Klinikum Konstanz

Konstanz, Germany

Klinikum Konstanz

Konstanz, Germany
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Schaeuble K.,University of Konstanz | Hauser M.A.,University of Konstanz | Singer E.,Klinikum Konstanz | Groettrup M.,University of Konstanz | Legler D.F.,University of Konstanz
Journal of Immunology | Year: 2011

Lymphocyte homing to, and motility within, lymph nodes is regulated by the chemokine receptor CCR7 and its two ligands CCL19 and CCL21. There, lymphocytes are exposed to a number of extracellular stimuli that influence cellular functions and determine the cell fate. In this study, we assessed the effect of TCR engagement on CCR7-mediated cell migration. We found that long-term TCR triggering of freshly isolated human T cells through CD3/CD28 attenuated CCR7-driven chemotaxis, whereas short-term activation significantly enhanced CCR7-mediated, but not CXCR4-mediated, migration efficiency. Short-term activation most prominently enhanced the migratory response of naive T cells of both CD4 and CD8 subsets. We identified distinct roles for Src family kinases in modulating CCR7-mediated T cell migration. We provide evidence that Fyn, together with Ca 2+-independent protein kinase C isoforms, kept the migratory response of naive T cells toward CCL21 at a low level. In nonactivated T cells, CCR7 triggering induced a Fyn-dependent phosphorylation of the inhibitory Tyr505 of Lck. Inhibiting Fyn in these nonactivated T cells prevented the negative regulation of Lck and facilitated high CCR7-driven T cell chemotaxis. Moreover, we found that the enhanced migration of short-term activated T cells was accompanied by a synergistic, Src-dependent activation of the adaptor molecule linker for activation of T cells. Collectively, we characterize a cross-talk between the TCR and CCR7 and provide mechanistic evidence that the activation status of T cells controls lymphocyte motility and sets a threshold for their migratory response. Copyright © 2011 by The American Association of Immunologists, Inc.


Bruckner M.,University of Konstanz | Dickel D.,University of Konstanz | Singer E.,Klinikum Konstanz | Legler D.F.,University of Konstanz
Cellular Immunology | Year: 2012

Dendritic cells (DCs) are key in regulating immune responses. DCs reside in tissues facing the environment and sample their surrounding for pathogens. Upon pathogen encounter, DCs mature and migrate into secondary lymphoid organs. Distinct maturation signals dictate the ability of DCs to produce distinct patterns of chemokines that orchestrate immunity. Prostaglandin E 2 (PGE 2) is produced during inflammation and modulates DC functions. We demonstrate that PGE 2 modulates distinct chemokine expression patterns of human monocyte-derived (Mo) DCs upon maturation with various stimuli. PGE 2 dampened early production of the inflammatory chemokines CCL2, CCL4, CCL5 and attenuated the expression of the T cell attractant CXCL10. In contrast, PGE 2 enhanced CXCL8 production early during maturation, whereas CXCL16 levels were continuously elevated, contributing to innate immune cell recruitment. Moreover, PGE 2 induces transcription of the homeostatic chemokines CCL17 and CCL22. Finally, mature MoDCs produced the homing chemokine CCL19 and its expression was down-regulated by PGE 2. © 2012 Elsevier Inc.


Czekelius P.,Klinikum Konstanz | Wenzel H.,Independent Health Economic Consultant
Zeitschrift fur Geburtshilfe und Neonatologie | Year: 2016

Introduction: Crowther et al. 3 analysed the effectivity of magnesium tocolysis in preventing preterm birth. They conclude that there is no evidence for protection. In its latest guidelines, based on this Cochrane analysis, the German Association of Gynaecology and Obstetrics (DGGG) does not recommend any more the use of magnesium for tocolysis. Magnesium tocolysis is said neither to delay nor to prevent preterm birth. Moreover, magnesium could be responsible for increased mortality in infants. These conclusions are mostly based on the research of Mittendorf et al. 4. In a Cochrane study from 2014, which in principal was identical to the study mentioned above 3, Crowther et al. 6 confirm the previous findings and conclusions. Method: Having successfully applied magnesium tocolysis for many years, these surprising conclusions led us to review the soundness of the publications mentioned above. Combining the practical experience of many years with the results of a comprehensive literature retrieval, we finally contrasted this knowledge with the findings of the aforementioned publications that caused the DGGG to withdraw the recommendation for magnesium. Results: To draw binding consequences from a meta-analysis is possible only when stringent quality guidelines are observed. The studies that were included in the Cochrane review of Crowther et al. 3 are very heterogeneous and are not suitable for concluding on poor or even lacking effectiveness of magnesium tocolysis. Furthermore, the cases of infant deaths, as stated by Mittendorf et al. 4, are very unlikely caused by magnesium. Conclusion: When including studies in a meta-analysis special attention has to be given to the relevance and unbiased selection of studies. To prevent any misjudgment, a thorough knowledge of the included studies seems essentiell. There is not sufficient evidence to withdraw the recommendation for applying magnesium tocolysis as a preventive measure to prevent preterm birth. In the sense of evidence-based medicine, long-standing, scientifically proven therapeutic success should be incorporated into the meta-analysis as well. © Georg Thieme Verlag KG.


