Georg Schett

Universitätsklinikum Erlangen, Erlangen, Bavaria, Germany

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Publications (509)2999.56 Total impact

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    ABSTRACT: To determine whether there is an additive effect of anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) on the number and size of bone erosions in patients with rheumatoid arthritis (RA) METHODS: 242 patients with RA received high-resolution peripheral quantitative CT (HR-pQCT) scans of the metacarpophalangeal joints. Demographic and disease-specific parameters including ACPA and RF levels were recorded from all patients. Erosion numbers and their size were assessed in 238 patients at 714 individual joints (MCP 2, 3 and 4) and 5712 sites (each 4 quadrants in metacarpal heads and phalangeal bases). The volume of erosions was calculated by a semiellipsoid formula.
    Annals of the rheumatic diseases. 08/2014;
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    ABSTRACT: Introduction A major subset of patients with rheumatoid arthritis (RA) is characterised by the presence of circulating autoantibodies directed to citrullinated proteins/peptides (ACPA). These autoantibodies, which are commonly detected using an ELISA assay based on synthetic cyclic citrullinated peptides (CCP), predict clinical onset and a destructive disease course. In the present study, we have utilised plasma and synovial fluids from patients with RA, for the affinity purification and characterisation of anti-CCP2 reactive antibodies, with an aim to generate molecular tools that can be utilized in vitro and in vivo for future investigations into the pathobiology of the ACPA response. Specifically, this study aims to demonstrate that the surrogate marker CCP2 can capture ACPA that bind to autoantigens expressed in vivo, in the major inflammatory lesions of RA, i.e. in the rheumatoid joint. Methods Plasma (n = 16) and synovial fluid (n = 26) samples were collected from RA patients with anti-CCP2 IgG levels above 300 AU/ml. Total IgG was isolated on Protein G columns, and subsequently applied to CCP2 affinity columns. Purified anti-CCP2 IgG was analysed for reactivity and specificity using the CCPlus® ELISA assay, in-house peptide-ELISAs, western blot and immunohisto-/immunocytochemistry. Results Approximately 2 % of the total IgG pool in both plasma and synovial fluid was CCP2-reactive. Purified anti-CCP2 reactive antibodies from different patients showed differences in binding to CCP2 and differences in binding to citrullinated peptides from α-enolase, −vimentin, −fibrinogen, and -collagen type II, illustrating different ACPA fine-specificity profiles. Furthermore, the purified ACPA bound not only in vitro citrullinated proteins but more importantly, in vivo-generated epitopes on synovial fluid cells and synovial tissues from RA patients. Conclusions We have isolated ACPA from plasma and synovial fluid, and demonstrated that the CCP2 peptides, frequently used in diagnostic ELISA assays, de facto act as surrogate antigens for at least four different, well-characterised, largely non cross-reactive, ACPA fine-specificities. Moreover, we have determined the concentration and proportion of CCP2-reactive IgG molecules in rheumatoid plasma and synovial fluid, and we have shown that the purified ACPA can be used to detect both in vitro- and in vivo-generated citrullinated epitopes by various techniques. We anticipate that these antibodies will provide us with new opportunities to investigate the potential pathogenic effects of human ACPAs.
    Arthritis research & therapy 07/2014; · 4.27 Impact Factor
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    ABSTRACT: Objectives: Both psoriatic arthritis (PSA) and hand osteoarthrits (HOA) lead to periarticular bone proliferation. Aim of this study was to investigate the different patterns of bony spur formation in PSA and HOA by high-resolution peripheral quantitative computed tomography (HR-pQCT).Methods: 70 patients, 25 with PSA, 25 with HOA and 20 healthy controls, with similar age and sex distribution and clinical involvement of the metacarpophalangeal (MCP) joints received a HR-pQCT examination of the MCP 2, 3 and 4 joint of the dominantly affected hand. Demographic and disease-specific data were recorded and number, size and distribution of bony spur were assessed and compared between PsA and HOA.Results: Overall number and size of bony spurs was similar between PsA and HOA. PsA and HOA, however, substantially differed in the localization of lesions within individual joints: Bony spurs in PsA dominated the radial sides of the joints (PsA vs. HOA: metacarpal head 2: p<0.001; phalangeal base 2: p<0.001), whereas the palmar and dorsal sites were the predilection sites in HOA. Detailed anatomical analysis showed that enthesial regions are almost exclusively affected in PsA, but are spared in HOA, whereas bony spurs in HOA typically emerge at the cartilage-bone interphase and the joint margins.Conclusions: Our findings suggest a similar burden of bony spurs in PsA and HOA. Nonetheless, the anatomical sites of bony proliferation in PsA and HOA are different between PsA and HOA. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 07/2014;
  • Georg Schett
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    ABSTRACT: The simultaneous presence of bone erosions and bony spurs (osteophytes, enthesophytes) in the joints of patients with psoriatic arthritis (PsA) suggests that the disease leads to enhanced bone resorption as well as increased bone formation, the latter of which has not been observed in patients with rheumatoid arthritis. At the 2013 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), members heard an update on the current research into the cytokine signature in PsA and its effects on new bone formation.
