weeks and 62% vs 56% at 96 weeks) and similar in BARI-combo-treated and BARI-mono-treated patients. b/ts DMARD naïve patients had lower mean DAS-28 scores over the follow-up and attained DAS-28 ESR remission earlier than patients with inadequate response to b/ts DMARDs (p=0.11). BARI was discontinued in 11/139 patients (7.9%) due to adverse effects. CONCLUSION: In routine practice, BARI is effective as monotherapy in case of MTX intolerance with overall high drug persistence rates. No new safety signals were observed.}, author = {Bayat, Sara and Tascilar, Koray and Bohr, Daniela and Krönke, Gerhard and Simon, David and Knitza, Johannes and Schett, Georg and Kleyer, Arnd and Hartmann, Fabian}, doi = {10.1136/rmdopen-2022-002674}, faupublication = {yes}, journal = {RMD Open}, keywords = {Baricitinib; Combination treatment; Drug survival; Remission; Rheumatoid Arthritis}, note = {CRIS-Team Scopus Importer:2022-12-02}, peerreviewed = {Yes}, title = {{Efficacy} and drug persistence of baricitinib monotherapy is similar to combination therapy in patients with active {RA}: a prospective observational study}, volume = {8}, year = {2022} } @article{faucris.266787790, abstract = {Objectives To test whether patients with immune-mediated inflammatory disease (IMIDs), who did not respond to two doses of the SARS-CoV-2 vaccine, develop protective immunity, if a third vaccine dose is administered. Methods Patients with IMID who failed to seroconvert after two doses of SARS-CoV-2 vaccine were subjected to a third vaccination with either mRNA or vector-based vaccines. Anti-SARS-CoV-2 IgG, neutralising activity and T cell responses were assessed at baseline and 3 weeks after revaccination and also evaluated seprarately in rituximab (RTX) and non-RTX exposed patients. Results 66 non-responders were recruited, 33 treated with RTX, and 33 non-exposed to RTX. Overall, 49.2% patients seroconverted and 50.0% developed neutralising antibody activity. Seroconversion (78.8% vs 18.2%) and neutralising activity (80.0% vs 21.9%) was higher in non-RTX than RTX-treated patients with IMID, respectively. Humoral vaccination responses were not different among patients showing positive (59.3%) or negative (49.7%) T cell responses at baseline. Patients remaining on mRNA-based vaccines showed similar vaccination responses compared with those switching to vector-based vaccines. Conclusions Overall, these data strongly argue in favor of a third vaccination in patients with IMID lacking response to standard vaccination irrespective of their B cell status.}, author = {Simon, David and Tascilar, Koray and Fagni, Filippo and Schmidt, Katja and Krönke, Gerhard and Kleyer, Arnd and Ramming, Andreas and Schönau, Verena and Bohr, Daniela and Knitza, Johannes and Harrer, Thomas and Manger, Karin and Manger, Bernhard and Schett, Georg}, doi = {10.1136/annrheumdis-2021-221554}, faupublication = {yes}, journal = {Annals of the Rheumatic Diseases}, note = {CRIS-Team WoS Importer:2021-12-03}, peerreviewed = {Yes}, title = {{Efficacy} and safety of {SARS}-{CoV}-2 revaccination in non-responders with immune-mediated inflammatory disease}, year = {2021} } @article{faucris.233229538, abstract = {Multinucleated giant cells (MGCs) are implicated in many diseases including schistosomiasis, sarcoidosis and arthritis. MGC generation is energy intensive to enforce membrane fusion and cytoplasmic expansion. Using receptor activator of nuclear factor kappa-Β ligand (RANKL) induced osteoclastogenesis to model MGC formation, here we report RANKL cellular programming requires extracellular arginine. Systemic arginine restriction improves outcome in multiple murine arthritis models and its removal induces preosteoclast metabolic quiescence, associated with impaired tricarboxylic acid (TCA) cycle function and metabolite induction. Effects of arginine deprivation on osteoclastogenesis are independent of mTORC1 activity or global transcriptional and translational inhibition. Arginine scarcity also dampens generation of IL-4 induced MGCs. Strikingly, in extracellular arginine absence, both cell types display flexibility as their formation can be restored with select arginine precursors. These data establish how environmental amino acids control the metabolic fate of polykaryons and suggest metabolic ways to manipulate MGC-associated pathologies and bone remodelling.}, author = {Brunner, Julia S. and Vulliard, Loan and Hofmann, Melanie and Kieler, Markus and Lercher, Alexander and Vogel, Andrea and Russier, Marion and Brüggenthies, Johanna B. and Kerndl, Martina and Saferding, Victoria and Niederreiter, Birgit and Junza, Alexandra and Frauenstein, Annika and Scholtysek, Carina and Mikami, Yohei and Klavins, Kristaps and Krönke, Gerhard and Bergthaler, Andreas and O’Shea, John J. and Weichhart, Thomas and Meissner, Felix and Smolen, Josef S. and Cheng, Paul and Yanes, Oscar and Menche, Jörg and Murray, Peter J. and Sharif, Omar and Blüml, Stephan and Schabbauer, Gernot}, doi = {10.1038/s41467-020-14285-1}, faupublication = {yes}, journal = {Nature Communications}, note = {CRIS-Team Scopus Importer:2020-02-04}, peerreviewed = {Yes}, title = {{Environmental} arginine controls multinuclear giant cell metabolism and formation}, volume = {11}, year = {2020} } @article{faucris.215699498, abstract = {Enzymatically oxidized phospholipids (eoxPLs) are formed through regulated processes by which eicosanoids or prostaglandins are attached to phospholipids (PLs) in immune cells. These eoxPLs comprise structurally diverse families of biomolecules with potent bioactivities, and they have important immunoregulatory roles in both health and disease. The formation of oxPLs through enzymatic pathways and their signaling capabilities are emerging concepts. This paradigm is changing our understanding of eicosanoid, prostaglandin, and PL biology in health and disease. eoxPLs have roles in cellular events such as ferroptosis, apoptosis, and blood clotting and diseases such as arthritis, diabetes, and cardiovascular disease. They are increasingly recognized as endogenous bioactive mediators and potential targets for drug development. This review will describe recent evidence that places eoxPLs and their biosynthetic pathways center stage in immunoregulation.}, author = {O'Donnell, Valerie B. and Aldrovandi, Maceler and Murphy, Robert C. and Krönke, Gerhard}, doi = {10.1126/scisignal.aau2293}, faupublication = {yes}, journal = {Science Signaling}, note = {CRIS-Team WoS Importer:2019-04-09}, peerreviewed = {Yes}, title = {{Enzymatically} oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death}, volume = {12}, year = {2019} } @article{faucris.110134244, abstract = {Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.}, author = {Uderhardt, Stefan and Ackermann, Jochen A. and Fillep, Tobias and Hammond, Victoria J. and Willeit, Johann and Santer, Peter and Mayr, Manuel and Biburger, Markus and Miller, Meike and Zellner, Katie R. and Stark, Konstantin and Zarbock, Alexander and Rossaint, Jan and Schubert, Irene and Mielenz, Dirk and Dietel, Barbara and Raaz-Schrauder, Dorette and Ay, Cihan and Gremmel, Thomas and Thaler, Johannes and Heim, Christian and Herrmann, Martin and Collins, Peter W. and Schabbauer, Gernot and Mackman, Nigel and Vöhringer, David and Nadler, Jerry L. and Lee, James J. and Massberg, Steffen and Rauh, Manfred and Kiechl, Stefan and Schett, Georg and O'Donnell, Valerie B. and Krönke, Gerhard}, doi = {10.1084/jem.20161070}, faupublication = {yes}, journal = {Journal of Experimental Medicine}, peerreviewed = {Yes}, title = {{Enzymatic} lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease.}, year = {2017} } @article{faucris.205185481, abstract = {Eosinophils were reported to serve as an essential component of the plasma cell niche within the bone marrow. As the potential contribution of eosinophils to humoral immunity has remained incompletely understood, we aimed to further characterize their role during antibody responses and to additionally investigate their role in autoimmune disease. Contrary to our expectations and the currently prevailing paradigm, we found that eosinophils are fully dispensable for the survival of murine bone marrow plasma cells and accordingly do not contribute to antibody production and autoantibody-mediated disease. Littermate wild type and eosinophil-deficient ΔdblGATA-1 animals showed similar numbers and frequencies of plasma cells and did not differ in steady state levels of immunoglobulins or their ability to raise antigen-specific antibody responses. Eosinophils were likewise dispensable for autoantibody production or autoantibody-induced disease in a mouse model of systemic lupus erythematosus. Our findings thus argue against a role of eosinophils during the maintenance of the plasma cell pool and challenge the hitherto postulated concept of an eosinophil-sustained bone marrow niche.}, author = {Haberland, Konrad and Ackermann, Jochen A. and Ipseiz, Natacha and Culemann, Stephan and Pracht, Katharina and Englbrecht, Matthias and Jäck, Hans-Martin and Schett, Georg and Schuh, Wolfgang and Krönke, Gerhard}, doi = {10.1002/eji.201747227}, faupublication = {yes}, journal = {European Journal of Immunology}, note = {EVALuna2:34472}, pages = {822-828}, peerreviewed = {Yes}, title = {{Eosinophils} are not essential for maintenance of murine plasma cells in the bone marrow}, volume = {48}, year = {2018} } @article{faucris.204711470, abstract = {BACKGROUND: Rheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation. METHODS: Postmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fcγ receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme β-galactoside α2,6-sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells. RESULTS: E2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fcγ receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody-producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG. CONCLUSIONS: E2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibody-producing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause.}, author = {Engdahl, Cecilia and Bondt, Albert and Harre, Ulrike and Raufer, Jasmin and Pfeifle, Rene and Camponeschi, Alessandro and Wuhrer, Manfred and Seeling, Michaela and Martensson, Inga-Lill and Nimmerjahn, Falk and Krönke, Gerhard and Scherer, Hans U. and Forsblad-D'Elia, Helena and Schett, Georg}, doi = {10.1186/s13075-018-1586-z}, faupublication = {yes}, journal = {Arthritis Research & Therapy}, note = {EVALuna2:34145}, peerreviewed = {Yes}, title = {{Estrogen} induces {St6gal1} expression and increases {IgG} sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women}, volume = {20}, year = {2018} } @inproceedings{faucris.209052265, author = {Engdahl, C. and Raufer, Jasmin and Harre, Ulrike and Bondt, A. and Pfeifle, René and Krönke, Gerhard and Scherer, H. U. and Forsblad, H. and Schett, Georg}, faupublication = {yes}, note = {EVALuna2:35033}, pages = {775-775}, peerreviewed = {Yes}, title = {{ESTROGEN} {INFLUENCES} {THE} {SIALYLATION} {PROFILE} {AND} {INFLAMMATORY} {PROPERTIES} {OF} {ANTIBODIES} - {A} {POTENTIAL} {EXPLANATION} {FOR} {THE} {SEX} {DIFFERENCES} {AND} {INCREASED} {RISK} {FOR} {RA} {IN} {POSTMENOPAUSAL} {WOMEN}}, volume = {76}, year = {2017} } @article{faucris.270415273, abstract = {In the bone marrow, B cells and bone-resorbing osteoclasts colocalize and form a specific microenvironment. How B cells functionally influence osteoclasts and bone architecture is poorly understood. Using genetically modified mice and high-throughput analyses, we demonstrate that prolonged HIF-1 alpha signaling in B cells leads to enhanced RANKL production and osteoclast formation. In addition, deletion of HIF-1 alpha in B cells prevents estrogen deficiency-induced bone loss in mice. Mechanistically, estrogen controls HIF-1 alpha protein stabilization through HSP70-mediated degradation in bone marrow B cells. The stabilization of HIF-1 alpha protein in HSP70-deficient bone marrow B cells promotes RANKL production and osteoclastogenesis. Induction of HSP70 expression by geranylgeranylacetone (GGA) administration alleviates ovariectomy-induced osteoporosis. Moreover, RANKL gene expression has a positive correlation with HIF1A expression in human B cells. In conclusion, HIF-1 alpha signaling in B cells is crucial for the control of osteoclastogenesis, and the HSP70/HIF-1 alpha axis may serve as a new therapeutic target for osteoporosis.}, author = {Meng, Xianyi and Lin, Zhen and Cao, Shan and Janowska, Iga and Sonomoto, Koshiro and Andreev, Darja and Knab, Katharina and Wen, Jinming and Knaup, Karl and Krönke, Gerhard and Rizzi, Marta and Schett, Georg and Bozec, Aline and Wiesener, Michael}, doi = {10.1038/s41413-022-00189-x}, faupublication = {yes}, journal = {Bone Research}, note = {CRIS-Team WoS Importer:2022-03-04}, peerreviewed = {Yes}, title = {{Estrogen}-mediated downregulation of {HIF}-1 alpha signaling in {B} lymphocytes influences postmenopausal bone loss}, volume = {10}, year = {2022} } @article{faucris.121335324, abstract = {OBJECTIVE\nFc-gamma receptors (FcγRs) have been shown to play a crucial role in cartilage degradation during experimental arthritis. Although most of their effect on cartilage degradation has been attributed to their potential to promote inflammation in the presence of immunoglobulins, activating FcγRs promote cartilage degeneration in antigen-induced arthritis (AIA) independently of the level of inflammation. This prompted us to investigate, whether FcγRs may also play a role in osteoarthritis (OA)-related cartilage degradation.\nMETHODS\nFcγR expression was measured by RT-PCR and FACS in murine cartilage tissue and chondrocytes. Experimental OA was induced by destabilisation of the medial meniscus (DMM) in WT mice and animals lacking either activating (Fc receptor γ-chain-deficient) or inhibitory (FcγRIIB-deficient) FcγRs. Cartilage damage was investigated histologically 8 weeks post-surgery by assessing proteoglycan loss and structural damage according to OARSI recommendations. Osteophyte size was measured to investigate alterations in bone turnover.\nRESULTS\nExpression analyses revealed significant levels for all four types of murine FcγRs in mouse chondrocytes and cartilage tissue from newborn and 8-week-old mice. Surprisingly, yet, ablation of either activating or inhibitory FcγRs did not affect cartilage damage or bone turnover during DMM-induced OA in mice.\nCONCLUSION\nWhile FcγRs appear to have a crucial role in cartilage degradation during inflammatory arthritis our data indicate that FcγRs do not influence cartilage destruction in experimental OA. This indicates that a certain threshold of inflammation is a prerequisite for FcγR-induced cartilage destruction in arthritis.}, author = {Stock, Michael and Distler, A. and Distler, Jörg and Beyer, Christian and Ruiz-Heiland, G. and Ipseiz, N. and Seeling, Michaela and Krönke, Gerhard and Nimmerjahn, Falk and Schett, Georg}, doi = {10.1016/j.joca.2015.02.019}, faupublication = {yes}, journal = {Osteoarthritis and Cartilage}, pages = {1221-5}, peerreviewed = {unknown}, title = {{Fc}-gamma receptors are not involved in cartilage damage during experimental osteoarthritis.