TY - JOUR A1 - Heidt, Christina A1 - Kämmerer, Ulrike A1 - Fobker, Manfred A1 - Rüffer, Andreas A1 - Marquardt, Thorsten A1 - Reuss-Borst, Monika T1 - Assessment of intestinal permeability and inflammation bio-markers in patients with rheumatoid arthritis JF - Nutrients N2 - Increased intestinal permeability and inflammation, both fueled by dysbiosis, appear to contribute to rheumatoid arthritis (RA) pathogenesis. This single-center pilot study aimed to investigate zonulin, a marker of intestinal permeability, and calprotectin, a marker of intestinal inflammation, measured in serum and fecal samples of RA patients using commercially available kits. We also analyzed plasma lipopolysaccharide (LPS) levels, a marker of intestinal permeability and inflammation. Furthermore, univariate, and multivariate regression analyses were carried out to determine whether or not there were associations of zonulin and calprotectin with LPS, BMI, gender, age, RA-specific parameters, fiber intake, and short-chain fatty acids in the gut. Serum zonulin levels were more likely to be abnormal with a longer disease duration and fecal zonulin levels were inversely associated with age. A strong association between fecal and serum calprotectin and between fecal calprotectin and LPS were found in males, but not in females, independent of other biomarkers, suggesting that fecal calprotectin may be a more specific biomarker than serum calprotectin is of intestinal inflammation in RA. Since this was a proof-of-principle study without a healthy control group, further research is needed to validate fecal and serum zonulin as valid biomarkers of RA in comparison with other promising biomarkers. KW - rheumatoid arthritis KW - zonulin KW - calprotectin KW - LPS KW - fecal short-chain fatty acids KW - fiber intake KW - intestinal permeability KW - intestinal inflammation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319377 SN - 2072-6643 VL - 15 IS - 10 ER - TY - JOUR A1 - Gernert, Michael A1 - Schmalzing, Marc A1 - Tony, Hans-Peter A1 - Strunz, Patrick-Pascal A1 - Schwaneck, Eva Christina A1 - Fröhlich, Matthias T1 - Calprotectin (S100A8/S100A9) detects inflammatory activity in rheumatoid arthritis patients receiving tocilizumab therapy JF - Arthritis Research & Therapy N2 - Background Assessing serological inflammation is difficult in tocilizumab (TCZ)-treated rheumatoid arthritis (RA) patients, as standard inflammation parameters, like erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are influenced by interleukin-6-receptor inhibition. Calprotectin in the serum, also named S100A8/S100A9, might be a more useful inflammation parameter in TCZ-treated patients. Methods Sixty-nine RA patients taking TCZ were included. Serum-calprotectin levels were assessed, as well as ESR, CRP, need for a change in disease-modifying anti-rheumatic drugs due to RA activity (= active RA), and the RA clinical disease activity score (CDAI). Forty-five RA patients taking tumor-necrosis factor-inhibitors (TNFi) were investigated for the same parameters. Results TCZ-treated patients with active RA had higher calprotectin values than not active RA patients (4155.5 [inter quartile range 1865.3–6068.3] vs 1040.0 [676.0–1638.0] ng/ml, P < 0.001). A calprotectin cut-off value of 1916.5 ng/ml resulted in a sensitivity and specificity of 80.0 %, respectively, for the detection of RA disease activity. Calprotectin values correlated with CDAI-scores (r = 0.228; P = 0.011). ESR and CRP were less suitable to detect RA activity in TCZ-treated patients. Also TNFi-treated patients with active RA had higher calprotectin values compared to not active RA (5422.0 [3749.0–8150.8] vs 1845.0 [832.0–2569.0] ng/ml, P < 0.001). The calprotectin value with the best sensitivity and specificity for detecting RA activity was 3690.5 ng/ml among TNFi-treated patients. Conclusion Calprotectin in the serum can be a useful inflammation parameter despite TCZ-treatment. KW - calprotectin KW - inflammation marker KW - c-reactive protein KW - tocilizumab KW - rheumatoid arthritis KW - S100A8/S100A9 Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300523 VL - 24 IS - 1 ER - TY - JOUR A1 - Schmidt, Thomas S. B. A1 - Hayward, Matthew R. A1 - Coelho, Luiis P. A1 - Li, Simone S. A1 - Costea, Paul I. A1 - Voigt, Anita Y. A1 - Wirbel, Jakob A1 - Maistrenko, Oleksandr M. A1 - Alves, Renato J. C. A1 - Bergsten, Emma A1 - de Beaufort, Carine A1 - Sobhani, Iradj A1 - Heintz-Buschart, Anna A1 - Sunagawa, Shinichi A1 - Zeller, Georg A1 - Wilmes, Paul A1 - Bork, Peer T1 - Extensive transmission of microbes along the gastrointestinal tract JF - eLife N2 - The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease. KW - Colonization KW - Annotation KW - Dynamics KW - Accurate KW - Strains KW - Barrier KW - Health KW - Acids KW - Research Article KW - Computational and Systems Biology KW - Microbiology and Infectious Disease KW - microbiome KW - gastrointestinal tract KW - colorectal cancer KW - rheumatoid arthritis KW - metagenomics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228954 VL - 8 ER - TY - JOUR A1 - Heim, Jana A1 - Almanzar, Giovanni A1 - Schmalzing, Marc A1 - Gernert, Michael A1 - Tony, Hans-Peter A1 - Prelog, Martina T1 - Induction of IL-9 in Peripheral Lymphocytes of Rheumatoid Arthritis Patients and Healthy Donors by Th17-Inducing Cytokine Conditions JF - Frontiers in Immunology N2 - IL-9-producing Th9 cells display a group of helper T cells with similarities to Th17 and Th2 T cells and have been shown to be involved in synovial inflammation in rheumatoid arthritis (RA) patients. So far, it is unclear which parameters drive Th9 differentiation in lymphocytes derived from RA patients compared to immunologically healthy individuals and whether autocrine mechanisms are able to enhance Th9 polarization. Further, parallel pathways of induction of IL-17-producing cells with Th9 phenotype have to be distinguished from exclusively Th9-inductive mechanisms. Thus, the present study aimed to determine the parameters of Th9 induction by simulation in a standardized inflammatory cytokine milieu.Peripheral naive and non-naive T cells of RA patients and healthy donors (HD) were cultured under Th9 and Th17-driving conditions and phenotypically analyzed by flow cytometry and molecular analysis.Our findings indicate a similar differentiation pathway of Th9 and Th17 cells and similar distributions of IL-9+ T cells in RA and HD regardless of Th9- or Th17-promoting cytokine milieus. Whereas the magnitude and direction of Th9- or Th17-polarization was about the same in RA and HD, IL-17+ CD4+ T cells were significantly stimulated by Th17-inducing conditions in HD. In conclusion, the results indicate that Th9- and Th17-inducing cytokine conditions mimicking autoimmune inflammation in RA may have similar stimulatory effects regarding polarization of peripheral naive and non-naive T cells into Th9 or Th17 cells. The results suggest that the differentiation of Th9 cells may be also induced by Th17-driving conditions. KW - Th9 KW - Th17 KW - interleukin-9 KW - rheumatoid arthritis KW - PU.1 Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237838 SN - 1664-3224 VL - 12 ER - TY - JOUR A1 - Drechsler, Johannes A1 - Groetzinger, Joachim A1 - Hermanns, Heike M. T1 - Characterization of the Rat Oncostatin M Receptor Complex Which Resembles the Human, but Differs from the Murine Cytokine Receptor JF - PLoS One N2 - Evaluation of a pathophysiological role of the interleukin-6-type cytokine oncostatin M (OSM) for human diseases has been complicated by the fact that mouse models of diseases targeting either OSM or the OSM receptor (OSMR) complex cannot fully reflect the human situation. This is due to earlier findings that human OSM utilizes two receptor complexes, glycoprotein 130 (gp130)/leukemia inhibitory factor receptor (LIFR) (type I) and gp130/OSMR (type II), both with wide expression profiles. Murine OSM on the other hand only binds to the gp130/OSMR (type II) receptor complex with high affinity. Here, we characterize the receptor usage for rat OSM. Using different experimental approaches (knock-down of the OSMR expression by RNA interference, blocking of the LIFR by LIF-05, an antagonistic LIF variant and stably transfected Ba/F3 cells) we can clearly show that rat OSM surprisingly utilizes both, the type I and type II receptor complex, therefore mimicking the human situation. Furthermore, it displays cross-species activities and stimulates cells of human as well as murine origin. Its signaling capacities closely mimic those of human OSM in cell types of different origin in the way that strong activation of the Jak/STAT, the MAP kinase as well as the PI3K/Akt pathways can be observed. Therefore, rat disease models would allow evaluation of the relevance of OSM for human biology. KW - in vitro KW - leukemia-inhibitory factor KW - ciliary neurotrophic factor KW - T cell development KW - swiss model KW - fetal liver KW - interleukin-6-type cytokines KW - rheumatoid arthritis KW - signal transduction KW - growth regulator Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133879 VL - 7 IS - 8 ER - TY - JOUR A1 - Kleinert, Stefan A1 - Tony, Hans-Peter A1 - Krause, Andreas A1 - Feuchtenberger, Martin A1 - Wassenberg, Siegfried A1 - Richter, Constanze A1 - Röther, Ekkehard A1 - Spieler, Wolfgang A1 - Gnann, Holger A1 - Wittig, Bianca M. T1 - Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German JF - Rheumatology International N2 - The objective of this study was to use data from a noninterventional study to evaluate the effectiveness of adalimumab in rheumatoid arthritis (RA) patients during routine clinical practice and to explore the potential impact of patient and disease characteristics in response to adalimumab therapy. A total of 2,625 RA patients with specified data at baseline (prior to initiating adalimumab treatment) and 12 months entered this study between April 2003 and March 2009. We evaluated response to adalimumab therapy and conducted