Hauser M.A.,University of Konstanz | Schaeuble K.,University of Konstanz | Schaeuble K.,University of Lausanne | Kindinger I.,University of Konstanz | And 5 more authors.
Immunity | Year: 2016

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and T cell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways. © 2016 Elsevier Inc.


PubMed | University of Zürich, University of Konstanz and Klinikum Konstanz
Type: Journal Article | Journal: Immunity | Year: 2016

Host defense depends on orchestrated cell migration guided by chemokines that elicit selective but biased signaling pathways to control chemotaxis. Here, we showed that different inflammatory stimuli provoked oligomerization of the chemokine receptor CCR7, enabling human dendritic cells and Tcell subpopulations to process guidance cues not only through classical G protein-dependent signaling but also by integrating an oligomer-dependent Src kinase signaling pathway. Efficient CCR7-driven migration depends on a hydrophobic oligomerization interface near the conserved NPXXY motif of G protein-coupled receptors as shown by mutagenesis screen and a CCR7-SNP demonstrating super-oligomer characteristics leading to enhanced Src activity and superior chemotaxis. Furthermore, Src phosphorylates oligomeric CCR7, thereby creating a docking site for SH2-domain-bearing signaling molecules. Finally, we identified CCL21-biased signaling that involved the phosphatase SHP2 to control efficient cell migration. Collectively, our data showed that CCR7 oligomers serve as molecular hubs regulating distinct signaling pathways.


Hauser M.A.,University of Konstanz | Kindinger I.,University of Konstanz | Laufer J.M.,University of Konstanz | Spate A.-K.,University of Konstanz | And 5 more authors.
Journal of Leukocyte Biology | Year: 2016

The homeostatic chemokines CCL19 and CCL21 and their common cognate chemokine receptor CCR7 orchestrate immune cell trafficking by eliciting distinct signaling pathways. Here, we demonstrate that human CCR7 is N-glycosylated on 2 specific residues in the N terminus and the third extracellular loop. Conceptually, CCR7 glycosylation adds steric hindrance to the receptor N terminus and extracellular loop 3, acting as a "swinging door" to regulate receptor sensitivity and cell migration. We found that freshly isolated human B cells, as well as expanded T cells, but not naïve T cells, express highly sialylated CCR7. Moreover, we identified that human dendritic cells imprint T cell migration toward CCR7 ligands by secreting enzymes that deglycosylate CCR7, thereby boosting CCR7 signaling on T cells, permitting enhanced T cell locomotion, while simultaneously decreasing receptor endocytosis. In addition, dendritic cells proteolytically convert immobilized CCL21 to a soluble form that is more potent in triggering chemotactic movement and does not desensitize the receptor. Furthermore, we demonstrate that soluble CCL21 functionally resembles neither the CCL19 nor the CCL21 phenotype but acts as a chemokine with unique features. Thus, we advance the concept of dendritic celldependent generation of micromilieus and lymph node conditioning by demonstrating a novel layer of CCR7 regulation through CCR7 sialylation. In summary, we demonstrate that leukocyte subsets express distinct patterns of CCR7 sialylation that contribute to receptor signaling and fine-tuning chemotactic responses. © Society for Leukocyte Biology.


Bruckner M.,University of Konstanz | Dickel D.,University of Konstanz | Singer E.,Klinikum Konstanz | Legler D.F.,University of Konstanz
European Journal of Immunology | Year: 2012

Migration and homing of DCs to lymphoid organs is pivotal for inducing adaptive immunity and tolerance. DC homing depends on the chemokine receptor CCR7. However, expression of CCR7 alone is not sufficient for effective DC migration. A second signal, mediated by prostaglandin E2 (PGE2), is critical for the development of a migratory DC phenotype. PGE2 is important for inducing efficient immune responses, but, if deregulated, contributes to chronic inflammation, autoimmune diseases through Th17-cell development and tumorigenesis. In contrast, activation of liver X receptor (LXR)α has recently been shown to interfere with CCR7 expression and migration of DCs resulting in a reduced immune response. Here, we demonstrate that PGE2 downregulates LXRα expression in human monocyte derived as well as ex vivo DCs. Moreover, PGE2 stimulation dampens LXR activation, auto-regulation and LXR-mediated gene transcription. Consequently, we show that PGE2 enhances CCR7 expression and migration of LXR-activated DCs. Furthermore, we provide evidence that PGE2 signaling and LXR activation specifically elicit converse effects on CCR7 expression and DC migration. In contrast, production of MMP9, CCL4, COX-2, and IL-23 is solely regulated by PGE2, but not by LXR activation, offering new perspectives for therapeutic interventions. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