}, volume = {23}, year = {2015} } @article{faucris.243032591, abstract = {Background and aims: Oxidation of low-density lipoprotein (LDL) and oxidized LDL-mediated activation of the innate immune system have been recognized as early key events during the pathogenesis of atherosclerosis. Recent evidence identified eosinophils as a major source of enzymatic lipid oxidation and suggested a potential role of type 2 immunity in atherogenesis. However, the involvement of individual type 2 immune cell subsets involved in this process has been incompletely defined. We therefore sought to determine the role of eosinophils during LDL oxidation and the pathogenesis of this disease. Methods: Using eosinophil-deficient dblGATA1 mice, we studied the role of eosinophils in two established mouse models of atherosclerosis. Results: These experiments revealed that the presence of eosinophils did neither affect biomarkers of LDL oxidation nor atherosclerotic lesion development. Conclusions: The obtained results show that LDL oxidation and development of atherosclerosis are largely independent of eosinophils or eosinophil-mediated LDL oxidation.}, author = {Hofheinz, Katharina and Seibert, Fabian and Ackermann, Jochen and Dietel, Barbara and Tauchi, Miyuki and Oszvar-Kozma, Maria and Kühn, Hartmut and Schett, Georg and Binder, Christoph J. and Krönke, Gerhard}, doi = {10.1016/j.atherosclerosis.2020.08.030}, faupublication = {yes}, journal = {Atherosclerosis}, keywords = {Atherosclerosis; Eosinophils; Lipid oxidation}, note = {CRIS-Team Scopus Importer:2020-09-25}, pages = {67-72}, peerreviewed = {Yes}, title = {{Formation} of atherosclerotic lesions is independent of eosinophils in male mice}, volume = {311}, year = {2020} } @article{faucris.110918324, abstract = {The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction.}, author = {Kurow, Olga and Frey, Benjamin and Schuster, Louis and Schmitt, Verena and Adam, Susanne and Hahn, Madelaine and Gilchrist, Derek and Mcinnes, Iain B. and Wirtz, Stefan and Gaipl, Udo and Krönke, Gerhard and Schett, Georg and Frey, Silke and Hueber, Axel}, doi = {10.3389/fimmu.2017.00722}, faupublication = {yes}, journal = {Frontiers in Immunology}, note = {EVALuna2:13432}, pages = {722}, peerreviewed = {Yes}, title = {{Full} {Length} {Interleukin} 33 {Aggravates} {Radiation}-{Induced} {Skin} {Reaction}}, volume = {8}, year = {2017} } @article{faucris.209056574, abstract = {BACKGROUND: Glucocorticoid (GC) therapy is frequently used to treat rheumatoid arthritis due to potent anti-inflammatory actions of GCs. Direct actions of GCs on immune cells were suggested to suppress inflammation. OBJECTIVES: Define the role of the glucocorticoid receptor (GR) in stromal cells for suppression of inflammatory arthritis. METHODS: Bone marrow chimeric mice lacking the GR in the hematopoietic or stromal compartment, respectively, and mice with impaired GR dimerisation (GRdim) were analysed for their response to dexamethasone (DEX, 1 mg/kg) treatment in serum transfer-induced arthritis (STIA). Joint swelling, cell infiltration (histology), cytokines, cell composition (flow cytometry) and gene expression were analysed and RNASeq of wild type and GRdim primary murine fibroblast-like synoviocytes (FLS) was performed. RESULTS: GR deficiency in immune cells did not impair GC-mediated suppression of STIA. In contrast, mice with GR-deficient or GR dimerisation-impaired stromal cells were resistant to GC treatment, despite efficient suppression of cytokines. Intriguingly, in mice with impaired GR function in the stromal compartment, GCs failed to stimulate non-classical, non-activated macrophages (Ly6Cneg, MHCIIneg) and associated anti-inflammatory markers CD163, CD36, AnxA1, MerTK and Axl. Mice with GR deficiency in FLS were partially resistant to GC-induced suppression of STIA. Accordingly, RNASeq analysis of DEX-treated GRdim FLS revealed a distinct gene signature indicating enhanced activity and a failure to reduce macrophage inflammatory protein (Mip)-1α and Mip-1β. CONCLUSION: We report a novel anti-inflammatory mechanism of GC action that involves GR dimerisation-dependent gene regulation in non-immune stromal cells, presumably FLS. FLS control non-classical, anti-inflammatory polarisation of macrophages that contributes to suppression of inflammation in arthritis.}, author = {Koenen, Mascha and Culemann, Stephan and Vettorazzi, Sabine and Caratti, Giorgio and Frappart, Lucien and Baum, Wolfgang and Krönke, Gerhard and Baschant, Ulrike and Tuckermann, Jan P.}, doi = {10.1136/annrheumdis-2017-212762}, faupublication = {yes}, journal = {Annals of the Rheumatic Diseases}, note = {EVALuna2:34952}, pages = {1610-1618}, peerreviewed = {Yes}, title = {{Glucocorticoid} receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis}, volume = {77}, year = {2018} } @article{faucris.122226104, abstract = {Immunglobulin G (IgG) sialylation represents a key checkpoint that determines the engagement of pro- or anti-inflammatory Fcγ receptors (FcγR) and the direction of the immune response. Whether IgG sialylation influences osteoclast differentiation and subsequently bone architecture has not been determined yet, but may represent an important link between immune activation and bone loss. Here we demonstrate that desialylated, but not sialylated, immune complexes enhance osteoclastogenesis in vitro and in vivo. Furthermore, we find that the Fc sialylation state of random IgG and specific IgG autoantibodies determines bone architecture in patients with rheumatoid arthritis. In accordance with these findings, mice treated with the sialic acid precursor N-acetylmannosamine (ManNAc), which results in increased IgG sialylation, are less susceptible to inflammatory bone loss. Taken together, our findings provide a novel mechanism by which immune responses influence the human skeleton and an innovative treatment approach to inhibit immune-mediated bone los}, author = {Harre, Ulrike and Lang, Stefanie and Pfeifle, René and Rombouts, Yoann and Frühbeißer, Sabine and Amara, Khaled and Bang, Holger and Lux, Anja and Koeleman, Carolien A. and Baum, Wolfgang and Dietel, Katharina and Gröhn, Franziska and Malmstroem, Vivianne and Klareskog, Lars and Krönke, Gerhard and Kocijan, Roland and Nimmerjahn, Falk and Toes, Rene E. M. and Herrmann, Martin and Scherer, Hans Ulrich and Schett, Georg}, doi = {10.1038/ncomms7651}, faupublication = {yes}, journal = {Nature Communications}, pages = {6651}, peerreviewed = {Yes}, title = {{Glycosylation} of immunoglobulin {G} determines osteoclast differentiation and bone loss.}, volume = {6}, year = {2015} } @article{faucris.205185249, abstract = {Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORαcre/GATA3fl/fl and Tie2cre/RORαfl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL-33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild-type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13-/- ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis.}, author = {Omata, Yasunori and Frech, Michael and Primbs, Tatjana and Lucas, Sebastien and Andreev, Darja and Scholtysek, Carina and Sarter-Zaiss, Kerstin and Kindermann, Markus and Yeremenko, Nataliya and Baeten, Dominique L. and Andreas, Nico and Kamradt, Thomas and Bozec, Aline and Ramming, Andreas and Krönke, Gerhard and Wirtz, Stefan and Schett, Georg and Zaiss, Mario}, doi = {10.1016/j.celrep.2018.06.005}, faupublication = {yes}, journal = {Cell Reports}, note = {EVALuna2:34467}, pages = {169-180}, peerreviewed = {Yes}, title = {{Group} 2 {Innate} {Lymphoid} {Cells} {Attenuate} {Inflammatory} {Arthritis} and {Protect} from {Bone} {Destruction} in {Mice}}, volume = {24}, year = {2018} } @article{faucris.266779344, abstract = {Objective: B cell depletion is an established therapeutic principle in a wide range of autoimmune diseases. However, B cells are also critical for inducing protective immunity after infection and vaccination. We undertook this study to assess humoral and cellular immune responses after infection with or vaccination against SARS–CoV-2 in patients with B cell depletion and controls who are B cell–competent. Methods: Antibody responses (tested using enzyme-linked immunosorbent assay) and T cell responses (tested using interferon-γ enzyme-linked immunospot assay) against the SARS–CoV-2 spike S1 and nucleocapsid proteins were assessed in a limited number of previously infected (n = 6) and vaccinated (n = 8) autoimmune disease patients with B cell depletion, as well as previously infected (n = 30) and vaccinated (n = 30) healthy controls. Results: As expected, B cell and T cell responses to the nucleocapsid protein were observed only after infection, while respective responses to SARS–CoV-2 spike S1 were found after both infection and vaccination. A SARS–CoV-2 antibody response was observed in all vaccinated controls (30 of 30 [100%]) but in none of the vaccinated patients with B cell depletion (0 of 8). In contrast, after SARS–CoV-2 infection, both the patients with B cell depletion (spike S1, 5 of 6 [83%]; nucleocapsid, 3 of 6 [50%]) and healthy controls (spike S1, 28 of 30 [93%]; nucleocapsid, 28 of 30 [93%]) developed antibodies. T cell responses against the spike S1 and nucleocapsid proteins were found in both infected and vaccinated patients with B cell depletion and in the controls. Conclusion: These data show that B cell depletion completely blocks humoral but not T cell SARS–CoV-2 vaccination response. Furthermore, limited humoral immune responses are found after SARS–CoV-2 infection in patients with B cell depletion.}, author = {Simon, David and Tascilar, Koray and Schmidt, Katja and Manger, Bernhard and Weckwerth, Leonie and Sokolova, Maria and Bucci, Laura and Fagni, Filippo and Manger, Karin and Schuch, Florian and Ronneberger, Monika and Hueber, Axel and Steffen, Ulrike and Mielenz, Dirk and Herrmann, Martin and Harrer, Thomas and Kleyer, Arnd and Krönke, Gerhard and Schett, Georg}, doi = {10.1002/art.41914}, faupublication = {yes}, journal = {Arthritis and Rheumatology}, note = {CRIS-Team Scopus Importer:2021-12-03}, peerreviewed = {Yes}, title = {{Humoral} and {Cellular} {Immune} {Responses} to {SARS}–{CoV}-2 {Infection} and {Vaccination} in {Autoimmune} {Disease} {Patients} {With} {B} {Cell} {Depletion}}, year = {2021} } @article{faucris.258193610, abstract = {Hydroxyapatite- or calcium phosphate-coated iron oxide nanoparticles have a high potential for use in many biomedical applications. In this study, a co-precipitation method for the synthesis of hydroxyapatite-coated nanoparticles (SPIONHAp), was used. The produced nanoparticles have been characterized by dynamic light scattering, X-ray diffraction, vibrating sample magnetometry, Fourier transform infrared spectrometry, atomic emission spectroscopy, scanning electron microscopy, transmission electron microscopy, selected area diffraction, and energy-dispersive X-ray spectroscopy. The results showed a successful synthesis of 190 nm sized particles and their stable coating, resulting in SPIONHAp. Potential cytotoxic effects of SPIONHAp on EL4, THP-1, and Jurkat cells were tested, showing only a minor effect on cell viability at the highest tested concentration (400 mu g Fe/mL). The results further showed that hydroxyapatite-coated SPIONs can induce minor TNF-alpha and IL-6 release by murine macrophages at a concentration of 100 mu g Fe/mL. To investigate if and how such particles interact with other substances that modulate the immune response, SPIONHAp-treated macrophages were incubated with LPS (lipopolysaccharides) and dexamethasone. We found that cytokine release in response to these potent pro- and anti-inflammatory agents was modulated in the presence of SPIONHAp. Knowledge of this behavior is important for the management of inflammatory processes following in vivo applications of this type of SPIONs.}, author = {Friedrich, Bernhard and Auger, Jean-Philippe and Dutz, Silvio and Cicha, Iwona and Schreiber, Eveline and Band, Julia and Boccaccini, Aldo R. and Krönke, Gerhard and Alexiou, Christoph and Tietze, Rainer}, doi = {10.3390/ijms22084143}, faupublication = {yes}, journal = {International Journal of Molecular Sciences}, note = {CRIS-Team WoS Importer:2021-05-14}, peerreviewed = {Yes}, title = {{Hydroxyapatite}-{Coated} {SPIONs} and {Their} {Influence} on {Cytokine} {Release}}, volume = {22}, year = {2021} } @article{faucris.235773428, abstract = {Patients with clinically suspect arthralgia have articular symptoms such as pain and stiffness of the small joints without clinical signs of arthritis. Some of these patients progress and develop 'true' disease, but how can we differentiate evolving chronic disease from disease that will resolve?}, author = {Krönke, Gerhard and Hueber, Axel}, doi = {10.1038/s41584-020-0400-x}, faupublication = {yes}, journal = {Nature Reviews Rheumatology}, note = {CRIS-Team WoS Importer:2020-03-13}, peerreviewed = {unknown}, title = {{Identifying} 'non-progressors' among patients with arthralgia}, year = {2020} } @inproceedings{faucris.207717355, author = {Pfeifle, R. and Rothe, Tobias and Scherer, H. U. and Wuhrer, M. and Rombouts, Y. and Koeleman, C. A. and Toes, R. and Holmdahl, R. and Herrmann, Martin and Blueml, S. and Nimmerjahn, Falk and Schett, Georg and Krönke, Gerhard}, faupublication = {yes}, note = {EVALuna2:13361}, pages = {726-726}, peerreviewed = {Yes}, title = {{IL}-17/23 {IN} {THE} {TRANSITION} {FROM} {AUTOIMMUNITY} {TO} {INFLAMMATION}}, volume = {34}, year = {2016} } @article{faucris.266344032, abstract = {Alternatively activated macrophages (AAMs) contribute to the resolution of inflammation and tissue repair. However, molecular pathways that govern their differentiation have remained incompletely understood. Here, we show that uncoupling protein-2-mediated mitochondrial reprogramming and the transcription factor GATA3 specifically controlled the differentiation of pro-resolving AAMs in response to the alarmin IL-33. In macrophages, IL-33 sequentially triggered early expression of pro-inflammatory genes and subsequent differentiation into AAMs. Global analysis of underlying signaling events revealed that IL-33 induced a rapid metabolic rewiring of macrophages that involved uncoupling of the respiratory chain and increased production of the metabolite itaconate, which subsequently triggered a GATA3-mediated AAM polarization. Conditional deletion of GATA3 in mononuclear phagocytes accordingly abrogated IL-33-induced differentiation of AAMs and tissue repair upon muscle injury. Our data thus identify an IL-4-independent and GATA3-dependent pathway in mononuclear phagocytes that results from mitochondrial rewiring and controls macrophage plasticity and the resolution of inflammation.