    The Journal of rheumatology. 06/2014; 41(6):1218-9.
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    ABSTRACT: The overexpression of tumor necrosis factor (TNF)-alpha leads to systemic as well as local loss of bone and cartilage and is also an important regulator during fracture healing. In this study, we investigate how TNF-alpha inhibition using a targeted monoclonal antibody affects fracture healing in a TNF-alpha driven animal model of human rheumatoid arthritis (RA) and elucidate the question whether enduring the anti TNF-alpha therapy after trauma is beneficial or not.
    BMC Musculoskeletal Disorders 05/2014; 15(1):184. · 1.88 Impact Factor
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    ABSTRACT: Vitamin D (Vit D) deficiency may be linked to the development of obesity-associated complications such as insulin resistance and type 2 diabetes. We therefore evaluated the relationship of Vit D serum concentrations with metabolic parameters and type 2 diabetes in middle-aged Caucasian men and women. One thousand six hundred and thirty-one Caucasians (832 males, 58.8 ± 9.7 years; 799 females, 59.7 ± 10.7 years) were evaluated in a cross-sectional study. Vit D status was assessed by measuring the serum concentration of 25-hydroxyvitamin D3 [25(OH)D3]. Type 2 diabetes prevalence was ascertained by medical history, fasting plasma glucose concentrations, oral glucose tolerance testing and/or glycosylated hemoglobin. Men displayed higher crude or seasonally adjusted 25(OH)D3 serum concentrations than women (24.64 ± 10.98 vs. 22.88 ± 11.6 ng/ml; P < 0.001). Strong associations between body mass index (BMI) and 25(OH)D3 were observed in both genders (P < 0.001). Seasonally adjusted levels of 25(OH)D3 revealed stronger associations with type 2 diabetes in women than men (P < 0.001). However, adjustment for BMI and other confounding variables revealed an independent inverse association of 25(OH)D3 with diabetes only in women (P < 0.001), whereas the association was abrogated in men. Using a 15 ng/ml 25(OH)D3 cutoff for binary comparison, adjusted odds ratios for having newly diagnosed or known type 2 diabetes more than doubled (2.95 [95 % CI 1.37-4.89] and 3.26 [1.59-6.68], respectively), in women below the cutoff. We conclude that in women, but not in men, low 25(OH)D3 serum levels are independently associated with type 2 diabetes. These findings suggest sex-specific effects of Vit D in the pathogenesis of type 2 diabetes.
    Acta Diabetologica 05/2014; · 4.63 Impact Factor
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    ABSTRACT: Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.
    Science translational medicine 05/2014; 6(235):235ra60. · 10.76 Impact Factor
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    ABSTRACT: Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated
    Nature medicine 04/2014; advance online publication. · 27.14 Impact Factor
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    ABSTRACT: Gout is characterized by an acute inflammatory reaction and the accumulation of neutrophils in response to monosodium urate (MSU) crystals. Inflammation resolves spontaneously within a few days, although MSU crystals can still be detected in the synovial fluid and affected tissues. Here we report that neutrophils recruited to sites of inflammation undergo oxidative burst and form neutrophil extracellular traps (NETs). Under high neutrophil densities, these NETs aggregate and degrade cytokines and chemokines via serine proteases. Tophi, the pathognomonic structures of chronic gout, share characteristics with aggregated NETs, and MSU crystals can induce NETosis and aggregation of NETs. In individuals with impaired NETosis, MSU crystals induce uncontrolled production of inflammatory mediators from neutrophils and persistent inflammation. Furthermore, in models of neutrophilic inflammation, NETosis-deficient mice develop exacerbated and chronic disease that can be reduced by adoptive transfer of aggregated NETs. These findings suggest that aggregated NETs promote the resolution of neutrophilic inflammation by degrading cytokines and chemokines and disrupting neutrophil recruitment and activation.
