Institute for Medical Immunology

Halle (Saale), Germany

Institute for Medical Immunology

Halle (Saale), Germany

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Langlet C.,Institute for Medical Immunology | Springael C.,Institute for Medical Immunology | Johnson J.,Institute for Medical Immunology | Thomas S.,Institute for Medical Immunology | And 4 more authors.
European Journal of Immunology | Year: 2010

Conventional PKC (cPKC)-α regulates TRIF-dependent IFN response factor 3 (IRF3)-mediated gene transcription, but its role in MyD88-dependent TLR signaling remains unknown. Herein, we demonstrate that PKC-α is induced by several MyD88-dependent TLR/IL-1R ligands and regulates cytokine expression in human and murine DC. First, inhibition of cPKC activity in human DC by cPKC-specific inhibitors, Gö6976 or HBDDe, downregulated the production of classical inflammatory/immunomodulatory cytokines induced by TLR2, TLR5 or IL-1R but not by TLR3 stimulation. Similarly, dominant negative PKC-α repressed Pam3CSK4 induced NF-κB- and AP-1-driven promoter activities in TLR2-expressing human embryonic kidney 293 T cells. Dominant negative PKC-α inhibited NF-κB reporter activity mediated by overexpression of MyD88 but not TRIF. Unexpectedly, BM-derived DC from PKC-α-/- mice exhibited decreased TNF-α and IL-12p40 production induced by both MyD88- and TRIF-dependent ligands. Furthermore, PKC-α is coupled to TLR2 signaling proximal to MyD88 since MAPK and IκB kinase-α/β phosphorylations and IκBα degradation were inhibited in PKC-αa-/- BM-derived DC. Finally, co-immunoprecipitation assays revealed that PKC-α physically interacts with Pam3CSK4 activated TLR2 in WT but not in MyD88 -/- DC. Collectively this study identifies a species-specific role of PKC-α as a key component that controls MyD88-dependent cytokine gene expression in human and mouse but differentially regulates production of TRIF-dependent cytokines. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Engel O.,Charité - Medical University of Berlin | Akyuz L.,Institute for Medical Immunology | Akyuz L.,Berlin Brandenburg Center for Regenerative Medicine | Da Costa Goncalves A.C.,Max Delbrück Center for Molecular Medicine | And 15 more authors.
Stroke | Year: 2015

Background and Purpose-Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive. Methods-The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity. Results-Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic anti-inflammatory signaling in the lung. Conclusions-Thus, cholinergic pathways play a pivotal role in the development of pulmonary infections after acute central nervous system injury. © 2015 American Heart Association, Inc.


Rosel A.L.,Institute for Medical Immunology | Scheibenbogen C.,Institute for Medical Immunology | Scheibenbogen C.,Berlin Brandenburg Center for Regenerative Therapies | Scheibenbogen C.,Charité - Medical University of Berlin | And 10 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background The population of patients with common variable immunodeficiency (CVID) comprises a heterogeneous group of patients with different causes of hypogammaglobulinemia predisposing to recurrent infections, higher incidence of autoimmunity, and malignancy. Although memory B cells (memBcs) are key players in humoral defense and their numbers are commonly reduced in these patients, their functionality is not part of any current classification.Objective We established and validated a memBc enzyme-linked immunosorbent spot (ELISpot) assay that reveals the capacity of memBcs to develop into antibody-secreting cells and present an idea for a new classification based on this functional capacity.Methods The memBc ELISpot assay, combined with flow cytometry, was applied to patients with confirmed CVID in comparison with age-matched healthy control subjects.Results Ex vivo frequency of IgG-, IgM-, and IgA-secreting plasmablasts was significantly diminished by 27.2-, 2.4-, and 23.3-fold, respectively, compared with that seen in healthy control subjects. Moreover, in vitro differentiation of memBcs into antibody-secreting cells was 6.1-, 2.6-, and 3.7-fold significantly reduced for IgG-, IgM-, and IgA-secreting cells, respectively. Proliferation of memBcs correlates inversely to immunoglobulin-secreting capacity, suggesting compensatory hyperproliferation. Furthermore, patients with no serum IgA can still have a detectable IgA ELISpot assay result in vitro. Most importantly, the large heterogeneity of memBc function in patients with CVID homogenously grouped by means of fluorescence-activated cell sorting allowed additional subclassification based on memBc/plasmablast function.Conclusion These data suggest almost normal memBc/immunoglobulin-secreting plasmablast functionality in some patients if sufficient stimulatory signals are delivered, which might open up opportunities for new therapeutic approaches. © 2014 American Academy of Allergy, Asthma & Immunology.