}, author = {Faas, Maria and Ipseiz, Natacha and Ackermann, Jochen and Culemann, Stephan and Grüneboom, Anika and Schröder, Fenja and Rothe, Tobias and Scholtysek, Carina and Eberhardt, Martin and Böttcher, Martin and Kirchner, Philipp and Stoll, Cornelia and Ekici, Arif Bülent and Fuchs, Maximilian and Kunz, Meik and Weigmann, Benno and Wirtz, Stefan and Lang, Roland and Hofmann, Jörg and Vera, Julio and Vöhringer, David and Michelucci, Alessandro and Mougiakakos, Dimitrios and Uderhardt, Stefan and Schett, Georg and Krönke, Gerhard}, doi = {10.1016/j.immuni.2021.09.010}, faupublication = {yes}, journal = {Immunity}, keywords = {alternatively activated macrophage; GATA3; interleukin-33; itaconate; mitochondrial rewiring; resolution of inlammation; UCP2; uncoupling}, note = {CRIS-Team Scopus Importer:2021-11-19}, pages = {2531-2546.e5}, peerreviewed = {Yes}, title = {{IL}-33-induced metabolic reprogramming controls the differentiation of alternatively activated macrophages and the resolution of inflammation}, volume = {54}, year = {2021} } @article{faucris.272554785, abstract = {Objective To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. Results In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). Conclusion IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.}, author = {Simon, David and Tascilar, Koray and Kleyer, Arnd and Fagni, Filippo and Krönke, Gerhard and Meder, Christine and Dietrich, Peter and Orlemann, Till and Kliem, Thorsten and Moessner, Johanna and Liphardt, Anna-Maria and Schoenau, Verena and Bohr, Daniela and Schuster, Louis and Hartmann, Fabian and Leppkes, Moritz and Ramming, Andreas and Pachowsky, Milena and Schuch, Florian and Ronneberger, Monika and Kleinert, Stefan and Hueber, Axel and Manger, Karin and Manger, Bernhard and Atreya, Raja and Berking, Carola and Sticherling, Michael and Neurath, Markus and Schett, Georg}, doi = {10.1002/art.42035}, faupublication = {yes}, journal = {Arthritis and Rheumatology}, note = {CRIS-Team WoS Importer:2022-04-08}, peerreviewed = {Yes}, title = {{Impact} of {Cytokine} {Inhibitor} {Therapy} on the {Prevalence}, {Seroconversion} {Rate}, and {Longevity} of the {Humoral} {Immune} {Response} {Against} {SARS}-{CoV}-2 in an {Unvaccinated} {Cohort}}, year = {2022} } @inproceedings{faucris.207717814, author = {Fischer, Anita and Boehm, Christina and Koenders, Marije and Van Den Berg, Wim and Rothe, Tobias and Krönke, Gerhard and Dudziak, Diana and Steiner, Guenter}, doi = {10.1136/annrheumdis-2016-211055.27}, faupublication = {yes}, note = {EVALuna2:34374}, pages = {A86-A86}, peerreviewed = {Yes}, title = {{IMPACT} {OF} {TOLL}-{LIKE} {RECEPTOR} 9 {IN} {INFLAMMATORY} {ARTHRITIS} {AND} {OSTEOCLASTOGENESIS}}, volume = {76}, year = {2017} } @inproceedings{faucris.222410950, address = {LONDON}, author = {Puchner, Antonia and Simader, Elisabeth and Saferding, Victoria and Krönke, Gerhard and Pfeifle, René and Aletaha, Daniel and Smolen, Josef S. and Blueml, Stephan}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, date = {2019-06-12/2019-06-15}, doi = {10.1136/annrheumdis-2019-eular.6534}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2019-07-16}, pages = {1094-1094}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{IMPORTANT} {ROLE} {OF} {CD11C}+{CELLSIN} {INFLAMMATORY} {ARTHRITIS}}, venue = {Madrid}, year = {2019} } @inproceedings{faucris.209053611, author = {Puchner, A. and Saferding, V. and Pfeifle, René and Krönke, Gerhard and Redlich, K. and Smolen, J. and Blueml, S.}, doi = {10.1136/annrheumdis-2018-ewrr2018.75}, faupublication = {yes}, note = {EVALuna2:35010}, pages = {A36-A37}, peerreviewed = {Yes}, title = {{IMPORTANT} {ROLE} {OF} {CD11C}+{DENDRITIC} {CELLS} {IN} {INFLAMMATORY} {ARTHRITIS}}, volume = {77}, year = {2018} } @inproceedings{faucris.209054565, author = {Puchner, Antonia and Saferding, Victoria and Bonelli, Michael and Leiss, Harald and Krönke, Gerhard and Pfeifle, René and Smolen, Josef S. and Redlich, Kurt and Blueml, Stephan}, faupublication = {yes}, note = {EVALuna2:35019}, peerreviewed = {Yes}, title = {{Important} {Role} of {CD11c}+{Dendtritic} {Cells} in {Inflammatory} {Arthritis}}, volume = {69}, year = {2017} } @inproceedings{faucris.235590793, author = {Simader, E. and Puchner, A. and Saferding, V. and Goncalves-Alves, E. and Pfeifle, René and Krönke, Gerhard and Smolen, J. and Blueml, S.}, doi = {10.1136/annrheumdis-2018-ewrr2019.110}, faupublication = {yes}, note = {EVALuna2:213241}, pages = {A54-A55}, peerreviewed = {Yes}, title = {{IMPORTANT} {ROLE} {OF} {DENDRITIC} {CELLS} {IN} {INFLAMMATORY} {ARTHRITIS}}, volume = {78}, year = {2019} } @inproceedings{faucris.207724149, author = {Renner, Nina and Kleyer, Arnd and Simon, David and Krönke, Gerhard and Rech, Jürgen and Schett, Georg and Welsch, Goetz and Pachowsky, Milena}, faupublication = {yes}, note = {EVALuna2:33441}, peerreviewed = {Yes}, title = {{Increased} {Cartilage} {Damage} in {Metacarpophalangeal} {Joints} of {ACPA} {Positive} {Rheumatoid} {Arthritis} ({RA}) {Patients} {Using} {T2} {Mapping} in 3 {Tesla} {Magnetresonance} {Imaging} ({MRI})}, volume = {69}, year = {2017} } @article{faucris.282098543, abstract = {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.}, author = {Simon, David and Tascilar, Koray and Fagni, Filippo and Kleyer, Arnd and Krönke, Gerhard and Meder, Christine and Dietrich, Peter and Orlemann, Till and Mößner, Johanna and Taubmann, Jule and Mutlu, Melek Yalcin and Knitza, Johannes and Kemenes, Stephan and Liphardt, Anna-Maria and Schönau, Verena and Bohr, Daniela and Schuster, Louis and Minopoulou, Ioanna and Leppkes, Moritz and Ramming, Andreas and Pachowsky, Milena and Schuch, Florian and Ronneberger, Monika and Kleinert, Stefan and Hueber, Axel and Manger, Karin and Manger, Bernhard and Atreya, Raja and Berking, Carola and Sticherling, Michael and Neurath, Markus and Schett, Georg and Hartmann, Fabian}, doi = {10.1016/S2665-9913(22)00191-6}, faupublication = {yes}, journal = {The Lancet Rheumatology}, note = {EVALuna2:506737}, pages = {e614-e625}, peerreviewed = {Yes}, title = {{Intensity} and longevity of {SARS}-{CoV}-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study.}, volume = {4}, year = {2022} } @article{faucris.107015524, abstract = {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.}, author = {Schwab, Inessa and Biburger, Markus and Krönke, Gerhard and Schett, Georg and Nimmerjahn, Falk}, doi = {10.1002/eji.201142260}, faupublication = {yes}, journal = {European Journal of Immunology}, keywords = {Fc-receptor · ITP · IVIg · Sialic acid · SIGNR1}, pages = {826-830}, peerreviewed = {Yes}, title = {{IVIg}-mediated amelioration of {ITP} in mice is dependent on sialic acid and {SIGNR1}}, volume = {42}, year = {2012} } @article{faucris.234647437, abstract = {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.}, author = {Adam, Susanne and Simon, Nils and Steffen, Ulrike and Andes, Fabian T. and Scholtysek, Carina and Müller, Dorothea and Weidner, Daniela and Andreev, Darja and Kleyer, Arnd and Culemann, Stephan and Hahn, Madelaine and Schett, Georg and Krönke, Gerhard and Frey, Silke and Hueber, Axel}, doi = {10.1126/scitranslmed.aay4447}, faupublication = {yes}, journal = {Science Translational Medicine}, note = {CRIS-Team Scopus Importer:2020-02-21}, peerreviewed = {Yes}, title = {{JAK} inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function}, volume = {12}, year = {2020} } @inproceedings{faucris.222107993, address = {LONDON}, author = {Adam, Susanne and Simon, Nils and Steffen, Ulrike and Harre, Nee and Andes, Fabian and Mueller, Dorothea and Culemann, Stephan and Andreev, Darja and Hahn, Madelaine and Scholtysek, Carina and Schett, Georg and Krönke, Gerhard and Frey, Silke and Hueber, Axel}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, date = {2019-06-12/2019-06-15}, doi = {10.1136/annrheumdis-2019-eular.4104}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2019-07-12}, pages = {110-110}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{JAK}-{INHIBITORS} {TOFACITINIB} {AND} {BARICITINIB} {IMPROVE} {PATHOLOGICAL} {BONE} {LOSS} {IN} {VIVO}}, venue = {Madrid}, year = {2019} } @article{faucris.205279019, abstract = {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.}, author = {Kleyer, Arnd and Scholtysek, Carina and Bottesch, Edith and Hillienhof, Ulrike and Beyer, Christian and Distler, Jörg and Tuckermann, Jan P. and Schett, Georg and Krönke, Gerhard}, doi = {10.1002/jbmr.1702}, faupublication = {yes}, journal = {Journal of Bone and Mineral Research}, note = {EVALuna2:12795}, pages = {2442-51}, peerreviewed = {Yes}, title = {{Liver} {X} receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss}, volume = {27}, year = {2012} } @article{faucris.224624385, abstract = {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.}, author = {Culemann, Stephan and Grüneboom, Anika and Nicolás-Ávila, José Ángel and Weidner, Daniela and Lämmle, Katrin Franziska and Rothe, Tobias and Quintana, Juan A. and Kirchner, Philipp and Krljanac, Branislav and Eberhardt, Martin and Ferrazzi, Fulvia and Kretzschmar, Elke and Schicht, Martin and Fischer, Kim and Gelse, Kolja and Faas, Maria and Pfeifle, René and Ackermann, Jochen A. and Pachowsky, Milena and Renner, Nina and Simon, David and Haseloff, Reiner F. and Ekici, Arif Bülent and Bäuerle, Tobias and Blasig, Ingolf E. and Vera, Julio and Vöhringer, David and Kleyer, Arnd and Paulsen, Friedrich and Schett, Georg and Hidalgo, Andrés and Krönke, Gerhard}, doi = {10.1038/s41586-019-1471-1}, faupublication = {yes}, journal = {Nature}, note = {CRIS-Team Scopus Importer:2019-08-16}, peerreviewed = {Yes}, title = {{Locally} renewing resident synovial macrophages provide a protective barrier for the joint}, year = {2019} } @inproceedings{faucris.284523260, address = {LONDON}, author = {Tascilar, Koray and Simon, David and Kleyer, Arnd and Fagni, Filippo and Krönke, Gerhard and Meder, Christine and Dietrich, Peter and Orlemann, Till and Kliem, Thorsten and Moessner, J. and Liphardt, Anna-Maria and Schönau, Verena and Bohr, D. and Schuster, Louis and Hartmann, F. and Taubmann, Jule and Leppkes, Moritz and Ramming, Andreas and Pachowsky, Milena and Schuch, Florian and Ronneberger, Monika and Kleinert, Stefan and Hueber, A. and Manger, Karin and Manger, Bernhard and Atreya, Raja and Berking, Carola and Sticherling, Michael and Neurath, Markus and Schett, Georg}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, doi = {10.1136/annrheumdis-2022-eular.5079}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2022-11-04}, pages = {371-372}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{LONG}-{TERM} {HUMORAL} {RESPONSE} {TO} {SARS}-{COV}-2 {VACCINATION} {IN} {PATIENTS} {WITH} {IMMUNE}-{MEDIATED} {INFLAMMATORY} {DISEASE}}, year = {2022} } @article{faucris.121783244, abstract = {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.}, author = {Sahin, Emine and Brunner, Julia S. and Kral, Julia B. and Kuttke, Mario and Hanzl, Leslie and Datler, Hannes and Paar, Hannah and Neuwinger, Nick and Saferding, Victoria and Zinser, Elisabeth and Halfmann, Angela and Soukup, Klara and Hainzl, Eva and Lohmeyer, Tobias and Niederreiter, Birgit and Haider, Thomas and Dohnal, Alexander M. and Krönke, Gerhard and Blüml, Stephan and Schabbauer, Gernot}, doi = {10.4049/jimmunol.1402511}, faupublication = {yes}, journal = {Journal of Immunology}, note = {EVALuna2:13151}, pages = {2560-70}, peerreviewed = {Yes}, title = {{Loss} of {Phosphatase} and {Tensin} {Homolog} in {APCs} {Impedes} {Th17}-{Mediated} {Autoimmune} {Encephalomyelitis}}, volume = {195}, year = {2015} } @article{faucris.286629829, abstract = {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.}, author = {Kohl, Lisa and Siddique, Md Nur A Alam and Bodendorfer, Barbara and Berger, Raffaela and Preikschat, Annica and Daniel, Christoph and Ölke, Martha and Liebler-Tenorio, Elisabeth and Schulze-Lührmann, Jan and Mauermeir, Michael and Yang, Kai-Ting and Hayek, Inaya and Szperlinski, Manuela and Andrack, Jennifer and Schleicher, Ulrike and Bozec, Aline and Krönke, Gerhard and Murray, Peter J. and Wirtz, Stefan and Yamamoto, Masahiro and Schatz, Valentin and Jantsch, Jonathan and Oefner, Peter and Degrandi, Daniel and Pfeffer, Klaus and Mertens-Scholz, Katja and Rauber, Simon and Bogdan, Christian and Dettmer, Katja and Lührmann, Anja and Lang, Roland}, doi = {10.15252/emmm.202215931}, faupublication = {yes}, journal = {Embo Molecular Medicine}, keywords = {Cis-aconitate decarboxylase 1; Coxiella burnetii; Immune responsive gene 1; immunometabolism; itaconate}, note = {CRIS-Team Scopus Importer:2022-12-16}, peerreviewed = {Yes}, title = {{Macrophages} inhibit {Coxiella} burnetii by the {ACOD1}-itaconate pathway for containment of {Q} fever}, year = {2022} } @article{faucris.246687018, abstract = {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.}, author = {Taubmann, Jule and Krishnacoumar, Brenda and Böhm, Christina and Faas, Maria and Müller, Dorothea and Adam, Susanne and Stoll, Cornelia and Böttcher, Martin and Mougiakakos, Dimitrios and Sonnewald, Uwe and Hofmann, Jörg and Schett, Georg and Krönke, Gerhard and Scholtysek, Carina}, doi = {10.1038/s41598-020-77892-4}, faupublication = {yes}, journal = {Scientific Reports}, note = {CRIS-Team Scopus Importer:2020-12-11}, peerreviewed = {Yes}, title = {{Metabolic} reprogramming of osteoclasts represents a therapeutic target during the treatment of osteoporosis}, volume = {10}, year = {2020} } @article{faucris.119199344, abstract = {The effect of metabolic stress on the bone marrow microenvironment is poorly defined. We show that high-fat diet (HFD) decreased long-term Lin(-)Sca-1(+)c-Kit(+) (LSK) stem cells and shifted lymphoid to myeloid cell differentiation. Bone marrow niche function was impaired after HFD as shown by poor reconstitution of hematopoietic stem cells. HFD led to robust activation of PPAR?2, which impaired osteoblastogenesis while enhancing bone marrow adipogenesis. At the same time, expression of genes such as Jag-1, SDF-1, and IL-7 forming the bone marrow niche was highly suppressed after HFD. Moreover, structural changes of microbiota were associated to HFD-induced bone marrow changes. Antibiotic treatment partially rescued HFD-mediated effects on the bone marrow niche, while transplantation of stools from HFD mice could transfer the effect to normal mice. These findings show that metabolic stress affects the bone marrow niche by alterations of gut microbiota and osteoblast-adipocyte homeostasis.