    Nature medicine 04/2014; · 27.14 Impact Factor
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    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-κB 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-κB 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."
    The Journal of Immunology 04/2014; · 5.52 Impact Factor
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    ABSTRACT: S100A4 is a calcium binding protein with regulatory functions in cell homeostasis, proliferation and differentiation that has been shown to promote cancer progression and metastasis. In the present study, we evaluated the role of S100A4 in fibroblast activation in systemic sclerosis (SSc). The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4(-/-)) mice. Transforming growth factor β (TGF-β) signalling was assessed by reporter assays, staining for phosphorylated Smad2/3 and analyses of target genes. The expression of S100A4 was increased in SSc skin and in experimental fibrosis in a TGF-β/Smad-dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4(-/-) mice were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower myofibroblast counts. Deficiency of S100A4 also ameliorated fibrosis in the tight-skin-1 (Tsk-1) mouse model. We characterised S100A4 as a downstream mediator of the stimulatory effects of TGF-β on fibroblasts in SSc. TGF-β induces the expression of S100A4 to stimulate the release of collagen in SSc fibroblasts and induce fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-β and neutralising antibodies against S100A4 are currently evaluated, S100A4 might be a candidate for novel antifibrotic therapies.
    Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
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    ABSTRACT: Osteoarthritis (OA) currently affects over 40 million Europeans, with its associated personal suffering and significant economic burden for health systems set to dramatically escalate in a rapidly ageing Europe. Given the very limited effective therapeutic options for OA, the European League Against Rheumatism (EULAR) created an ad hoc committee of OA researchers, clinicians and patients to consider a research agenda focussed on the areas of epidemiology, pathogenesis, imaging and biomarkers, and therapies. The committee deliberated and listed research needs in these areas and also established some cross-area priority themes: predictors of OA progression, especially where this might enable stratified interventions; understanding mechanisms of OA pain; improved understanding of tissue communication in a process where multiple tissue pathologies are common; developing concepts of, and consequently interventions for, early OA where both pain and structural processes may be more effectively targeted than in typical clinical presentations; and the need for new treatment strategies, with examples discussed on pathology-targeted therapies and optimal combinations of therapies. This research agenda should provide useful guidance for all researchers in this field and hopefully lead to improved OA care.
    Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    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 LXRα-, LXRβ- and LXR-α/β-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. LXRα-, LXRβ- and LXRα/β-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.
    Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    ABSTRACT: Imaging is essential to the evaluation of bone and joint diseases, and the digital era has contributed to an exponential increase in the number of publications on noninvasive analytical techniques for the quantification of changes to bone and joints that occur in health and in disease. One such technique is high-resolution peripheral quantitative CT (HR-pQCT), which has introduced a new dimension in the imaging of bone and joints by providing images that are both 3D and at high resolution (82 μm isotropic voxel size), with a low level of radiation exposure (3-5 μSv). HR-pQCT enables the analysis of cortical and trabecular properties separately and to apply micro-finite element analysis for calculating bone biomechanical competence in vivo at the distal sites of the skeleton (distal radius and distal tibia). Moreover, HR-pQCT makes possible the in vivo assessment of the spatial distribution, dimensions and delineation of cortical bone erosions, osteophytes, periarticular cortical and trabecular microarchitecture, and 3D joint-space volume of the finger joints and wrists. HR-pQCT is, therefore, a technique with a high potential for improving our understanding of bone and joint diseases at the microarchitectural level.
    Nature Reviews Rheumatology 03/2014; · 9.75 Impact Factor
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    ABSTRACT: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. NCT01172938.