Rother M.,Institute for Medical Immunology | Krohn S.,Charite Centrum | Kania G.,Charité - Medical University of Berlin | Vanhoutte D.,Catholic University of Leuven | And 15 more authors.
Circulation | Year: 2010

Background- CCN1 is an evolutionary ancient matricellular protein that modulates biological processes associated with tissue repair. Induction at sites of injury was observed in conditions ranging from skin wounds to cardiac diseases, including ischemic and inflammatory cardiomyopathy. Here, we provide evidence of a novel function of CCN1 as a modulator of immune cell migration. Methods and results- To understand the role of CCN1 in cardiomyopathies and to evaluate its therapeutic potential, we overexpressed CCN1 using an adenoviral hepatotropic vector in murine experimental autoimmune myocarditis, a model of human inflammatory cardiomyopathy. CCN1 gene transfer significantly reduced cardiac disease score and immune cell infiltration. In vivo tracking of hemagglutinin epitope-tagged CCN1 revealed binding to spleen macrophages but not to cardiomyocytes. Unexpectedly, CCN1 therapy left cardiac chemokine and cytokine expression unchanged but instead strongly inhibited the migration of spleen macrophages and lymphocytes, as evidenced by ex vivo transwell assays. In accordance with the ex vivo data, in vitro preincubation with CCN1 diminished transwell migration of human monocytes and abrogated their chemotactic response to monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and stromal cell-derived factor-1α. Further mechanistic studies showed that CCN1-driven modulation of immune cell migration is mimicked in part by cyclic RGD peptides currently in clinical evaluation for cancer therapy. Conclusions- Our proof-of-concept study suggests investigation of CCN1 as a novel, endogenous "parent compound" for chemotaxis modulation and of cyclic RGD peptides as a class of partially CCN1-mimetic drugs with immediate potential for clinical evaluation in cardiac diseases associated with chronic pathogenic inflammation. © 2010 American Heart Association. All rights reserved.


Villabona L.,Karolinska University Hospital | Leon Rodriguez D.A.,Karolinska University Hospital | Leon Rodriguez D.A.,El Rosario University | Andersson E.K.,Karolinska University Hospital | And 3 more authors.
Modern Pathology | Year: 2014

The aim of this study was to establish a novel approach for human leukocyte antigen (HLA)-typing from formalin-fixed paraffin-embedded-derived DNA. HLAs can be a prognostic factor in cancer and have an extensive polymorphism. This polymorphism is predominantly restricted to exons, which encode the peptide-binding domain of the protein. Formalin-fixed paraffin-embedded material is routinely collected in the clinic and therefore a great source of DNA for genetic analyses. However, its low quality due to fragmentation and nucleotide changes has often created obstacles in designing genetic assays. In this study, we amplified the most polymorphic exons of the HLA-A gene, exons 2, 3, and 4, in 16 formalin-fixed paraffin-embedded samples >10 years old. These tissue samples belonged to patients already HLA-typed by peripheral blood samples at the routine laboratory. Acquired amplification products were used for sequencing, which provided enough information to establish an HLA allele. The same method was applied to DNA extracted from peripheral blood from a healthy volunteer with known HLA type. Of the samples, 14/16 (88%) were successfully typed, in one sample only one of the alleles could be determined, and in one sample no allele could be determined. The amplification of the most polymorphic exons of HLA-A was a successful alternative when DNA quality prevented positive results with previously described methods. The method is usable when an HLA type is needed but the patients are deceased and/or no whole blood samples can be collected. It has thus potential to be used in several fields such as the clinic, research, and forensic science.Modern Pathology advance online publication, 7 February 2014; doi:10.1038/modpathol.2013.210.