}, author = {Luo, Yubin and Chen, Guangliang and Hannemann, Nicole and Ipseiz, Natacha and Krönke, Gerhard and Bäuerle, Tobias and Munos, Luis and Wirtz, Stefan and Schett, Georg and Bozec, Aline}, doi = {10.1016/j.cmet.2015.08.020}, faupublication = {yes}, journal = {Cell Metabolism}, note = {EVALuna2:1968}, pages = {886-94}, peerreviewed = {Yes}, title = {{Microbiota} from {Obese} {Mice} {Regulate} {Hematopoietic} {Stem} {Cell} {Differentiation} by {Altering} the {Bone} {Niche}}, volume = {22}, year = {2015} } @inproceedings{faucris.222411202, address = {LONDON}, author = {Kleyer, Arnd and Simon, David and Bui, Cong Duy and Hueber, Axel and Bang, Holger and Rech, Jürgen and Krönke, Gerhard and Schett, Georg and Ramming, Andreas}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, date = {2019-06-12/2019-06-15}, doi = {10.1136/annrheumdis-2019-eular.4638}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2019-07-16}, pages = {133-133}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{MICRO}-{STRUCTURAL} {CHANGES} {ASSOCIATED} {WITH} {ANTI}-{CITRULLINATED} {VIMENTIN} {AUTOIMMUNITY} {IN} {RA}-{AT}-{RISK} {INDIVIDUALS} {PRECIPITATE} {THE} {ONSET} {OF} {RHEUMATOID} {ARTHRITIS}}, venue = {Madrid}, year = {2019} } @article{faucris.209673913, abstract = {Problem: The generation of tissue-engineered cartilage constructs has made great progress over the last decades, however, the fixation of the grafts to the subchondral bone plate is still an unresolved problem. The aim of this study was to investigate a modular lattice concept as an anchoring basis for biological joint resurfacing that is stably fixed to subchondral bone, versatile for any surface shape, and permissive for cellular repopulation. Methods: Ceramic building blocks (hydroxyapatite, β-tricalcium phosphate, biphasic calcium phosphate, alumina and bioactive glass) including anchoring pins were fabricated by transfer injection molding technique. The cellular repopulation of the building blocks and cellular differentiation of human mesenchymal stem cells (hBMSC) was analysed under the influence of platelet-rich plasma, transforming growth factor-β and bone morphogenetic protein-2. A lattice construct of anchoring pins fixed to subchondral bone specimen and interposed hBMSC within collagen-hydrogel were cultured under dynamic conditions in spinner flasks for 4 weeks. The 3D constructs were analyzed by high-resolution micro computertomography (µCT), light-sheet fluorescence microscopy and histology. Pin fixation was analysed by pull-out tests. Results: Building Block-modules of complex shape with anchoring pins can be individually arranged to the subchondral bone by simple press-fit principle. Pull-out tensile stress exceeded 6 MPa. Human BMSCs required stimulation by TGF-β or BMP-2 to undergo chondrogenic differentiation. Dynamic culturinges of 3-dimensional explant constructscultures demonstrated the stability of the modular lattice construct and the interposed cell-loaded hydrogel remained within the lattice elements. hBMSCs within the collagen hydrogel underwent chondrogenic differentiation and formed a matrix that merged with the lattice structure of building blocks. Conclusions: The current work presents a proof-of-principle concept for a lattice structure that provides the stable mechanical bonding and biological milieu for the bone-cartilage interface. The anchoring elements represent an integral part of the lattice structure and provide the basis for future biological joint resurfacing by multilayer constructs.Objectives A randomized, controlled trial to evaluate the feasibility, acceptability and accuracy of an upper arm self-sampling device (UA) and finger prick-test (FP) to measure capillary blood from RA patients for C-reactive protein (CRP) levels and the presence of IgM rheumatoid factor (RF IgM) and anti-cyclic citrullinated protein antibodies (anti-CCP IgG).
Methods 50 RA patients were randomly assigned in a 1:1 ratio to self-collection of capillary blood via UA or FP. Venous blood sampling (VBS) was performed as gold standard in both groups to assess the concordance of CRP levels as well as RF IgM and CCP IgG. General acceptability and pain during sampling were measured and compared between UA, FP and VBS. The number of attempts for successful sampling, requests for assistance, volume and duration of sample collection were also assessed.
Results 49/50 (98%) patients were able to successfully collect capillary blood. Overall agreement between capillary and venous analyses for CRP (0.992), CCP IgG (0.984) and RF IgM (0.994) were good. In both groups 4/25 (16%) needed a second attempt and 8/25 (32%) in the UA and 7/25 (28%) in the FP group requested assistance. Mean pain scores for capillary self-sampling (1.7/10 ± 1.1 (UA) and 1.9/10 ± 1.9 (FP)) were lower on a numeric rating scale compared to venous blood collection (UA: 2.8/10 ± 1.7; FP: 2.1 ± 2.0). UA patients were more likely to promote the use of capillary blood sampling (net promoter score: +28% vs. -20% for FP) and were more willing to perform blood collection at home (60%) vs. 32% for FP).
Conclusion This study shows that self-sampling is accurate, feasible and well accepted among patients. The implementation could allow tight remote monitoring of disease activity as well as identifying patients at-risk for RA and potentially other rheumatic disease}, address = {LONDON}, author = {Knitza, Johannes and Tascilar, Koray and Vuillerme, N. and Vogt, E. and Matusewicz, P. and Corte, Giulia and Schuster, Louis and Aubourg, T. and Bendzuck, G. and Korinth, M. and Elling-Audersch, C. and Kleyer, Arnd and Böltz, Sebastian and Hueber, Axel and Krönke, Gerhard and Schett, Georg and Simon, David}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, doi = {10.1136/annrheumdis-2022-eular.775}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2022-11-04}, pages = {1117-1117}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{PATIENT} {SELF}-{SAMPLING} {IN} {RHEUMATOID} {ARTHRITIS}: {RESULTS} {FROM} {A} {RANDOMIZED} {CONTROLLED} {TRIAL}}, year = {2022} } @inproceedings{faucris.247786493, address = {HOBOKEN}, author = {Simon, David and Tascilar, Koray and Krönke, Gerhard and Kleyer, Arnd and Zaiss, Mario and Heppt, Franz and Meder, Christine and Atreya, Raja and Klenske, Entcho and Dietrich, Peter and Abdullah, Abdullah and Kliem, Thorsten and Corte, Giulia and Morf, Harriet and Leppkes, Moritz and Kremer, Andreas and Ramming, Andreas and Pachowsky, Milena and Schuch, Florian and Ronneberger, Monika and Kleinert, Stefan and Maier, Clara and Hueber, Axel and Manger, Karin and Manger, Bernhard and Berking, Carola and Tenbusch, Matthias and Überla, Klaus and Sticherling, Michael and Neurath, Markus and Schett, Georg}, booktitle = {ARTHRITIS & RHEUMATOLOGY}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2021-01-15}, peerreviewed = {unknown}, publisher = {WILEY}, title = {{Patients} {Receiving} {Cytokine} {Inhibitors} {Have} {Low} {Prevalence} of {SARS}-{CoV}-2 {Infection}}, year = {2020} } @inproceedings{faucris.264310220, address = {LONDON}, author = {Tascilar, Koray and Simon, David and Krönke, Gerhard and Kleyer, Arnd and Ramming, Andreas and Atreya, Raja and Tenbusch, Matthias and Überla, Klaus and Berking, Carola and Sticherling, Michael and Neurath, Markus and Schett, Georg}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, doi = {10.1136/annrheumdis-2021-eular.1598}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2021-09-24}, pages = {996-997}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{PATIENTS} {WITH} {IMMUNE} {MEDIATED} {INFLAMMATORY} {DISEASES} {ARE} {OVERREPRESENTED} {IN} {LOW}-{FREQUENCY} {VIRAL} {SYMPTOM} {CLUSTERS}}, year = {2021} } @article{faucris.241251378, abstract = {Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.}, author = {Simon, David and Tascilar, Koray and Krönke, Gerhard and Kleyer, Arnd and Zaiss, Mario and Heppt, Franz and Meder, Christine and Atreya, Raja and Klenske, Entcho and Dietrich, Peter and Abdullah, Abdullah and Kliem, Thorsten and Corte, Giulia and Morf, Harriet and Leppkes, Moritz and Kremer, Andreas and Pachowsky, Milena and Schuch, Florian and Ronneberger, Monika and Kleinert, Stefan and Meier, Clara and Hueber, Axel and Manger, Karin and Manger, Bernhard and Berking, Carola and Tenbusch, Matthias and Überla, Klaus and Sticherling, Michael and Neurath, Markus and Schett, Georg and Ramming, Andreas}, doi = {10.1038/s41467-020-17703-6}, faupublication = {yes}, journal = {Nature Communications}, note = {CRIS-Team Scopus Importer:2020-08-07}, peerreviewed = {Yes}, title = {{Patients} with immune-mediated inflammatory diseases receiving cytokine inhibitors have low prevalence of {SARS}-{CoV}-2 seroconversion}, volume = {11}, year = {2020} } @article{faucris.216798528, abstract = {Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE − / − mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE − / − deletion, and many were absent in Alox − / − mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.}, author = {Allen-Redpath, Keith and Aldrovandi, Maceler and Lauder, Sarah N. and Gketsopoulou, Anastasia and Tyrrell, Victoria J. and Slatter, David A. and Andrews, Robert and Watkins, W. John and Atkinson, Georgia and Mcneill, Eileen and Gilfedder, Anna and Protty, Majd and Burston, James and Johnson, Sam R. C. and Rodrigues, Patricia R. S. and Jones, Dylan O. and Lee, Regent and Handa, Ashok and Channon, Keith and Obaji, Samya and Alvarez-Jarreta, Jorge and Krönke, Gerhard and Ackermann, Jochen and Jenkins, P. Vince and Collins, Peter W. and O'Donnell, Valerie B.}, doi = {10.1073/pnas.1814409116}, faupublication = {yes}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, keywords = {Aneurysm; Angiotensin; Lipid; Lipoxygenase; Phospholipid}, note = {CRIS-Team Scopus Importer:2019-05-02}, pages = {8038-8047}, peerreviewed = {unknown}, title = {{Phospholipid} membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity}, volume = {116}, year = {2019} } @article{faucris.111726384, abstract = {Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of physiological and immunological processes. Recently, one of their members PPAR?/? has been identified as major player in the maintenance of bone homeostasis, by promoting Wnt signalling activity in osteoblast and mesenchymal stem cells (MSC). PPAR?/? not only controls the fate of MSC but also regulates their immunosuppressive properties by directly modulating their NF-?B activity. In this review, we discuss how the regulation of PPAR?/? provides an innovative strategy for an optimisation of MSC-based therapy.}, author = {Djouad, Farida and Ipseiz, Natacha and Luz-Crawford, Patricia and Scholtysek, Carina and Krönke, Gerhard and Jorgensen, Christian}, doi = {10.1016/j.biochi.2016.11.011}, faupublication = {yes}, journal = {Biochimie}, note = {EVALuna2:13380}, peerreviewed = {Yes}, title = {{PPARβ}/δ: {A} master regulator of mesenchymal stem cell functions}, year = {2016} } @article{faucris.240759011, abstract = {Mesenchymal stem cell (MSC)-based therapy is being increasingly considered a powerful opportunity for several disorders based on MSC immunoregulatory properties. Nonetheless, MSC are versatile and plastic cells that require an efficient control of their features and functions for their optimal use in clinic. Recently, we have shown that PPARβ/δ is pivotal for MSC immunoregulatory and therapeutic functions. However, the role of PPARβ/δ on MSC metabolic activity and the relevance of PPARβ/δ metabolic control on MSC immunosuppressive properties have never been addressed. Here, we demonstrate that PPARβ/δ deficiency forces MSC metabolic adaptation increasing their glycolytic activity required for their immunoregulatory functions on Th1 and Th17 cells. Additionally, we show that the inhibition of the mitochondrial production of ATP in MSC expressing PPARβ/δ, promotes their metabolic switch towards aerobic glycolysis to stably enhance their immunosuppressive capacities significantly. Altogether, these data demonstrate that PPARβ/δ governs the immunoregulatory potential of MSC by dictating their metabolic reprogramming and pave the way for enhancing MSC immunoregulatory properties and counteracting their versatility.}, author = {Contreras-Lopez, R. A. and Elizondo-Vega, R. and Torres, M. J. and Vega-Letter, A. M. and Luque-Campos, N. and Paredes-Martinez, M. J. and Pradenas, C. and Tejedor, G. and Oyarce, K. and Salgado, M. and Jorgensen, C. and Khoury, M. and Krönke, Gerhard and Garcia-Robles, M. A. and Altamirano, C. and Luz-Crawford, P. and Djouad, F.}, doi = {10.1038/s41598-020-68347-x}, faupublication = {yes}, journal = {Scientific Reports}, note = {CRIS-Team Scopus Importer:2020-07-24}, peerreviewed = {Yes}, title = {{PPARβ}/δ-dependent {MSC} metabolism determines their immunoregulatory properties}, volume = {10}, year = {2020} } @article{faucris.112254164, abstract = {To define how peroxisome proliferator-activated receptor (PPAR) ?/? expression level in mesenchymal stem cells (MSCs) could predict and direct both their immunosuppressive and therapeutic properties. PPAR?/? interacts with factors such as nuclear factor-kappa B (NF-?B) and regulates the expression of molecules including vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1. Since these molecules are critical for MSC function, we investigated the role of PPAR?/? on MSC immunosuppressive properties.We either treated human MSCs (hMSCs) with the irreversible PPAR?/? antagonist (GSK3787) or derived MSCs from mice deficient for PPAR?/? (PPAR?/?(-/-) MSCs). We used the collagen-induced arthritis (CIA) as model of immune-mediated disorder and the MSC-immune cell coculture assays.Modulation of PPAR?/? expression in hMSCs either using GSK3787 or hMSCs from different origin reveals that MSC immunosuppressive potential is inversely correlated with Ppard expression. This was consistent with the higher capacity of PPAR?/?(-/-) MSCs to inhibit both the proliferation of T lymphocytes, in vitro, and arthritic development and progression in CIA compared with PPAR?/?(+/+) MSCs. When primed with proinflammatory cytokines to exhibit an immunoregulatory phenotype, PPAR?/?(-/-) MSCs expressed a higher level of mediators of MSC immunosuppression including VCAM-1, ICAM-1 and nitric oxide (NO) than PPAR?/?(+/+) MSCs. The enhanced NO2 production by PPAR?/?(-/-) MSCs was due to the increased retention of NF-?B p65 subunit on the ?B elements of the inducible nitric oxide synthase promoter resulting from PPAR?/? silencing.Our study is the first to show that the inhibition or knockdown of PPAR?/? in MSCs primes their immunoregulatory functions. Thus, the regulation of PPAR?/? expression provides a new strategy to generate therapeutic MSCs with a stable regulatory phenotype.}, author = {Luz-Crawford, P. and Ipseiz, N. and Espinosa-Carrasco, G. and Caicedo, A. and Tejedor, G. and Toupet, K. and Loriau, J. and Scholtysek, C. and Stoll, C. and Khoury, M. and Noel, D. and Jorgensen, C. and Krönke, Gerhard and Djouad, F.}, doi = {10.1136/annrheumdis-2015-208696}, faupublication = {yes}, journal = {Annals of the Rheumatic Diseases}, note = {EVALuna2:13232}, pages = {2166-2174}, peerreviewed = {Yes}, title = {{PPARβ}/δ directs the therapeutic potential of mesenchymal stem cells in arthritis}, volume = {75}, year = {2016} } @article{faucris.204848439, abstract = {Peroxisome proliferator-activated receptors (PPARs) act as metabolic sensors and central regulators of fat and glucose homeostasis. Furthermore, PPAR? has been implicated as major catabolic regulator of bone mass in mice and humans. However, a potential involvement of other PPAR subtypes in the regulation of bone homeostasis has remained elusive. Here we report a previously unrecognized role of PPAR?/? as a key regulator of bone turnover and the crosstalk between osteoblasts and osteoclasts. In contrast to activation of PPAR?, activation of PPAR?/? amplified Wnt-dependent and ?-catenin-dependent signaling and gene expression in osteoblasts, resulting in increased expression of osteoprotegerin (OPG) and attenuation of osteoblast-mediated osteoclastogenesis. Accordingly, PPAR?