    Annals of the rheumatic diseases 03/2014; · 8.11 Impact Factor
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    ABSTRACT: The cytokine interleukin 33 (IL-33), a member of the IL-1 family, is released in response to various types of endothelial or epithelial cell damage. IL-33 is constitutively expressed in epidermal keratinocytes, upregulated in inflamed skin and acts as an endogenous danger signal that mediates the recruitment of immune cells to sites of cellular damage. Our preliminary data have shown that psoriatic lesions express more nuclear IL-33 compared to perilesional biopsies from the same patients and mature IL-33 induces skin inflammation in a mouse model. To determine the role and function of IL-33 in skin inflammation, in particular to understand the mechanism how IL-33 contributes to the pathology and recruitment of inflammatory cells. Transgenic mice with skin-specific expression of full length IL-33 were generated via pronuclear injection of K14-IL-33. This construct with IL-33 under keratin 14 promotor was tested for the functionality in vitro following the generation of the transgenic mice. For analysis control littermates with no transgene were used. K14-IL-33 mice were tested in various skin inflammation models including TLR7 agonistic stimulation with imiquimod 5%, ear injection model (rIL-23, 500 ng/ear for 14 days), and skin tape stripping. As readout we used caliper measurement of the ear thickness, skin histology H&E staining and immunohistochemistry as well as mRNA expression by quantitative RT-PCR. Pronuclear injection resulted in 16 pups with 2 transgenic mice expressing the IL-33 transgene. K14-IL-33 mice were born and developed normally with no obvious phenotype. Increased expression in the skin in K14-IL-33 compare to wildtype (WT) mice was detected using RT-PCR and immunohistology; as expected IL-33 was localised in the nuclei of the keratinocytes. No significant expression was measured in other organs. Due to the lack of a skin phenotype we performed different skin inflammation models in the K14-IL-33 mouse. Neither TLR7 stimulation via imiquimod, ear injection of IL-23, a pivotal cytokine for psoriasis, nor skin tape stripping as a model for chronic skin damage induced a clinical/histological change compared to littermates. We demonstrate that local skin overexpression of the alarmin IL-33 does not induce spontaneous or triggered skin inflammation. In comparison to a published K14-IL-33 mouse with atopic inflammatory phenotype our data could not reproduce the described phenotype. These data suggest that different expression thresholds might lead to exacerbation of skin diseases.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A78. · 8.11 Impact Factor
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    ABSTRACT: Dendritic cells (DCs) are essential for the initiation of synovial inflammation, but it is unclear which subset of DCs performs this task. We have shown that FMS-like tyrosine kinase 3 ligand (Flt3L)-dependent DCs are important for disease development in a mouse model for RA. However since Flt3L-/- mice have reductions in all conventional (c)DCs it remained unclear which subset is required for disease induction. CIA was induced in Flt3L-/-, Batf3-/- (mice lacking both CD103(+) and CD8a(+)DCs) and WT C57/BL6 littermates. In vitro and in vivo uptake and migration was performed using bone marrow (BM)-DCs and dermal DCs. Antigen presentation was studied in vivo by adoptive transfer of CFSE-labeled OT-I or OT-II T cells + OVA in Flt3L-/- and WT mice and in vitro by culturing BM-DCs with OT-I and OT-II cells. T cell proliferation was analysed by CFSE dilution. To study BM-DC function qPCR array (Dendritic and Antigen Presenting Cell PCR Array- Qiagen) for 84 genes was performed. To test the potential of a Flt3 inhibitor (CEP701) in the prevention of CIA, an in vivo study was performed injecting CEP701 before the onset of disease in DBA-1 mice. Flt3L-/- mice were susceptible to innate K/BxN arthritic model and arthritic T cell transfer. Batf3-/- mice lacking both CD103 + and CD8a + DCs were resistant to CIA, demonstrating that CD11b + and monocyte-derived DCs (moDCs) were not sufficient to induce CIA. The amount of DCs carrying antigen reaching the LN in Flt3L-/- mice was reduced compared with WT. Uptake and migratory capacity was similar in Flt3L-/- BM-DCs compared to WT BM-DCs. CEP701 (a Flt3L inhibitor) treatment prevented CIA induction, and reduced dramatically CD103 + DCs in the lymph nodes and synovium. Human CD141hi DCs, homologues of mouse CD103 + DCs, were present and increased in inflamed rheumatoid arthritis (RA) synovium. Antigen presentation in Flt3L-/- mice is impaired. As CD103 + DCs are absent in Flt3L-/- mice and are important in (cross)-presenting antigens our data reveals a crucial role for CD103 + DCs in the induction of CIA. As a consequence of CD103 + DC absence Flt3L-/- mice showed a reduction in T cell activation in particularly reduced CD8 T cell responses. Hence this study identified non-lymphoid CD103 + DCs as the main subset orchestrating the initiation of cell-mediated immunity in arthritis. Targeting this DC subset might be of interest in individuals at risk of developing autoimmune disorders.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A83-4. · 8.11 Impact Factor