Villabona L.,Karolinska University Hospital | Villabona L.,El Rosario University | Villabona L.,Institute for Medical Immunology
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2014

The aim of this study was to establish a novel approach for human leukocyte antigen (HLA)-typing from formalin-fixed paraffin-embedded-derived DNA. HLAs can be a prognostic factor in cancer and have an extensive polymorphism. This polymorphism is predominantly restricted to exons, which encode the peptide-binding domain of the protein. Formalin-fixed paraffin-embedded material is routinely collected in the clinic and therefore a great source of DNA for genetic analyses. However, its low quality due to fragmentation and nucleotide changes has often created obstacles in designing genetic assays. In this study, we amplified the most polymorphic exons of the HLA-A gene, exons 2, 3, and 4, in 16 formalin-fixed paraffin-embedded samples >10 years old. These tissue samples belonged to patients already HLA-typed by peripheral blood samples at the routine laboratory. Acquired amplification products were used for sequencing, which provided enough information to establish an HLA allele. The same method was applied to DNA extracted from peripheral blood from a healthy volunteer with known HLA type. Of the samples, 14/16 (88%) were successfully typed, in one sample only one of the alleles could be determined, and in one sample no allele could be determined. The amplification of the most polymorphic exons of HLA-A was a successful alternative when DNA quality prevented positive results with previously described methods. The method is usable when an HLA type is needed but the patients are deceased and/or no whole blood samples can be collected. It has thus potential to be used in several fields such as the clinic, research, and forensic science.


de Bellefon L.M.,Institute for Medical Immunology | Heiman P.,Laboratory of Cytogenetics | Kanaan S.B.,French Institute of Health and Medical Research | Azzouz D.F.,French Institute of Health and Medical Research | And 5 more authors.
Chimerism | Year: 2010

We report the case of a 40-year-old man diagnosed with a scleroderma-like disease. Clinical similarities with graft versus host disease prompted initial testing for chimerism employing fluorescence in situ hybridization (FI SH). Female cells were observed within peripheral blood mononuclear cells from the patient. Because maternal cells have been detected in healthy immunologically competent adults and patients with autoimmune conditions, we hypothesized that these cells were of maternal origin. Contrary to our expectations, HLA-specific quantitative PCR (QPCR) ruled out maternal microchimerism. However, HLA-specific QPCR testing was positive for the paternal HLA haplotype that the patient did not inherit. We reasoned that the most likely origin of chimerism with non-inherited paternal HLA alleles was from an unrecognized "vanished" twin. The patient had never received a blood transfusion. This report suggests that cells from a vanished twin are a possible source of chimerism. The frequency of chimerism from this source is not yet known and whether the scleroderma-like disease observed in the patient is anecdotal or implies a potential association with autoimmune disease remains to be elucidated. © 2010 Landes Bioscience.


Survival of lung transplant recipients is currently limited by the primary graft dysfunction, an acute phenomenon occurring within 72 hours after the transplantation, but also by the chronic rejection that appears more than one year later. IL-17 might be implicated in these two diseases. The heterotopic trachea transplantation in mice generates epithelial lesions mimicking the human pathology. Using this model, we show that IL-17 was crucially implicated in early, but not chronic lesions after transplantation. The main intragraft cellular sources of IL-17 are recipient-derived gammadelta T cells. However, the IL17-dependent lesions in our model are not mediated by a direct effect of IL-17 on donor-derived cells. Nevertheless, its inhibition protects CK-14+ basal epithelial stem cells that are known to be capable of renewing of the whole epithelium.