/?-deficient mice had lower Wnt signaling activity, lower serum concentrations of OPG, higher numbers of osteoclasts and osteopenia. Pharmacological activation of PPAR?/? in a mouse model of postmenopausal osteoporosis led to normalization of the altered ratio of tumor necrosis factor superfamily, member 11 (RANKL, also called TNFSF11) to OPG, a rebalancing of bone turnover and the restoration of normal bone density. Our findings identify PPAR?/? as a promising target for an alternative approach in the treatment of osteoporosis and related diseases.}, author = {Scholtysek, Carina and Katzenbeisser, Julia and Fu, He and Uderhardt, Stefan and Ipseiz, Natacha and Stoll, Cornelia and Zaiss, Mario and Stock, Michael and Donhauser, Laura-Robina and Boehm, Christina and Kleyer, Arnd and Heß, Andreas and Engelke, Klaus and David, Jean-Pierre and Djouad, Farida and Tuckermann, Jan Peter and Desvergne, Beatrice and Schett, Georg and Krönke, Gerhard}, doi = {10.1038/nm.3146}, faupublication = {yes}, journal = {Nature Medicine}, note = {EVALuna2:8501}, pages = {608-13}, peerreviewed = {Yes}, title = {{PPARβ}/δ governs {Wnt} signaling and bone turnover}, volume = {19}, year = {2013} } @article{faucris.238879433, abstract = {Bone turnover, which is determined by osteoclast-mediated bone resorption and osteoblast-mediated bone formation, represents a highly energy consuming process. The metabolic requirements of osteoblast differentiation and mineralization, both essential for regular bone formation, however, remain incompletely understood. Here we identify the nuclear receptor peroxisome proliferator-activated receptor (PPAR) δ as key regulator of osteoblast metabolism. Induction of PPARδ was essential for the metabolic adaption and increased rate in mitochondrial respiration necessary for the differentiation and mineralization of osteoblasts. Osteoblast-specific deletion of PPARδ in mice, in turn, resulted in an altered energy homeostasis of osteoblasts, impaired mineralization and reduced bone mass. These data show that PPARδ acts as key regulator of osteoblast metabolism and highlight the relevance of cellular metabolic rewiring during osteoblast-mediated bone formation and bone-turnover.}, author = {Müller, Dorothea and Stoll, Cornelia and Palumbo-Zerr, Katrin and Böhm, Christina and Krishnacoumar, Brenda and Ipseiz, Natacha and Taubmann, Jule and Zimmermann, Max and Böttcher, Martin and Mougiakakos, Dimitrios and Tuckermann, Jan and Djouad, Farida and Schett, Georg and Scholtysek, Carina and Krönke, Gerhard}, doi = {10.1038/s41598-020-65305-5}, faupublication = {yes}, journal = {Scientific Reports}, note = {CRIS-Team Scopus Importer:2020-06-02}, peerreviewed = {Yes}, title = {{PPARδ}-mediated mitochondrial rewiring of osteoblasts determines bone mass}, volume = {10}, year = {2020} } @article{faucris.271006994, abstract = {Background: The accumulation of risk for the development of rheumatoid arthritis (RA) is regarded as a continuum that may start with interacting environmental and genetic factors, proceed with the initiation of autoimmunity, and result in the formation of autoantibodies such as anti-citrullinated peptide antibodies (ACPA). In parallel, at-risk individuals may be asymptomatic or experience joint pain (arthralgia) that is itself non-specific or clinically suspicious for evolving RA, even in the absence of overt arthritis. Optimal strategies for the management of people at-risk of RA, both for symptom control and to delay or prevent progression to classifiable disease, remain poorly understood. Methods: To help address this, groups of stakeholders from academia, clinical rheumatology, industry and patient research partners have collaborated to advance understanding, define and study different phases of the at-risk state. In this current report we describe different European initiatives in the field and the successful effort to build a European Registry of at-risk people to facilitate observational and interventional research. Results: We outline similarities and differences between cohorts of at-risk individuals at institutions spanning several countries, and how to best combine them within the new database. Over the past 2 years, besides building the technical infrastructure, we have agreed on a core set of variables that all partners should strive to collect for harmonization purposes. Conclusion: We emphasize to address this process from different angles and touch on the biologic, epidemiologic, analytic, and regulatory aspects of collaborative studies within a meta-database of people at-risk of RA.}, author = {Studenic, Paul and Hensvold, Aase and Kleyer, Arnd and Van Der Helm-Van Mil, Annette and Pratt, Arthur G. and Sieghart, Daniela and Krönke, Gerhard and Williams, Ruth and De Souza, Savia and Karlfeldt, Susanne and Johannesson, Martina and Krogh, Niels Steen and Klareskog, Lars and Catrina, Anca I.}, doi = {10.3389/fmed.2022.824501}, faupublication = {yes}, journal = {Frontiers in Medicine}, keywords = {database; multi-center study; observational; prevention; rheumatoid arthritis}, note = {CRIS-Team Scopus Importer:2022-03-18}, peerreviewed = {Yes}, title = {{Prospective} {Studies} on the {Risk} of {Rheumatoid} {Arthritis}: {The} {European} {Risk} {RA} {Registry}}, volume = {9}, year = {2022} } @article{faucris.265775188, abstract = {Macrophages are among the phylogenetically oldest cells of the immune system and are found in all tissues and organs. In addition to playing an important role in immune response against pathogenic microorganisms, these cells were previously described to play a vital role in chronic inflammatory diseases such as rheumatoid arthritis. Using novel techniques such as single-cell sequencing and advanced microscopy techniques it has now been shown that macrophages are far more versatile. Thus, these cells contribute considerably to tissue homeostasis and tissue regeneration. As each tissue has to fulfill special requirements, macrophages vary in their phenotype and function between organs. New data have now identified a specialised population of epithelioid macrophages that exert a protective and anti-inflammatory function in synovial tissue and prevent the initial onset as well as episodes of joint inflammation in rheumatoid arthritis.}, author = {Knab, Katharina and Chambers, David and Krönke, Gerhard}, doi = {10.1007/s00393-021-01112-1}, faupublication = {yes}, journal = {Zeitschrift für Rheumatologie}, keywords = {Macrophage heterogeneity; Macrophage ontogeny; Resident macrophages; Synovial macrophages; Synovial microenvironment}, note = {CRIS-Team Scopus Importer:2021-11-05}, peerreviewed = {Yes}, title = {{Protektive} {Makrophagen}: {Neue} {Einblicke} zur {Rolle} von {Synovialmakrophagen} bei entzündlichen {Gelenkerkrankungen}}, year = {2021} } @article{faucris.122732104, abstract = {Abstract Aims: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation.A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin.Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans.We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans. Antioxid. Redox Signal. 21, 2231-2245.}, author = {Kelkka, Tiina and Kienhoefer, Deborah and Hoffmann, Markus and Linja, Marjo and Wing, Kajsa and Sareila, Outi and Hultqvist, Malin and Laajala, Essi and Chen, Zhi and Vasconcelos, Julia and Neves, Esmeralda and Guedes, Margarida and Marques, Laura and Krönke, Gerhard and Helminen, Merja and Kainulainen, Leena and Olofsson, Peter and Jalkanen, Sirpa and Lahesmaa, Riitta and Margarida Souto-Carneiro, M. and Holmdahl, Rikard}, doi = {10.1089/ars.2013.5828}, faupublication = {yes}, journal = {Antioxidants & Redox Signaling}, note = {EVALuna2:13008}, pages = {2231-45}, peerreviewed = {Yes}, title = {{Reactive} oxygen species deficiency induces autoimmunity with type 1 interferon signature}, volume = {21}, year = {2014} } @inproceedings{faucris.222104494, address = {LONDON}, author = {Krönke, Gerhard}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, date = {2019-06-12/2019-06-15}, doi = {10.1136/annrheumdis-2019-eular.8521}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2019-07-12}, pages = {30-30}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{REGULATION} {OF} {AUTOANTIBODY} {ACTIVITY} {BY} {T} {CELL} {SUBSETS}}, venue = {Madrid}, year = {2019} } @article{faucris.108415164, abstract = {The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-TH17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotoleranc}, author = {Pfeifle, René and Rothe, Tobias and Ipseiz, Natacha and Scherer, Hans U. and Culemann, Stephan and Harre, Ulrike and Ackermann, Jochen and Seefried, Martina and Kleyer, Arnd and Uderhardt, Stefan and Haugg, Benjamin and Huebert, Axel J. and Daum, Patrick and Heidkamp, Gordon Frederik and Ge, Changrong and Böhm, Sybille and Lux, Anja and Schuh, Wolfgang and Magorivskal, Iryna and Nandakumar, Kutty S. and Loennblom, Erik and Becker, Christoph and Dudziak, Diana and Wuhrer, Manfred and Rombouts, Yoann and Koeleman, Carolien A. and Toes, Rene and Winkler, Thomas and Holmdahl, Rikard and Herrmann, Martin and Blueml, Stephan and Nimmerjahn, Falk and Schett, Georg and Krönke, Gerhard}, doi = {10.1038/ni.3579}, faupublication = {yes}, journal = {Nature Immunology}, month = {Jan}, pages = {104-113}, peerreviewed = {unknown}, title = {{Regulation} of autoantibody activity by the {IL}-23-{TH17} axis determines the onset of autoimmune disease.}, volume = {18}, year = {2017} } @article{faucris.220853562, abstract = {Alternatively activated macrophages (AAMs) can contribute to wound healing, regulation of glucose and fat metabolism, resolution of inflammation, and protective immunity against helminths. Their differentiation, tissue distribution, and effector functions are incompletely understood. Murine AAMs express high levels of resistin-like molecule (RELM) α, an effector protein with potent immunomodulatory functions. To visualize RELMα+ macrophages (MΦs) in vivo and evaluate their role in defense against helminths, we generated RELMα reporter/deleter mice. Infection with the helminth Nippostrongylus brasiliensis induced expansion of RELMα+ lung interstitial but not alveolar MΦs in a STAT6-dependent manner. RELMα+ MΦs were required for prevention of fatal lung damage during primary infection. Furthermore, protective immunity was lost upon specific deletion of RELMα+ MΦs during secondary infection. Thus, RELMα reporter/deleter mice reveal compartmentalization of AAMs in different tissues and demonstrate their critical role in resolution of severe lung inflammation and protection against migrating helminths.}, author = {Krljanac, Branislav and Schubart, Christoph and Naumann, Ronald and Wirtz, Stefan and Culemann, Stephan and Krönke, Gerhard and Vöhringer, David}, doi = {10.1126/sciimmunol.aau3814}, faupublication = {yes}, journal = {Science immunology}, note = {CRIS-Team Scopus Importer:2019-06-18}, peerreviewed = {Yes}, title = {{RELMα}-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection}, volume = {4}, year = {2019} } @article{faucris.282054336, abstract = {Objectives To evaluate the feasibility, accuracy, usability and acceptability of two upper arm self-sampling devices for measurement of autoantibodies and C reactive protein (CRP) levels in patients with immune-mediated rheumatic diseases (IMRDs). Methods 70 consecutive patients with IMRD with previously documented autoantibodies were assigned to supervised and unsupervised self-collection of capillary blood with the Tasso+ or TAP II device. Interchangeability of 17 biomarkers with standard venesection was assessed by: concordance, correlation, paired sample hypothesis testing and Bland-Altman plots. Patients completed an evaluation questionnaire, including the System Usability Scale (SUS) and Net Promoter Score (NPS). Results While 80.0% and 77.0% were able to safely and successfully collect capillary blood using the Tasso+ and TAP II within the first attempt, 69 of 70 (98.6%) patients were successful in collecting capillary blood within two attempts. Concordance between venous and capillary samples was high; 94.7% and 99.5% for positive and negative samples, respectively. For connective tissue disease screen, anti-Ro52 and anti-proteinase 3 autoantibody levels, no significant differences were observed. Self-sampling was less painful than standard venesection for the majority of patients (Tasso+: 71%; TAP II: 63%). Both devices were well accepted (NPS; both: +28%), usability was perceived as excellent (SUS; Tasso+: 88.6 of 100; TAP II: 86.0 of 100) and 48.6 %/62.9% of patients would prefer to use the Tasso+/TAP II, respectively, instead of a traditional venous blood collection. Conclusions Remote self-collection of capillary blood using upper arm-based devices for autoantibody and CRP analysis in patients with autoimmune rheumatic diseases is feasible, accurate and well accepted among patients.}, author = {Zarbl, Joshua and Eimer, Ekaterina and Gigg, Camilla and Bendzuck, Gerlinde and Korinth, Marianne and Elling-Audersch, Corinna and Kleyer, Arnd and Simon, David and Böltz, Sebastian and Krusche, Martin and Mucke, Johanna and Muehlensiepen, Felix and Vuillerme, Nicolas and Krönke, Gerhard and Schett, Georg and Knitza, Johannes}, doi = {10.1136/rmdopen-2022-002641}, faupublication = {yes}, journal = {RMD Open}, note = {CRIS-Team WoS Importer:2022-09-23}, peerreviewed = {Yes}, title = {{Remote} self-collection of capillary blood using upper arm devices for autoantibody analysis in patients with immune-mediated inflammatory rheumatic diseases}, volume = {8}, year = {2022} } @article{faucris.245488419, abstract = {Objective. During the course of different musculoskeletal diseases, joints are progressively damaged by inflammatory, infectious, or mechanical stressors, leading to joint destruction and disability. While effective strategies to inhibit joint inflammation, such as targeted cytokine-blocking therapy, have been developed during the last decade, the molecular mechanisms of joint damage are still poorly understood. This study was undertaken to investigate the role of the Wnt pathway modulator R-Spondin 1 (RSpo1) in protecting bone and cartilage in a mouse model of arthritis. Methods. Tumor necrosis factor α (TNFα)-transgenic mice were treated with vehicle or Rspo1. Mice were evaluated for signs of arthritis, and histologic analysis of the hind paws was performed. Moreover, we determined the effect of Rspo1 on Wnt signaling activity and osteoprotegerin (OPG) expression in murine primary osteoblasts. Results. The secreted Wnt pathway modulator RSpo1 was highly effective in preserving the structural integrity of joints in a TNFα-transgenic mouse model of arthritis by protecting bone and cartilage from inflammation-related damage. RSpo1 antagonized the Wnt inhibitor Dkk-1 and modulated Wnt signaling in mouse mesenchymal cells. In osteoblasts, RSpo1 induced differentiation and expression of OPG, thereby inhibiting osteoclastogenesis in vitro. In vivo, RSpo1 promoted osteoblast differentiation and bone formation while blocking osteoclast development, thereby contributing to the integrity of joints during inflammatory arthritis. Conclusion. Our results demonstrate the therapeutic potential of RSpo1 as an anabolic agent for the preservation of joint architecture. © 2010, American College of Rheumatology.