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    ABSTRACT: Besides phagocytosis as mechanism to combat pathogens, neutrophils are able to eject DNA decorated with microbicidal proteins (neutrophil extracellular traps-NETs), that can immobilize and kill microorganisms extracellularly. Procoagulative properties of NETs have already been shown, however, a role of NETs formation in atherosclerotic disease has not been described so far. The process of chromatin release is referred to as NETosis. The aim of this study was to assess if cholesterol crystals are able to induce NETosis in vivo and in vitro. Polymorphonuclear cells-PMNs were isolated from blood obtained from healthy volunteers after informed consent. Isolated PMNs as well as whole blood were co/cultured with cholesterol crystals. After the treatment, cytospins were prepared and stained for DNA and neutrophil elastase. Extracelullar DNA was quantified by fluorometry. For in vivo experiments, cholesterol crystals were injected into murine air pouches. After 24h, air pouches were lavaged with PBS. After centrifugation cells were used for cytospins and supernatants for cytokines determination. Tophus-like aggregates were isolated and characterised by immune histochemistry and immunobloting. In addition, human autopsy specimens obtained from subject died of cardiac diseases were assessed for presence of NET markers. Cholesterol induced dose dependent NETosis in isolated PMNs as well as in whole blood samples. The maximal applied concentration of cholesterol crystals induced 236.5% higher DNA release when compared to control. Cholesterol crystal injected in air pouches induced tophus-like aggregates composed of aggregated NETs attached to the cholesterol crystals. These structures were highly positive for citrullinated histones, markers of NET formation. NET markers were also found in atherosclerotic blood vessels in zones surrounding necrotic core of atheromatous plaque, which is rich in cholesterol crystals This study showed for the first time ability of cholesterol crystals to induce NETosis in vitro, as well as in vivo. These data may explain prompt thrombus formation in atherosclerotic disease after rupture of fibrous cap of an atheromatous plaque containing huge amount of cholesterol crystals, which will be the subject of our future research.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A94. · 8.11 Impact Factor
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    ABSTRACT: Objective: The colony stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We therefore determined CSF-1R expression in human RA and the efficacy of a specific CSF-1R antibody in two different animal models of RA. Methods: CSF-1R expression was examined in the blood, synovium and bone of RA patients, osteoarthritis (OA) patients and healthy subjects. The efficacy of CSF-1R monoclonal antibody (mAb, AFS98) neutralization was examined by clinical assessment, histology and bone histomorphometry in collagen-induced (CIA) and serum transfer arthritis. Results: In humans, CSF-1R expression was increased in the synovium of RA compared to OA and healthy controls in fibroblast-like synoviocytes (FLS), follicular dendritic cells, macrophages and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R positive. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion and systemic bone loss associated with the depletion of osteoclasts in both models. Whereas blockade of CSF-1R did not affect inflammation in the passive serum transfer arthritis, it significantly reduced inflammation in CIA, associated with absent synovial macrophages and reduced splenic CD11b+Gr-1- monocytes. Conclusion: CSF-1R was broadly expressed in human RA. In the mouse model, blockade of anti-CSF-R protected against bone and cartilage destruction and also showed significant anti-inflammatory effects in the CIA arthritis model. These data supports evidence for CSF-1R as a therapeutic target in RA, combining anti.-inflammatory effect and protecting from bone and cartilage damage. © 2014 American College of Rheumatology.