stepwise regression and subgroup analyses of factors influencing therapeutic response. During the 1-year adalimumab treatment period, disease activity decreased from a baseline mean disease activity score-28 joints (DAS28) of 5.9–3.9, while functional capacity improved from 59.0 to 68.4 Funktionsfragebogen Hannover (FFbH) percentage points. In multivariate regression models, high baseline DAS28 was the strongest positive predictor for decrease in disease activity, and high baseline functional capacity was associated with reduced gains in functional capacity. Male gender was a positive predictor of therapeutic response for both disease activity and functional capacity, while older age and multiple previous biologics were associated with a reduced therapeutic response. Subset analyses provided further support for the impact of baseline DAS28, FFbH, and prior biologic therapy on therapeutic response during treatment. We conclude that treatment with adalimumab leads to decreased disease activity and improved function during routine clinical practice. Patients with high disease activity and low functional capacity are particularly benefitted by adalimumab therapy. KW - antirheumatic agents KW - adalimumab KW - rheumatoid arthritis KW - treatment outcome KW - regression analysis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126220 VL - 32 IS - 9 ER - TY - JOUR A1 - Zadeh-Khorasani, Maryam A1 - Nolte, Thomas A1 - Mueller, Thomas D. A1 - Pechlivanis, Markos A1 - Rueff, Franziska A1 - Wollenberg, Andreas A1 - Fricker, Gert A1 - Wolf, Eckhard A1 - Siebeck, Matthias A1 - Gropp, Roswitha T1 - NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human peripheral blood mononuclear cells as a model to test therapeutics targeting human signaling pathways JF - Journal of Translational Medicine N2 - Background: Animal models of human inflammatory diseases have limited predictive quality for human clinical trials for various reasons including species specific activation mechanisms and the immunological background of the animals which markedly differs from the genetically heterogeneous and often aged patient population. Objective: Development of an animal model allowing for testing therapeutics targeting pathways involved in the development of Atopic Dermatitis (AD) with better translatability to the patient. Methods: NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from AD and healthy volunteers were treated with IL-4 and the antagonistic IL-4 variant R121/Y124D (Pitrakinra). Levels of human (h) IgE, amount of B-, T- and plasma-cells and ratio of CD4 : CD8 positive cells served as read out for induction and inhibition of cell proliferation and hIgE secretion. Results were compared to in vitro analysis. Results: hIgE secretion was induced by IL-4 and inhibited by the IL-4 antagonist Pitrakinra in vivo when formulated with methylcellulose. B-cells proliferated in response to IL-4 in vivo; the effect was abrogated by Pitrakinra. IL-4 shifted CD4 : CD8 ratios in vitro and in vivo when hPBMC derived from healthy volunteers were used. Pitrakinra reversed the effect. Human PBMC derived from patients with AD remained inert and engrafted mice reflected the individual responses observed in vitro. Conclusion: NOD-scid IL2R \(\gamma^{null}\) mice engrafted with human PBMC reflect the immunological history of the donors and provide a complementary tool to in vitro studies. Thus, studies in this model might provide data with better translatability from bench to bedside. KW - atopic dermatitis KW - T-cells KW - rheumatoid arthritis KW - human interleukin-4 KW - TGN1412 KW - oxazolone colitis KW - cytokine release KW - expression KW - antagonists KW - responses Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122960 SN - 1479-5876 VL - 11 IS - 4 ER - TY - JOUR A1 - Mitchell, Anna L. A1 - Macarthur, Katie D. R. A1 - Gan, Earn H. A1 - Baggott, Lucy E. A1 - Wolff, Anette S. B. A1 - Skinningsrud, Beate A1 - Platt, Hazel A1 - Short, Andrea A1 - Lobell, Anna A1 - Kampe, Olle A1 - Bensing, Sophie A1 - Betterle, Corrado A1 - Kasperlik-Zaluska, Anna A1 - Zurawek, Magdalena A1 - Fichna, Marta A1 - Kockum, Ingrid A1 - Eriksson, Gabriel Nordling A1 - Ekwall, Olov A1 - Wahlberg, Jeanette A1 - Dahlqvist, Per A1 - Hulting, Anna-Lena A1 - Penna-Martinez, Marissa A1 - Meyer, Gesine A1 - Kahles, Heinrich A1 - Badenhoop, Klaus A1 - Hahner, Stephanie A1 - Quinkler, Marcus A1 - Falorni, Alberto A1 - Phipps-Green, Amanda A1 - Merriman, Tony R. A1 - Ollier, William A1 - Cordell, Heather J. A1 - Undlien, Dag A1 - Czarnocka, Barbara A1 - Husebye, Eystein A1 - Pearce, Simon H. S. T1 - Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts JF - PLOS ONE N2 - Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis. KW - Graves disease KW - identical twins KW - hashimotos-thyroiditis KW - population KW - gene KW - polymorphism KW - susceptibility KW - prevalence KW - haplotype KW - rheumatoid arthritis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117105 VL - 9 IS - 3 ER -