}, author = {Krönke, Gerhard and Uderhardt, Stefan and Kim, Kyung-Ah and Stock, Michael and Scholtysek, Carina and Zaiss, Mario and Surmann-Schmitt, Cordula and Luther, Julia and Katzenbeisser, Julia and David, Jean-Pierre and Abdollahi-Roodsaz, Shahla and Tran, Karolyn and Bright, Jessica M. and Binnerts, Minke E. and Akhmetshina, Alfiya and Böhm, Christina and Distler, Jörg and Joosten, Leo A. B. and Schett, Georg and Abo, Arie}, doi = {10.1002/art.27496}, faupublication = {yes}, journal = {Arthritis and Rheumatism}, note = {CRIS-Team Scopus Importer:2020-11-20}, pages = {2303-2312}, peerreviewed = {Yes}, title = {{R}-spondin 1 protects against inflammatory bone damage during murine arthritis by modulating the {Wnt} pathway}, volume = {62}, year = {2010} } @article{faucris.119921384, abstract = {Knowledge concerning expression and function of Suppression of Tumorigenicity 2 (ST2) in chondrocytes is at present, limited. Analysis of murine growth plates and ATDC5 chondrocytes indicated peak expression of the ST2 transmembrane receptor (ST2L) and soluble (sST2) isoforms during the hypertrophic differentiation concomitant with the expression of the hypertrophic markers Collagen X (Col X), Runx2 and MMP-13. Gain- and loss-of-function experiments in ATDC5 and primary human growth plate chondrocytes (PHCs), confirmed regulation of ST2 by the key transcription factor Runx2, indicating ST2 to be a novel Runx2 target. ST2 knock-out mice (ST2-/-) exhibited noticeable hypertrophic zone (HZ) reduction in murine growth plates, accompanied by lower expression of Col X and Osteocalcin (OSC) compared to wild-type (WT) mice. Likewise, ST2 knockdown resulted in decreased Col X expression and downregulation of OSC and Vascular Endothelial Growth Factor (VEGF) in ATDC5 cells. The ST2 suppression was also associated with upregulation of the proliferative stage markers Sox9 and Collagen II (Col II), indicating ST2 to be a new regulator of ATDC5 chondrocyte differentiation. Runx3 was, furthermore, identified as a novel Runx2 target in chondrocytes. This study suggests that Runx2 mediates ST2 and Runx3 induction to cooperatively regulate hypertrophic differentiation of ATDC5 chondrocytes.}, author = {Rad, Ehsan Bonyadi and Musumeci, Giuseppe and Pichler, Karin and Heidary, Maryam and Szychlinska, Marta Anna and Castrogiovanni, Paola and Marth, Egon and Boehm, Christina and Srinivasaiah, Sriveena and Krönke, Gerhard and Weinberg, Annelie and Schaefer, Ute}, doi = {10.1038/s41598-017-18044-z}, faupublication = {yes}, journal = {Scientific Reports}, note = {EVALuna2:13522}, pages = {17947}, peerreviewed = {Yes}, title = {{Runx2} mediated {Induction} of {Novel} {Targets} {ST2} and {Runx3} {Leads} to {Cooperative} {Regulation} of {Hypertrophic} {Differentiation} in {ATDC5} {Chondrocytes}}, volume = {7}, year = {2017} } @article{faucris.258796083, abstract = {Objectives: To better understand the factors that influence the humoral immune response to vaccination against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). Methods: Patients and controls from a large COVID-19 study, with (1) no previous history of COVID-19, (2) negative baseline anti-SARS-CoV-2 IgG test and (3) SARS-CoV-2 vaccination at least 10 days before serum collection were measured for anti-SARS-CoV-2 IgG. Demographic, disease-specific and vaccination-specific data were recorded. Results: Vaccination responses from 84 patients with IMID and 182 controls were analysed. While all controls developed anti-SARS-CoV-2 IgG, five patients with IMID failed to develop a response (p=0.003). Moreover, 99.5% of controls but only 90.5% of patients with IMID developed neutralising antibody activity (p=0.0008). Overall responses were delayed and reduced in patients (mean (SD): 6.47 (3.14)) compared with controls (9.36 (1.85); p<0.001). Estimated marginal means (95% CI) adjusted for age, sex and time from first vaccination to sampling were 8.48 (8.12-8.85) for controls and 6.90 (6.45-7.35) for IMIDs. Significantly reduced vaccination responses pertained to untreated, conventionally and anticytokine treated patients with IMID. Conclusions: Immune responses against the SARS-CoV-2 are delayed and reduced in patients with IMID. This effect is based on the disease itself rather than concomitant treatment.}, author = {Simon, David and Tascilar, Koray and Fagni, Filippo and Krönke, Gerhard and Kleyer, Arnd and Meder, Christine and Meder, Christine and Atreya, Raja and Leppkes, Moritz and Kremer, Andreas E. and Pachowsky, Milena and Schuch, Florian and Ronneberger, Monika and Kleinert, Stefan and Hueber, Axel and Manger, Karin and Manger, Bernhard and Berking, Carola and Sticherling, Michael and Neurath, Markus F. and Schett, Georg and Ramming, Andreas}, doi = {10.1136/annrheumdis-2021-220461}, faupublication = {yes}, journal = {Annals of the Rheumatic Diseases}, keywords = {biological therapy; COVID-19; epidemiology; vaccination}, note = {CRIS-Team Scopus Importer:2021-05-21}, peerreviewed = {Yes}, title = {{SARS}-{CoV}-2 vaccination responses in untreated, conventionally treated and anticytokine-treated patients with immune-mediated inflammatory diseases}, year = {2021} } @article{faucris.284998746, abstract = {Introduction: Being able to independently determine vaccine induced antibody responses by minimal-invasive methods is of great interest to enable a flexible and effective vaccination strategy. This study aimed to evaluate (1) the accuracy, feasibility, usability and acceptability of capillary blood and saliva self-sampling to determine SARS-CoV-2 antibody responses in patients with immune-mediated inflammatory diseases (IMIDs) and health professionals (HP). Methods: IMID patients and HP having received two doses of SARS-CoV-2 vaccines, self-collected capillary blood (Tasso+) and saliva samples. Capillary samples were considered interchangeable with venous blood if three criteria were met: Spearman's correlation coefficient (r) > 0.8, non-significant Wilcoxon signed-rank test (i.e., p > 0.05), and a small bias or 95% of tests within 10% difference through Bland-Altman. Participants completed a survey to investigate self-sampling usability (system usability scale; SUS) and acceptability (net promoter score; NPS). Study personnel monitored correct self-sampling completion and recorded protocol deviations. Results: 60 participants (30 IMID patients and 30 HP) were analyzed. We observed interchangeability for capillary samples with an accuracy of 98.3/100% for Anti-SARS-CoV-2 IgG/IgA antibodies, respectively. Fifty-eight capillary blood samples and all 60 saliva samples were successfully collected within the first attempt. Usability of both self-sampling procedures was rated as excellent, with significantly higher saliva ratings (p < 0.001). Capillary self-sampling was perceived as significantly (p < 0.001) less painful compared to traditional venous blood collection. Participants reported a NPS for capillary and saliva self-sampling of +68% and +63%, respectively. The majority of both groups (73%) preferred capillary self-sampling over professional venous blood collection. Conclusion: Our results indicate that capillary self-sampling is accurate, feasible and preferred over conventional venous blood collection. Implementation could enable easy access, flexible vaccination monitoring, potentially leading to a better protection of vulnerable patient groups. Self-collection of saliva is feasible and safe however more work is needed to determine its application in clinical practice.}, author = {Schmetzer, Caroline and Vogt, Ekaterina and Stellar, Laura and Godonou, Elie-Tino and Liphardt, Anna-Maria and Muehlensiepen, Felix and Vuillerme, Nicolas and Hueber, Axel and Kleyer, Arnd and Krönke, Gerhard and Schett, Georg and Simon, David and Knitza, Johannes}, doi = {10.3389/fpubh.2022.994770}, faupublication = {yes}, journal = {Frontiers in Public Health}, keywords = {capillary blood; COVID-19; remote care; self-collection; self-sampling; telehealth}, note = {CRIS-Team Scopus Importer:2022-11-11}, peerreviewed = {Yes}, title = {{Self}-collection of capillary blood and saliva to determine {COVID}-19 vaccine immunogenicity in patients with immune-mediated inflammatory diseases and health professionals}, volume = {10}, year = {2022} } @article{faucris.201391433, author = {Lucas, S. and Omata, Y. and Böttcher, Martin and Hofmann, Jörg and Krishnacoumar, B. and Krönke, Gerhard and Mougiakakos, Dimitrios and Iljazovic, A. and Sonnewald, Uwe and Strowig, T. and Schett, Georg and Zaiss, Mario}, faupublication = {yes}, journal = {European Journal of Immunology}, pages = {217-217}, peerreviewed = {Yes}, title = {{Short} chain fatty acids are potent regulators of systemic bone mass and protect for pathological bone loss by inhibiting osteoclasts}, volume = {47}, year = {2017} } @article{faucris.109610644, abstract = {Microbial metabolites are known to modulate immune responses of the host. The main metabolites derived from microbial fermentation of dietary fibers in the intestine, short-chain fatty acids (SCFA), affect local and systemic immune functions. Here we show that SCFA are regulators of osteoclast metabolism and bone mass in vivo. Treatment of mice with SCFA as well as feeding with a high-fiber diet significantly increases bone mass and prevents postmenopausal and inflammation-induced bone loss. The protective effects of SCFA on bone mass are associated with inhibition of osteoclast differentiation and bone resorption in vitro and in vivo, while bone formation is not affected. Mechanistically, propionate (C3) and butyrate (C4) induce metabolic reprogramming of osteoclasts resulting in enhanced glycolysis at the expense of oxidative phosphorylation, thereby downregulating essential osteoclast genes such as TRAF6 and NFATc1. In summary, these data identify SCFA as potent regulators of osteoclast metabolism and bone homeostasis.}, author = {Lucas, Sebastien and Omata, Yasunori and Hofmann, Jörg and Böttcher, Martin and Iljazovic, Aida and Sarter, Kerstin and Albrecht, Olivia and Schulz, Oscar and Krishnacoumar, Brenda and Krönke, Gerhard and Herrmann, Martin and Mougiakakos, Dimitrios and Strowig, Till and Schett, Georg and Zaiss, Mario}, doi = {10.1038/s41467-017-02490-4}, faupublication = {yes}, journal = {Nature Communications}, note = {EVALuna2:13520}, pages = {55}, peerreviewed = {Yes}, title = {{Short}-chain fatty acids regulate systemic bone mass and protect from pathological bone loss}, volume = {9}, year = {2018} } @inproceedings{faucris.264582520, address = {LONDON}, author = {Tascilar, Koray and Simon, David and Liphardt, Anna-Maria and Meinderink, Timo and Bayat, Sara and Rech, Jürgen and Hueber, A. and Krönke, Gerhard and Schett, Georg and Kleyer, Arnd}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, doi = {10.1136/annrheumdis-2021-eular.4176}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2021-10-01}, pages = {88-89}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{SPATIOTEMPORAL} {DYNAMICS} {OF} {BONE} {LOSS} {BEFORE} {AND} {AFTER} {THE} {ONSET} {OF} {RHEUMATOID} {ARTHRITIS}}, year = {2021} } @article{faucris.229742804, abstract = {Cytokines of the interleukin (IL)-1 family regulate immune and inflammatory responses. The recently discovered IL-36 family members are involved in psoriasis, rheumatoid arthritis, and pulmonary diseases. Here, we show that IL-36α interacts with heme thereby contributing to its regulation. Based on in-depth spectroscopic analyses, we describe two heme-binding sites in IL-36α that associate with heme in a pentacoordinated fashion. Solution NMR analysis reveals structural features of IL-36α and its complex with heme. Structural investigation of a truncated IL-36α supports the notion that the N-terminus is necessary for association with its cognate receptor. Consistent with our structural studies, IL-36-mediated signal transduction was negatively regulated by heme in synovial fibroblast-like synoviocytes from rheumatoid arthritis patients. Taken together, our results provide a structural framework for heme-binding proteins and add IL-1 cytokines to the group of potentially heme-regulated proteins.}, author = {Wißbrock, Amelie and Goradia, Nishit B. and Kumar, Amit and Paul George, Ajay Abisheck and Kühl, Toni and Bellstedt, Peter and Ramachandran, Ramadurai and Hoffmann, Patrick and Galler, Kerstin and Popp, Jürgen and Neugebauer, Ute and Hampel, Kornelia and Zimmermann, Bastian and Adam, Susanne and Wiendl, Maximilian and Krönke, Gerhard and Hamza, Iqbal and Heinemann, Stefan H. and Frey, Silke and Hueber, Axel and Ohlenschläger, Oliver and Imhof, Diana}, doi = {10.1038/s41598-019-53231-0}, faupublication = {yes}, journal = {Scientific Reports}, note = {CRIS-Team Scopus Importer:2019-11-26}, pages = {16893-}, peerreviewed = {Yes}, title = {{Structural} insights into heme binding to {IL}-36α proinflammatory cytokine}, volume = {9}, year = {2019} } @article{faucris.298216833, abstract = {The authors show that the anti-inflammatory effects of clodronate liposomes do not result from the depletion of mononuclear phagocytes but from a functional stunning of polymorphonuclear neutrophils. These findings necessitate a critical revision of the current literature on the role of monocytes and macrophages in inflammation.}, author = {Culemann, Stephan and Knab, Katharina and Euler, Maximilien and Wegner, Anja and Garibagaoglu, Hilal and Ackermann, Jochen and Fischer, Kim and Kienhoefer, Deborah and Crainiciuc, Georgiana and Hahn, Jonas and Grüneboom, Anika and Nimmerjahn, Falk and Uderhardt, Stefan and Hidalgo, Andres and Schett, Georg and Hoffmann, Markus and Krönke, Gerhard}, doi = {10.1084/jem.20220525}, faupublication = {yes}, journal = {Journal of Experimental Medicine}, note = {CRIS-Team WoS Importer:2023-04-28}, peerreviewed = {Yes}, title = {{Stunning} of neutrophils accounts for the anti-inflammatory effects of clodronate liposomes}, volume = {220}, year = {2023} } @article{faucris.286945957, abstract = {Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell–targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell–suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.