PubMed | University of Konstanz and Klinikum Konstanz
Type: Journal Article | Journal: Journal of leukocyte biology | Year: 2016

The homeostatic chemokines CCL19 and CCL21 and their common cognate chemokine receptor CCR7 orchestrate immune cell trafficking by eliciting distinct signaling pathways. Here, we demonstrate that human CCR7 is N-glycosylated on 2 specific residues in the N terminus and the third extracellular loop. Conceptually, CCR7 glycosylation adds steric hindrance to the receptor N terminus and extracellular loop 3, acting as a swinging door to regulate receptor sensitivity and cell migration. We found that freshly isolated human B cells, as well as expanded T cells, but not nave T cells, express highly sialylated CCR7. Moreover, we identified that human dendritic cells imprint T cell migration toward CCR7 ligands by secreting enzymes that deglycosylate CCR7, thereby boosting CCR7 signaling on T cells, permitting enhanced T cell locomotion, while simultaneously decreasing receptor endocytosis. In addition, dendritic cells proteolytically convert immobilized CCL21 to a soluble form that is more potent in triggering chemotactic movement and does not desensitize the receptor. Furthermore, we demonstrate that soluble CCL21 functionally resembles neither the CCL19 nor the CCL21 phenotype but acts as a chemokine with unique features. Thus, we advance the concept of dendritic cell-dependent generation of micromilieus and lymph node conditioning by demonstrating a novel layer of CCR7 regulation through CCR7 sialylation. In summary, we demonstrate that leukocyte subsets express distinct patterns of CCR7 sialylation that contribute to receptor signaling and fine-tuning chemotactic responses.


PubMed | Dokuz Eylül University and Klinikum Konstanz
Type: Journal Article | Journal: Digital journal of ophthalmology : DJO | Year: 2016

To report the prevalence of postoperative retinal tear or rhegmatogenous retinal detachment secondary to intravitreal injections.Surgical and medical records of patients who received intravitreal injections at the practice of a single retina specialist from January 2004 to May 2013 and who were followed for at least 6 months were investigated retrospectively.During the study period, a total of 3,907 intravitreal injections were performed in 1,049 eyes of 784 patients (416 males [47%]). The mean number of injections per eye was 3.72 3.43 (range, 1-22). The mean age of the participants was 67.03 13.56 (range, 5-94 years). The mean follow-up time was 31.98 22.86 months (range, 6-144 months). Retinal break or rhegmatogenous retinal detachment occurred in 3 injections of 3 eyes, yielding an overall prevalence of 0.077% per injection and 0.29% per eye.Retinal tear and rhegmatogenous detachment are rare complications of intravitreal injection. Precautions should be taken especially in patients having predisposing conditions, such as high myopia, or any other vitreoretinal disorders.


PubMed | University of Leipzig and Klinikum Konstanz
Type: Journal Article | Journal: International journal of clinical pharmacy | Year: 2016

Background Pharmacist-led medication reviews have shown to prevent drug-related problems (DRPs). So far, data is rare about the implementation in routine care, the conditions for intensifying this service and the practical skills of community pharmacists to perform medication reviews. Objective To assess the current status of medication review implementation in German community pharmacies and the performance of identifying DRPs in a ficticious patient example. Setting German community pharmacies. Method An online survey was conducted from July to September 2015 including questions about medication reviews currently performed in routine care of community pharmacies and hidden DRPs in a ficticious patient example. Pharmacists were invited via newsletters from three local chambers of pharmacists. Main outcome measure (i) Frequency, conditions for implementation, and criteria of medication reviews currently being performed in routine care, (ii) requested further information to perform medication reviews, and (iii) proportion of pharmacists who identify DRPs in the patient example. Results A total of 143 community pharmacists completed the questionnaire. (i) One hundred and twenty-seven respondents (89%) reported reviewing the medication regularly in routine care, whereas 56 (39%) stated that they performed medication reviews between one and five times monthly. For 124 pharmacists (87%), remuneration would be a necessary condition for performing medication reviews more frequently. When reviewing the medication, 112 (78%) of the pharmacists considered the criterion drug-drug interactions and 107 (75%) reviewed the criterion correct dosage. One of the least reviewed criteria was effectiveness of medication [22 (16%)]. (ii) According to the participants, laboratory values should be available in the community pharmacy, since 87/143 (61%) would appreciate the GFR and the HbA1c level. Twenty-two of 54 respondents (41%) would appreciate further administration instructions and 5 of 54 (15%) think they would benefit from information about the recommended duration of drug use. (iii) Depending on the category, 4 (3%) to 49 (34%) of all 143 pharmacists identified the hidden DRP in the patient example. Conclusion German community pharmacists reported reviewing the medication of their patients regularly; however, most of the respondents review the medication very rarely in routine care. Consequently, their practical performance needs to be improved.

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