    Arthritis & Rheumatology. 03/2014;
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    ABSTRACT: Infection with helminth triggers strong Th2 immune response, which modulates the development of systemic autoimmune diseases. The aim of this study was to investigate whether infection with Nippostrongylus brasiliensis influence rheumatoid arthritis development as well as the molecular mechanism from Th2 and eosinophil cells in this effect. 5 to 7 weeks old human TNF transgenic (hTNFtg) mice were infected with Nippostrongylus brasiliensis subcutaneously. Moreover, wild-type, IL-4(-/-)IL-13(-/-) and CD4-Cre IL-4(-/-)IL-13(-/)mice were infected with Nippostrongylus brasiliensis subcutaneously 6 days before induction of experimental arthritis through injection of 150 µl K/BxN serum intraperitoneally. Clinical arthritis score and histomorphometric analysis in the inflammatory hind paw were evaluated. Infection with Nippostrongylus brasiliensis alleviated spontaneous chronic arthritis in hTNFtg mice accompanied with a reduction of the systemic and local bone loss. Moreover, wild-type and CD4cre IL-4(-/-)IL-13(-/)mice infected with Nippostrongylus brasiliensis have a reduction of the arthritis score whereas arthritis in IL-4(-/-)IL-13(-/-) mice with infection remained comparable to the non-infected control mice. Histomorphometric analyses revealed that inflammation area and bone erosion were decreased in wild-type and CD4cre IL-4(-/-)IL-13(-/)mice with infection compared with IL-4(-/-)IL-13(-/-) or noninfected wild-type control. Consistently, osteoclast marker such as Trap, RANK and CathepsinK mRNA expression levels in the inflammatory joint were lower in wild-type mice with infection than control. In order to define the role of eosinophil, induction of K/BxN serum transfer arthritis in delta-dblGATA mice was performed. Interestingly genetically lack of eosinophil showed increased inflammation and bone erosion than wild-type control. Infection with Nippostrongylus brasiliensis significantly alleviated bone erosion in experimental arthritis models, which is dependent of IL-4 and IL-13. In addition, eosinophils might play a crucial role in arthritis protection induced by Nippostrongylus brasiliensis infection.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A72. · 8.11 Impact Factor

Publication Stats

10k Citations
2,999.56 Total Impact Points

Institutions

  • 2007–2014
    • Universitätsklinikum Erlangen
      • Institute of Human Genetics
      Erlangen, Bavaria, Germany
    • Justus-Liebig-Universität Gießen
      • Department of Internal Medicine
      Gieben, Hesse, Germany
  • 2006–2014
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • • Nikolaus-Fiebiger-Center of Molecular Medicine (NFZ)
      • • Department of Biology
      Erlangen, Bavaria, Germany
  • 2013
    • Inselspital, Universitätsspital Bern
      • Department of Rheumatology, Clinical Immunology and Allergology
      Bern, BE, Switzerland
    • University of Leeds
      • Leeds Institute of Rheumatic and Musculoskeletal Medicine
      Leeds, England, United Kingdom
  • 1998–2013
    • Medical University of Vienna
      • Department of Medicine II
      Wien, Vienna, Austria
  • 1996–2013
    • University of Innsbruck
      • Institute of Biochemistry
      Innsbruck, Tyrol, Austria
  • 2012
    • Nordic Bioscience
      København, Capital Region, Denmark
    • Universitair Ziekenhuis Leuven
      Louvain, Flanders, Belgium
    • Ghent University
      • Rheumatology
      Gent, VLG, Belgium
    • Ludwig Boltzmann Institute for Osteology
      Wien, Vienna, Austria
  • 2008–2012
    • University of Zurich
      • Center for Integrative Human Physiology
      Zürich, ZH, Switzerland
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2006–2012
    • Medizinische Universität Innsbruck
      • • Department für Innere Medizin
      • • Univ.-Klinik für Neurologie
      Innsbruck, Tyrol, Austria
  • 2011
    • Università degli studi di Parma
      Parma, Emilia-Romagna, Italy
    • National Academy of Sciences of Ukraine
      • Institute of Cell Biology
      Kharkiv, Kharkivs'ka Oblast', Ukraine
  • 2007–2011
    • University of Glasgow
      • • College of Medical, Veterinary and Life Sciences
      • • Institute of Infection, Immunity and Inflammation
      Glasgow, SCT, United Kingdom
  • 2010
    • Detská fakultná nemocnica s poliklinikou v Bratislave
      Presburg, Bratislavský, Slovakia
    • Comenius University in Bratislava
      Presburg, Bratislavský, Slovakia
  • 2009
    • University of California, San Diego
      • Division of Rheumatology, Allergy and Immunology
      San Diego, CA, United States
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 1998–2008
    • University of Vienna
      • • Department of Internal Medicine III
      • • Department of Pharmacology and Toxicology
      • • Universitätsklinik für Innere Medizin I
      Wien, Vienna, Austria
  • 2004–2006
    • Biomedical Sciences Research Center Alexander Fleming
      • Institute of Immunology
      Βάρη, Attica, Greece
  • 2000
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 1995–2000
    • Austrian Academy of Sciences
      • Institut für Biomedizinische Alternsforschung
      Vienna, Vienna, Austria
  • 1998–1999
    • Ludwig Boltzmann Institute of Rheumatology and Balneology
      Wien, Vienna, Austria