}, author = {Kretschmann, S. and Völkl, Simon and Reimann, Hannah and Krönke, Gerhard and Schett, Georg and Achenbach, Susanne and Lutzny-Geier, Gloria and Müller, Fabian and Mougiakakos, Dimitrios and Dingfelder, Janin and Flamann, Cindy and Hanssens, L. and Gary, Regina and Mackensen, Andreas and Aigner, Michael}, doi = {10.1016/j.jtct.2022.10.004}, faupublication = {yes}, journal = {Transplantation and Cellular Therapy}, keywords = {Chimeric antigen receptor; Systemic lupus erythematosus; T cells}, note = {CRIS-Team Scopus Importer:2022-12-23}, peerreviewed = {Yes}, title = {{Successful} {Generation} of {CD19} {Chimeric} {Antigen} {Receptor} {T} {Cells} from {Patients} with {Advanced} {Systemic} {Lupus} {Erythematosus}}, year = {2022} } @inproceedings{faucris.274160341, abstract = {The resolution of chemical exchange saturation transfer (CEST) magnetic resonance imaging is limited by physical constraints. To visualize metabolic processes of small structures using CEST in patients knees, an increased resolution is necessary. In this work, we compared trilinear interpolation and zero-filling to neural network-based approaches to estimate a high-resolution image given the corresponding low-resolution data. We could show that a substantial quantitative improvement using neural networks could be achieved for unsaturated images while maintaining a comparable CEST contrast. Generalization of the method to brain CEST MRI was achieved without retraining of the networ}, author = {Folle, Lukas and Tkotz, Katharina and Liebert, Andrzej and Gadjimuradov, Fasil and Kapsner, Lorenz and Fabian, Moritz and Bickelhaupt, Sebastian and Simon, David and Kleyer, Arnd and Krönke, Gerhard and Roemer, Frank and Zaiß, Moritz and Nagel, Armin Michael and Maier, Andreas}, booktitle = {Joint annual meeting ISMRM-ESMRMB ISMRT}, date = {2022-05-07/2022-05-12}, faupublication = {yes}, keywords = {MRI; Super-resolution}, peerreviewed = {Yes}, title = {{Super}-{Resolution} for {CEST} {MRI}}, url = {https://submissions.mirasmart.com/ISMRM2022/itinerary/PresentationDetail.aspx?evdid=3032}, venue = {London, England}, year = {2022} } @article{faucris.281409695, abstract = {The synovial tissue is an immunologically challenging environment where, under homeostatic conditions, highly specialized subsets of immune-regulatory macrophages and fibroblasts constantly prevent synovial inflammation in response to cartilage- and synovial fluid-derived danger signals that accumulate in response to mechanical stress. During inflammatory joint diseases, this immune-regulatory environment becomes perturbed and activated synovial fibroblasts and infiltrating immune cells start to contribute to synovial inflammation and joint destruction. This review summarizes our current understanding of the phenotypic and molecular characteristics of resident synovial macrophages and fibroblasts and highlights their crosstalk during joint homeostasis and joint inflammation, which is increasingly appreciated as vital to understand the molecular basis of prevalent inflammatory joint diseases such as rheumatoid arthritis.}, author = {Knab, Katharina and Chambers, David and Krönke, Gerhard}, doi = {10.3389/fmed.2022.862161}, faupublication = {yes}, journal = {Frontiers in Medicine}, keywords = {fibroblasts; inflammation; macrophages; rheumatoid arthritis; single-cell sequencing; synovial tissue}, note = {CRIS-Team Scopus Importer:2022-09-09}, peerreviewed = {Yes}, title = {{Synovial} {Macrophage} and {Fibroblast} {Heterogeneity} in {Joint} {Homeostasis} and {Inflammation}}, volume = {9}, year = {2022} } @article{faucris.235030297, abstract = {OBJECTIVE: Rheumatoid arthritis (RA) is associated with damage of the articular cartilage and the periarticular bone. While imaging of bone damage has substantially improved in the last years, direct imaging of the articular cartilage of the hand joints in patients with RA is still challenging. METHODS: 3 Tesla Magnetic Resonance Imaging (MRI) was done in 30 RA patients and T2 relaxation times visualizing alteration in the collagen network and hydration of articular cartilage were mapped in six cartilage regions of the metacarpophalangeal joints 2 and 3. Values were related to autoantibody (anti-citrullinated peptide antibodies (ACPA), rheumatoid factor (RF)) status, disease duration, disease activity as well as sex and age of the RA patients. RESULTS: T2 relaxation times could be reliably measured in the six regions of the metacarpophalangeal joints. Significantly higher relaxation times indicating more advanced cartilage alterations were observed in ACPA-positive (p=0.001-0.010) and RF-positive patients (p=0.013-0.025) as well as those with longer disease duration (>3 years; p=0.028-0.043). Current disease activity, sex and age did not influence T2 relaxation times. CONCLUSION: These data show that cartilage damage can be localized and quantified in the hand joints of RA patients by T2 mapping. Furthermore, ACPA and RF positivity as well as disease duration appear to be the crucial factors influencing cartilage damage.}, author = {Renner, Nina and Kleyer, Arnd and Krönke, Gerhard and Simon, David and Söllner, Stefan and Rech, Jürgen and Uder, Michael and Janka, Rolf Matthias and Schett, Georg and Welsch, Goetz and Pachowsky, Milena}, doi = {10.3899/jrheum.180728}, faupublication = {yes}, journal = {Journal of Rheumatology}, note = {EVALuna2:210913}, peerreviewed = {Yes}, title = {{T2} {Mapping} as a {New} {Method} for {Quantitative} {Assessment} of {Cartilage} {Damage} in {RA}}, year = {2019} } @article{faucris.238006380, abstract = {Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoint in translating autoimmunity to inflammation. Zonulin family peptide (zonulin), a potent regulator for intestinal tight junctions, is highly expressed in autoimmune mice and humans and can be used to predict transition from autoimmunity to inflammatory arthritis. Increased serum zonulin levels are accompanied by a leaky intestinal barrier, dysbiosis and inflammation. Restoration of the intestinal barrier in the pre-phase of arthritis using butyrate or a cannabinoid type 1 receptor agonist inhibits the development of arthritis. Moreover, treatment with the zonulin antagonist larazotide acetate, which specifically increases intestinal barrier integrity, effectively reduces arthritis onset. These data identify a preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function.}, author = {Tajik, Narges and Frech, Michael and Schulz, Oscar and Schälter, Fabian and Lucas, Sébastien and Azizov, Vugar and Dürholz, Kerstin and Steffen, Franziska and Omata, Yasunori and Rings, Andreas and Bertog, Marko and Rizzo, Aroldo and Iljazovic, Aida and Basic, Marijana and Kleyer, Arnd and Culemann, Stephan and Krönke, Gerhard and Luo, Yubin and Überla, Klaus and Gaipl, Udo and Frey, Benjamin and Strowig, Till and Sarter, Kerstin and Bischoff, Stephan C. and Wirtz, Stefan and Cañete, Juan D. and Ciccia, Francesco and Schett, Georg and Zaiss, Mario}, doi = {10.1038/s41467-020-15831-7}, faupublication = {yes}, journal = {Nature Communications}, note = {CRIS-Team Scopus Importer:2020-05-05}, peerreviewed = {Yes}, title = {{Targeting} zonulin and intestinal epithelial barrier function to prevent onset of arthritis}, volume = {11}, year = {2020} } @article{faucris.268141283, abstract = {Innovative strategies are needed to adequately assess and monitor disease activity of patients with rheumatoid arthritis (RA) in times of scarce appointments. The aim of the TELERA study is to evaluate the feasibility and performance of asynchronous telemedicine visits based on patient-generated data and patient's drug history. RA patients use a medical app, ABATON, that captures the results of a self-performed quick CRP-test, joint-count, and electronic patient-reported outcomes in between visits. This is a prospective, multi-center, randomized controlled trial performed in four German university centers. The estimated sample size is 120 patients. The main outcome is the agreement of rheumatologists' treatment decisions based on asynchronous telemedicine patient-generated data with traditional in-person rheumatology clinic-based decisions and with patient suggestions. The TELERA trial will provide evidence regarding the implementation of remote care in rheumatology.}, author = {Mucke, Johanna and Knitza, Johannes and Muehlensiepen, Felix and Grahammer, Manuel and Stenzel, Ramona and Simon, David and Kleyer, Arnd and Krönke, Gerhard and Sharp, Charlotte and Bendzuck, Gerlinde and Korinth, Marianne and Elling-Audersch, Corinna and Vuillerme, Nicolas and Schett, Georg and Pecher, Ann-Christin and Krusche, Martin}, doi = {10.3389/fmed.2021.791715}, faupublication = {yes}, journal = {Frontiers in Medicine}, note = {CRIS-Team WoS Importer:2022-01-14}, peerreviewed = {Yes}, title = {{TELERA}-{Asynchronous} {TELEmedicine} for {Patients} {With} {Rheumatoid} {Arthritis}: {Study} {Protocol} for a {Prospective}, {Multi}-{Center}, {Randomized} {Controlled} {Trial}}, volume = {8}, year = {2021} } @article{faucris.245488170, abstract = {Background: Idiopathic and inflammation-dependent fibrotic diseases such systemic sclerosis (SSc) impose a major burden on modern societies. Understanding endogenous mechanisms, which counteract fibrosis, may yield new therapeutic approaches. Lipoxins are highly potent lipid mediators, which have recently been found to be decreased in SSc. Objectives: To determine the potential role of 12/15-lipoxygenase (12/15-LO), the key enzyme for the synthesis of lipoxins, in fibrosis. Methods: Two mouse models for experimental dermal fibrosis (bleomycin-induced dermal fibrosis and tight-skin 1 mouse model) together with bone marrow transfers were used in wildtype and 12/15-LO -/- mice to elucidate the role of this enzyme during dermal fibrosis. Primary dermal fibroblasts of wildtype and 12/15-LO -/- mice, and 12/15-LO-derived eicosanoids, were used to identify underlying molecular mechanisms Results: In both models, 12/15-LO -/- mice exhibited a significant exacerbation of the fibrotic tissue response. Bone marrow transfer experiments disclosed a predominant role of mesenchymal cell-derived 12/15-LO in these antifibrotic effects. Indeed, 12/15-LO -/- fibroblasts showed an enhanced activation of the mitogen-activated protein-kinase pathway and an increased col 1a2 mRNA expression in response to stimulation with transforming growth factor β (TGFβ), whereas 12/15-LO-derived eicosanoids blocked these TGFβ-induced effects. Conclusions: These data indicate that 12/15-LO and its metabolites have a prominent antifibrotic role during dermal fibrosis. This opens new opportunities for therapeutic approaches in the treatment of fibrotic diseases.}, author = {Krönke, Gerhard and Reich, Nicole and Scholtysek, Carina and Akhmetshina, Alfiya and Uderhardt, Stefan and Zerr, Pawel and Palumbo, Katrin and Lang, Veronika and Dees, Clara and Distler, Oliver and Schett, Georg and Distler, Jörg}, doi = {10.1136/annrheumdis-2011-200745}, faupublication = {yes}, journal = {Annals of the Rheumatic Diseases}, note = {CRIS-Team Scopus Importer:2020-11-20}, pages = {1081-1087}, peerreviewed = {Yes}, title = {{The} 12/15-lipoxygenase pathway counteracts fibroblast activation and experimental fibrosis}, volume = {71}, year = {2012} } @article{faucris.245488917, abstract = {Although 12/15-lipoxygenase (12/15-LO) has been implicated as negative regulator of systemic bone mass in mice and humans, the underlying mechanisms remain elusive. Here, we show that 12/15-LO is a positive regulator of osteoclast (OC) development. Enzymatic inhibition as well as genetic ablation of 12/15-LO significantly impaired osteoclastogenesis. Conversely, addition of the 12/15-LO-derived eicosanoids 12- and 15-HETE augmented differentiation of precursors into fully matured OCs. Together these data point towards a crucial role of 12/15-LO in the regulation of OC development. Therefore, 12/15-LO and its human homologue 15-LO may display novel targets for the treatment of diseases such as osteoporosis and rheumatoid arthritis. © 2009 Informa UK Ltd All rights reserved.}, author = {Krönke, Gerhard and Uderhardt, Stefan and Katzenbeisser, Julia and Schett, Georg}, doi = {10.1080/08916930902832488}, faupublication = {yes}, journal = {Autoimmunity}, keywords = {12/15-LO; HETE; OC}, note = {CRIS-Team Scopus Importer:2020-11-20}, pages = {383-385}, peerreviewed = {Yes}, title = {{The} 12/15-lipoxygenase pathway promotes osteoclast development and differentiation}, volume = {42}, year = {2009} } @article{faucris.204401342, abstract = {The immune response to citrullinated antigens is found almost exclusively in patients with rheumatoid arthritis (RA). It is a dynamic response that expands before the onset of disease and generates antibodies (anti-citrullinated protein antibodies (ACPAs)) that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and warrants detailed investigation, as it can offer insights into the earliest immunologic mechanisms that lead up to the development of RA. The acquisition of variable domain glycans, in fact, could enable ACPA-expressing B cells to breach tolerance. Although the underlying mechanisms are still elusive, data to support this concept are emerging, owing to the reliable identification and isolation of citrullinated antigen-directed B cells from patients with RA. This technological proficiency also allows for the generation of an increasing number of well-defined monoclonal ACPAs, and provides the opportunity to test and define the mechanisms by which the citrullinated antigen-directed B cell response contributes to the onset and persistence of inflammation. Together with a revised perception of the HLA-risk effect and novel insights into how T cells can govern antibody effector functions, these developments shape an increasingly clear picture of the B cell response to citrullinated antigens in the development of RA. }, author = {Scherer, Hans Ulrich and Huizinga, Tom W. J. and Krönke, Gerhard and Schett, Georg and Toes, Rene E. M.}, doi = {10.1038/nrrheum.2018.10}, faupublication = {yes}, journal = {Nature Reviews Rheumatology}, note = {EVALuna2:34155}, pages = {157-169}, peerreviewed = {Yes}, title = {{The} {B} cell response to citrullinated antigens in the development of rheumatoid arthritis}, volume = {14}, year = {2018} } @article{faucris.255557842, abstract = {Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.}, author = {Friščić, Jasna and Böttcher, Martin and Reinwald, Christiane and Bruns, Heiko and Wirth, Benjamin and Popp, Sebastian and Walker, Kellie Irene and Ackermann, Jochen A. and Chen, Xi and Turner, Jason and Zhu, Honglin and Seyler, Lisa and Euler, Maximilien and Kirchner, Philipp and Krüger, René and Ekici, Arif Bülent and Major, Triin and Aust, Oliver and Weidner, Daniela and Fischer, Anita and Andes, Fabian T. and Stanojevic, Zeljka and Trajkovic, Vladimir and Herrmann, Martin and Korb-Pap, Adelheid and Wank, Isabel and Heß, Andreas and Winter, Johnathan and Wixler, Viktor and Distler, Jörg and Steiner, Günter and Kiener, Hans P. and Frey, Benjamin and Kling, Lasse and Raza, Karim and Frey, Silke and Kleyer, Arnd and Bäuerle, Tobias and Hughes, Timothy R. and Grüneboom, Anika and Steffen, Ulrike and Krönke, Gerhard and Croft, Adam P. and Filer, Andrew and Köhl, Jörg and Klein, Kerstin and Buckley, Christopher D. and Schett, Georg and Mougiakakos, Dimitrios and Hoffmann, Markus}, doi = {10.1016/j.immuni.2021.03.003}, faupublication = {yes}, journal = {Immunity}, keywords = {arthritis; cell metabolism; cellular senescence; complement system; inflammasome; inflammation; mechanistic target of rapamycin; synovial fibroblasts; tissue priming; trained immunity}, note = {CRIS-Team Scopus Importer:2021-04-19}, peerreviewed = {Yes}, title = {{The} complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts}, year = {2021} } @article{faucris.122953204, abstract = {12/15-Lipoxygenase (12/15-LOX) mediates the enzymatic oxidation of polyunsaturated fatty acids, thereby contributing to the generation of various bioactive lipid mediators. Although 12/15-LOX has been implicated in the pathogenesis of multiple chronic inflammatory diseases, its physiologic functions seem to include potent immune modulatory properties that physiologically contribute to the resolution of inflammation and the clearance of inflammation-associated tissue damage. This review aims to give a comprehensive overview about our current knowledge on the role of this enzyme during the regulation of inflammation and immunity. "This article is part of a Special Issue entitled: Lipid modification and lipid peroxidation products in innate immunity and inflammation edited by Christoph J. Binder".