PubMed | Institute for Medical Immunology, Karolinska University Hospital and El Rosario University
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2014

The aim of this study was to establish a novel approach for human leukocyte antigen (HLA)-typing from formalin-fixed paraffin-embedded-derived DNA. HLAs can be a prognostic factor in cancer and have an extensive polymorphism. This polymorphism is predominantly restricted to exons, which encode the peptide-binding domain of the protein. Formalin-fixed paraffin-embedded material is routinely collected in the clinic and therefore a great source of DNA for genetic analyses. However, its low quality due to fragmentation and nucleotide changes has often created obstacles in designing genetic assays. In this study, we amplified the most polymorphic exons of the HLA-A gene, exons 2, 3, and 4, in 16 formalin-fixed paraffin-embedded samples >10 years old. These tissue samples belonged to patients already HLA-typed by peripheral blood samples at the routine laboratory. Acquired amplification products were used for sequencing, which provided enough information to establish an HLA allele. The same method was applied to DNA extracted from peripheral blood from a healthy volunteer with known HLA type. Of the samples, 14/16 (88%) were successfully typed, in one sample only one of the alleles could be determined, and in one sample no allele could be determined. The amplification of the most polymorphic exons of HLA-A was a successful alternative when DNA quality prevented positive results with previously described methods. The method is usable when an HLA type is needed but the patients are deceased and/or no whole blood samples can be collected. It has thus potential to be used in several fields such as the clinic, research, and forensic science.


News Article | December 7, 2016
Site: www.eurekalert.org

Chronobiologists from Charité - Universitätsmedizin Berlin have shown that the body's carbon monoxide metabolism is closely linked to the body's circadian (internal) clock. Carbon monoxide, a toxic gas found in exhaust fumes and cigarette smoke, is also an endogenous by-product of the degradation of heme, the hemoglobin cofactor responsible for giving red blood cells their color. The production of carbon monoxide is regulated by the body's internal clock, and this clock, in turn, is regulated by carbon monoxide. An article discussing the close reciprocal relationship between these two regulatory mechanisms has been published in the current issue of the journal Nature Structural & Molecular Biology*. A close link between metabolic processes and the body's internal clock ensures that our bodies are optimally adapted to environmental conditions, such as the availability and timing of meals. Cell-based circadian clocks, which detect signals from metabolic processes, also cause the relevant cellular metabolic processes to adapt in response to these signals. The disruption of one of these regulatory mechanisms results in the disruption of the other - a phenomenon manifested by the occurrence of conditions such as diabetes or metabolic syndrome in people whose internal clocks are disrupted e.g. as a result of shift work. Under the leadership of Prof. Dr. Achim Kramer, Head of the Chronobiology Research Unit at Charité's Institute for Medical Immunology, a team of researchers has been studying the role of heme (the iron-containing red pigment in red blood cells) for the body's circadian rhythms. Heme is a complex molecule that is part of numerous other proteins and acts as a metabolic sensor. "Our research has shown that carbon monoxide, a toxic gas that is also a by-product of the degradation of heme, has a crucial role in keeping the body's internal clock ticking as it should," explains Prof. Kramer. He adds: "The production of this molecule inside the cells of the liver can be disrupted through pharmacological inhibition, or by genetically switching off the expression of heme oxygenase - the enzyme required for its synthesis. As a result, normal internal rhythmicity is disrupted, the clock is slowed down." Perturbations of this kind result in the dysregulation of hundreds of different genes, which also happen to be responsible for essential metabolic processes, such as the synthesis of glucose. Results from this study help us to further understand how metabolic disorders and the body's internal clock are interlinked. By identifying the molecular mechanisms responsible for the body's circadian rhythms, we may be able to develop targeted therapies. * Roman Klemz, Silke Reischl, Thomas Wallach, Nicole Witte, Karsten Jürchott, Sabrina Klemz, Veronika Lang, Stephan Lorenzen, Miriam Knauer, Steffi Heidenreich, Min Xu, Jürgen A Ripperger, Michael Schupp, Ralf Stanewsky & Achim Kramer. Reciprocal regulation of carbon monoxide metabolism and the circadian clock. Nature, Nov. 2016. doi: 10.1038/nsmb.3331

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