}, author = {Ackermann, Jochen A. and Hofheinz, Katharina and Zaiss, Mario and Krönke, Gerhard}, doi = {10.1016/j.bbalip.2016.07.014}, faupublication = {yes}, journal = {BBA - Biochimica et Biophysica Acta}, note = {EVALuna2:13307}, peerreviewed = {Yes}, title = {{The} double-edged role of 12/15-lipoxygenase during inflammation and immunity}, year = {2016} } @inproceedings{faucris.264314012, address = {LONDON}, author = {Pfeifle, René and Kittler, Julia and Wuhrer, M. and Schett, Georg and Krönke, Gerhard}, booktitle = {ANNALS OF THE RHEUMATIC DISEASES}, doi = {10.1136/annrheumdis-2021-eular.1087}, faupublication = {yes}, note = {CRIS-Team WoS Importer:2021-09-24}, pages = {1042-1043}, peerreviewed = {unknown}, publisher = {BMJ PUBLISHING GROUP}, title = {{THE} {IMPACT} {OF} {IL}-{17A} {THERAPY} {ON} {IGG} {SIALYLATION} {IN} {HUMANS}}, year = {2021} } @article{faucris.208213412, abstract = {Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, α-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW)-induced arthritis was reduced in the T cell-dependent phase, whereas T cell-independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis. }, author = {Fischer, Anita and Abdollahi-Roodsaz, Shahla and Boehm, Christina and Niederreiter, Birgit and Meyer, Brigitte and Yau, Anthony C. Y. and Lonnblom, Erik and Joosten, Leo A. B. and Koenders, Marije and Lehmann, Christian and Dudziak, Diana and Krönke, Gerhard and Holmdahl, Rikard and Steiner, Guenter}, doi = {10.1111/jcmm.13735}, faupublication = {yes}, journal = {Journal of Cellular and Molecular Medicine}, note = {EVALuna2:34780}, pages = {4399-4409}, peerreviewed = {Yes}, title = {{The} involvement of {Toll}-like receptor 9 in the pathogenesis of erosive autoimmune arthritis}, volume = {22}, year = {2018} } @article{faucris.111765984, abstract = {Microglia cells fulfill key homeostatic functions and essentially contribute to host defense within the CNS. Altered activation of microglia, in turn, has been implicated in neuroinflammatory and neurodegenerative diseases. In this study, we identify the nuclear receptor (NR) Nr4a1 as key rheostat controlling the activation threshold and polarization of microglia. In steady-state microglia, ubiquitous neuronal-derived stress signals such as ATP induced expression of this NR, which contributed to the maintenance of a resting and noninflammatory microglia phenotype. Global and microglia-specific deletion of Nr4a1 triggered the spontaneous and overwhelming activation of microglia and resulted in increased cytokine and NO production as well as in an accelerated and exacerbated form of experimental autoimmune encephalomyelitis. Ligand-induced activation of Nr4a1 accordingly ameliorated the course of this disease. Our current data thus identify Nr4a1 as regulator of microglia activation and potentially new target for the treatment of inflammatory CNS diseases such as multiple sclerosis.}, author = {Rothe, Tobias and Ipseiz, Natacha and Faas, Maria and Lang, Stefanie and Perez-Branguli, Francesc and Metzger, Daniel and Ichinose, Hiroshi and Winner, Beate and Schett, Georg and Krönke, Gerhard}, doi = {10.4049/jimmunol.1600638}, faupublication = {yes}, journal = {Journal of Immunology}, note = {EVALuna2:13374}, peerreviewed = {Yes}, title = {{The} {Nuclear} {Receptor} {Nr4a1} {Acts} as a {Microglia} {Rheostat} and {Serves} as a {Therapeutic} {Target} in {Autoimmune}-{Driven} {Central} {Nervous} {System} {Inflammation}}, year = {2017} } @article{faucris.106126284, abstract = {Uptake of apoptotic cells (ACs) by macrophages ensures the nonimmunogenic clearance of dying cells, as well as the maintenance of self-tolerance to AC-derived autoantigens. Upon ingestion, ACs exert an inhibitory influence on the inflammatory signaling within the phagocyte. However, the molecular signals that mediate these immune-modulatory properties of ACs are incompletely understood. In this article, we show that the phagocytosis of apoptotic thymocytes was enhanced in tissue-resident macrophages where this process resulted in the inhibition of NF-?B signaling and repression of inflammatory cytokines, such as IL-12. In parallel, ACs induced a robust expression of a panel of immediate early genes, which included the Nr4a subfamily of nuclear receptors. Notably, deletion of Nr4a1 interfered with the anti-inflammatory effects of ACs in macrophages and restored both NF-?B signaling and IL-12 expression. Accordingly, Nr4a1 mediated the anti-inflammatory properties of ACs in vivo and was required for maintenance of self-tolerance in the murine model of pristane-induced lupus. Thus, our data point toward a key role for Nr4a1 as regulator of the immune response to ACs and of the maintenance of tolerance to "dying self."}, author = {Ipseiz, Natacha and Uderhardt, Stefan and Scholtysek, Carina and Steffen, Martin and Schabbauer, Gernot and Bozec, Aline and Schett, Georg and Krönke, Gerhard}, doi = {10.4049/jimmunol.1303377}, faupublication = {yes}, journal = {Journal of Immunology}, note = {EVALuna2:12878}, pages = {4852-8}, peerreviewed = {Yes}, title = {{The} nuclear receptor {Nr4a1} mediates anti-inflammatory effects of apoptotic cells}, volume = {192}, year = {2014} } @inproceedings{faucris.235741838, author = {Pfeifle, René and Kittler, Julia and Rothe, Tobias and Schett, Georg and Krönke, Gerhard}, doi = {10.1136/annrheumdis-2018-ewrr2019.85}, faupublication = {yes}, note = {EVALuna2:213239}, pages = {A42-A42}, peerreviewed = {Yes}, title = {{THE} {ROLE} {OF} {THE} {IL}-23/{TH17} {AXIS} {AS} {MODULATOR} {OF} {B} {CELL}-{MEDIATED} ({AUTO}){IMMUNE} {RESPONSES}}, volume = {78}, year = {2019} } @inproceedings{faucris.274471228, author = {Aust, Oliver and Thies, Mareike and Weidner, Daniela and Wagner, Fabian and Pechmann, Sabrina and Mill, Leonid and Andreev, Darja and Miyagawa, Ippei and Krönke, Gerhard and Christiansen, Silke and Uderhardt, Stefan and Maier, Andreas and Grüneboom, Anika}, booktitle = {Informatik aktuell}, date = {2022-06-26/2022-06-28}, doi = {10.1007/978-3-658-36932-3{\_}68}, editor = {Klaus Maier-Hein, Thomas M. Deserno, Heinz Handels, Andreas Maier, Christoph Palm, Thomas Tolxdorff}, faupublication = {yes}, isbn = {9783658369316}, note = {CRIS-Team Scopus Importer:2022-05-06}, pages = {333-338}, peerreviewed = {unknown}, publisher = {Springer Science and Business Media Deutschland GmbH}, title = {{Tibia} {Cortical} {Bone} {Segmentation} in {Micro}-{CT} and {X}-ray {Microscopy} {Data} {Using} a {Single} {Neural} {Network}}, venue = {Heidelberg}, year = {2022} } @incollection{faucris.270872767, abstract = {The onset of rheumatic diseases such as rheumatoid arthritis is typically subclinical, which results in challenging early detection of the disease. However, characteristic changes in the anatomy can be detected using imaging techniques such as MRI or CT. Modern imaging techniques such as chemical exchange saturation transfer (CEST) MRI drive the hope to improve early detection even further through the imaging of metabolites in the body. To image small structures in the joints of patients, typically one of the first regions where changes due to the disease occur, a high resolution for the CEST MR imaging is necessary. Currently, however, CEST MR suffers from an inherently low resolution due to the underlying physical constraints of the acquisition. In this work we compared established up-sampling techniques to neural network-based super-resolution approaches. We could show, that neural networks are able to learn the mapping from low-resolution to high-resolution unsaturated CEST images considerably better than present methods. On the test set a PSNR of 32.29 dB (+10%), a NRMSE of 0.14 (+28%), and a SSIM of 0.85 (+15%) could be achieved using a ResNet neural network, improving the baseline considerably. This work paves the way for the prospective investigation of neural networks for super-resolution CEST MRI and, followingly, might lead to a earlier detection of the onset of rheumatic diseases.}, address = {Wiesbaden}, author = {Folle, Lukas and Tkotz, Katharina and Gadjimuradov, Fasil and Kapsner, Lorenz and Fabian, Moritz and Bickelhaupt, Sebastian and Simon, David and Kleyer, Arnd and Krönke, Gerhard and Zaiß, Moritz and Nagel, Armin Michael and Maier, Andreas}, booktitle = {Bildverarbeitung für die Medizin 2022}, doi = {10.1007/978-3-658-36932-3{\_}45}, editor = {Klaus Maier-Hein, Thomas M. Deserno, Heinz Handels, Andreas Maier, Christoph Palm, ThomasTolxdorff}, faupublication = {yes}, isbn = {978-3-658-36932-3}, keywords = {Deep Learning, Rheumatic diseases, Reconstruction}, pages = {210-215}, peerreviewed = {unknown}, publisher = {Springer Vieweg}, series = {Proceedings, German Workshop on Medical Image Computing, Heidelberg, June 26–28, 2022}, title = {{Towards} {Super}-resolution {CEST} {MRI} for {Visualization} of {Small} {Structures}}, year = {2022} } @article{faucris.245489167, abstract = {Objective. To investigate the kinetics of bony spur formation and the relationship of bony spur formation to synovial inflammation and bone erosion in 2 rat arthritis models, and to address whether bony spur formation depends on the expression of tumor necrosis factor α (TNFα) or RANKL. Methods. Analysis of the kinetics of synovial inflammation, bone erosion, osteoclast formation, and growth of bony spurs was performed in rat collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). In addition, inhibition experiments were performed to assess whether inhibition of TNFα and RANKL by pegylated soluble TNF receptor type I (pegTNFRI) and osteoprotegerin (OPG), respectively, affected bony spur formation. Results. Bony spurs emerged from the periosteal surface close to joints, and initial proliferation of mesenchymal cells was noted as early as 3 days and 5 days after onset of CIA and AIA, respectively. Initiation of bony spur formation occurred shortly after the onset of inflammation and bone erosion. Neither pegTNFRI nor OPG could significantly halt the osteophytic responses in CIA and AIA. Conclusion. These results suggest that bony spur formation is triggered by inflammation and initial structural damage in these rat models of inflammatory arthritis. Moreover, emergence of bony spurs depends on periosteal proliferation and is not affected by inhibition of either TNFα or RANKL. Bony spur formation can thus be considered a process that occurs independent of TNFα and RANKL and is triggered by destructive arthritis. © 2009, American College of Rheumatology.}, author = {Schett, Georg and Stolina, Marina and Dwyer, Denise and Zack, Debra and Uderhardt, Stefan and Krönke, Gerhard and Kostenuik, Paul and Feige, Ulrich}, doi = {10.1002/art.24767}, faupublication = {yes}, journal = {Arthritis and Rheumatism}, note = {CRIS-Team Scopus Importer:2020-11-20}, pages = {2644-2654}, peerreviewed = {Yes}, title = {{Tumor} necrosis factor α and {RANKL} blockade cannot halt bony spur formation in experimental inflammatory arthritis}, volume = {60}, year = {2009} } @article{faucris.264873355, abstract = {Immune-mediated chronic inflammatory diseases have emerged as a leading cause of morbidity and mortality in Western countries over the last decades. Although multiple putative factors have been suspected to be causally related to the diseases, their overarching etiology remains unknown. This review article summarizes the current state of scientific knowledge and understanding of the role of non-receptor tyrosine kinases, with a special focus on the Janus kinase TYK2 in autoimmune and immune mediated diseases as well as on the clinical properties of its inhibition. A panel of experts in the field discussed the scientific evidence and molecular rationale for TYK2 inhibition and its clinical application. Reviewing this meeting, we aim at providing an integrated overview of the clinical profile of TYK2 inhibition and its potential in targeted pharmacological therapy of chronic autoimmune and immune-mediated diseases, with a special focus on inflammatory diseases of the skin.}, author = {Ghoreschi, Kamran and Augustin, Matthias and Baraliakos, Xenofon and Krönke, Gerhard and Schneider, Matthias and Schreiber, Stefan and Schulze-Koops, Hendrik and Zeissig, Sebastian and Thaci, Diamant}, doi = {10.1111/ddg.14585}, faupublication = {yes}, journal = {Journal der Deutschen Dermatologischen Gesellschaft}, note = {CRIS-Team WoS Importer:2021-10-08}, peerreviewed = {Yes}, title = {{TYK2} inhibition and its potential in the treatment of chronic inflammatory immune diseases}, year = {2021} } @article{faucris.265507403, author = {Ghoreschi, Kamran and Augustin, Matthias and Baraliakos, Xenofon and Krönke, Gerhard and Schneider, Matthias and Schreiber, Stefan and Schulze-Koops, Hendrik and Zeißig, Sebastian and Thaçi, Diamant}, doi = {10.1111/ddg.14585{\_}g}, faupublication = {yes}, journal = {Journal der Deutschen Dermatologischen Gesellschaft}, note = {CRIS-Team Scopus Importer:2021-10-29}, pages = {1409-1420}, peerreviewed = {Yes}, title = {{TYK2}-{Inhibition}: {Potenzial} bei der {Behandlung} chronisch-entzündlicher {Immunerkrankungen}}, volume = {19}, year = {2021} } @article{faucris.257705690, abstract = {COVID-19 is a life-threatening disease leading to bilateral pneumonia and respiratory failure. The underlying reasons why a smaller percentage of patients present with severe pulmonary symptoms whereas the majority is only mildly affected are to date not well understood.}, author = {Spoerl, Silvia and Kremer, Anita and Aigner, Michael and Eisenhauer, Nina and Koch, Pauline and Meretuk, Lina and Loeffler, Patrick and Tenbusch, Matthias and Maier, Clara and Überla, Klaus and Heinzerling, Lucie and Frey, Benjamin and Lutzny-Geier, Gloria and Winkler, Thomas and Krönke, Gerhard and Vetter, Marcel and Bruns, Heiko and Neurath, Markus and Mackensen, Andreas and Kremer, Andreas and Völkl, Simon}, doi = {10.1002/eji.202049135}, faupublication = {yes}, journal = {European Journal of Immunology}, note = {CRIS-Team WoS Importer:2021-05-07}, peerreviewed = {Yes}, title = {{Upregulation} of {CCR4} in activated {CD8}(+) {T} cells indicates enhanced lung homing in patients with severe acute {SARS}-{CoV}-2 infection}, year = {2021} }