Flügel, Alexander

[["dc.bibliographiccitation.firstpage","94"],["dc.bibliographiccitation.issue","7269"],["dc.bibliographiccitation.journal","Nature"],["dc.bibliographiccitation.lastpage","U104"],["dc.bibliographiccitation.volume","462"],["dc.contributor.author","Bartholomaeus, Ingo"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Schlaeger, Christian"],["dc.contributor.author","Miljkovic, Djordje"],["dc.contributor.author","Ellwart, Joachim W."],["dc.contributor.author","Klinkert, Wolfgang E. F."],["dc.contributor.author","Fluegel-Koch, Cassandra"],["dc.contributor.author","Issekutz, Thomas B."],["dc.contributor.author","Wekerle, Hartmut"],["dc.contributor.author","Fluegel, Alexander"],["dc.date.accessioned","2018-11-07T11:22:12Z"],["dc.date.available","2018-11-07T11:22:12Z"],["dc.date.issued","2009"],["dc.description.abstract","The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks(1). Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce pro-inflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations."],["dc.identifier.doi","10.1038/nature08478"],["dc.identifier.isi","000271419200039"],["dc.identifier.pmid","19829296"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6204"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/55942"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","0028-0836"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1930"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","1943"],["dc.bibliographiccitation.volume","133"],["dc.contributor.author","Cordiglieri, Chiara"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Zhang, B. O."],["dc.contributor.author","Nebel, Merle"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Klinkert, Wolfgang E. F."],["dc.contributor.author","Lodygin, Dimtri"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Breunig, Esther"],["dc.contributor.author","Schild, Detlev"],["dc.contributor.author","Ulaganathan, Vijay Kumar"],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Potter, Barry V. L."],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Fluegel, Alexander"],["dc.date.accessioned","2018-11-07T08:41:30Z"],["dc.date.available","2018-11-07T08:41:30Z"],["dc.date.issued","2010"],["dc.description.abstract","Nicotinic acid adenine dinucleotide phosphate represents a newly identified second messenger in T cells involved in antigen receptor-mediated calcium signalling. Its function in vivo is, however, unknown due to the lack of biocompatible inhibitors. Using a recently developed inhibitor, we explored the role of nicotinic acid adenine dinucleotide phosphate in autoreactive effector T cells during experimental autoimmune encephalomyelitis, the animal model for multiple sclerosis. We provide in vitro and in vivo evidence that calcium signalling controlled by nicotinic acid adenine dinucleotide phosphate is relevant for the pathogenic potential of autoimmune effector T cells. Live two photon imaging and molecular analyses revealed that nicotinic acid adenine dinucleotide phosphate signalling regulates T cell motility and re-activation upon arrival in the nervous tissues. Treatment with the nicotinic acid adenine dinucleotide phosphate inhibitor significantly reduced both the number of stable arrests of effector T cells and their invasive capacity. The levels of pro-inflammatory cytokines interferon-gamma and interleukin-17 were strongly diminished. Consecutively, the clinical symptoms of experimental autoimmune encephalomyelitis were ameliorated. In vitro, antigen-triggered T cell proliferation and cytokine production were evenly suppressed. These inhibitory effects were reversible: after wash-out of the nicotinic acid adenine dinucleotide phosphate antagonist, the effector T cells fully regained their functions. The nicotinic acid derivative BZ194 induced this transient state of non-responsiveness specifically in post-activated effector T cells. Naive and long-lived memory T cells, which express lower levels of the putative nicotinic acid adenine dinucleotide phosphate receptor, type 1 ryanodine receptor, were not targeted. T cell priming and recall responses in vivo were not reduced. These data indicate that the nicotinic acid adenine dinucleotide phosphate/calcium signalling pathway is essential for the recruitment and the activation of autoaggressive effector T cells within their target organ. Interference with this signalling pathway suppresses the formation of autoimmune inflammatory lesions and thus might qualify as a novel strategy for the treatment of T cell mediated autoimmune diseases."],["dc.identifier.doi","10.1093/brain/awq135"],["dc.identifier.isi","000279473900008"],["dc.identifier.pmid","20519328"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6202"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19486"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0006-8950"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","10678"],["dc.bibliographiccitation.issue","26"],["dc.bibliographiccitation.journal","PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA"],["dc.bibliographiccitation.lastpage","10683"],["dc.bibliographiccitation.volume","106"],["dc.contributor.author","Dammermann, Werner"],["dc.contributor.author","Zhang, B. O."],["dc.contributor.author","Nebel, Merle"],["dc.contributor.author","Cordiglieric, Chiara"],["dc.contributor.author","Odoardi, Francesca"],["dc.contributor.author","Kirchberger, Tanja"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Dowden, James"],["dc.contributor.author","Schmid, Frederike"],["dc.contributor.author","Dornmair, Klaus"],["dc.contributor.author","Hohenegger, Martin"],["dc.contributor.author","Fluegel, Alexander"],["dc.contributor.author","Guse, Andreas H."],["dc.contributor.author","Potter, Barry V. L."],["dc.date.accessioned","2018-11-07T08:28:38Z"],["dc.date.available","2018-11-07T08:28:38Z"],["dc.date.issued","2009"],["dc.description.abstract","The nucleotide NAADP was recently discovered as a second messenger involved in the initiation and propagation of Ca2+ signaling in lymphoma T cells, but its impact on primary T cell function is still unknown. An optimized, synthetic, small molecule inhibitor of NAADP action, termed BZ194, was designed and synthesized. BZ194 neither interfered with Ca2+ mobilization by D-myo-inositol 1,4,5-trisphosphate or cyclic ADP-ribose nor with capacitative Ca2+ entry. BZ194 specifically and effectively blocked NAADP-stimulated [H-3] ryanodine binding to the purified type 1 ryanodine receptor. Further, in intact T cells, Ca2+ mobilization evoked by NAADP or by formation of the immunological synapse between primary effector T cells and astrocytes was inhibited by BZ194. Downstream events of Ca2+ mobilization, such as nuclear translocation of \"nuclear factor of activated T cells\" (NFAT), T cell receptor-driven interleukin-2 production, and proliferation in antigen-experienced CD4(+) effector T cells, were attenuated by the NAADP antagonist. Taken together, specific inhibition of the NAADP signaling pathway constitutes a way to specifically and effectively modulate T-cell activation and has potential in the therapy of autoimmune diseases."],["dc.identifier.doi","10.1073/pnas.0809997106"],["dc.identifier.isi","000267564300053"],["dc.identifier.pmid","19541638"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6205"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/16468"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Natl Acad Sciences"],["dc.relation.issn","0027-8424"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","275"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Seminars in Immunopathology"],["dc.bibliographiccitation.lastpage","287"],["dc.bibliographiccitation.volume","32"],["dc.contributor.author","Kawakami, Naoto"],["dc.contributor.author","Fluegel, Alexander"],["dc.date.accessioned","2018-11-07T08:40:11Z"],["dc.date.available","2018-11-07T08:40:11Z"],["dc.date.issued","2010"],["dc.description.abstract","Since the first applications of two-photon microscopy in immunology 10 years ago, the number of studies using this advanced technology has increased dramatically. The two-photon microscope allows long-term visualization of cell motility in the living tissue with minimal phototoxicity. Using this technique, we examined brain autoantigen-specific T cell behavior in experimental autoimmune encephalitomyelitis, the animal model of human multiple sclerosis. Even before disease symptoms appear, the autoreactive T cells arrive at their target organ. There they crawl along the intraluminal surface of central nervous system (CNS) blood vessels before they extravasate. In the perivascular environment, the T cells meet phagocytes that present autoantigens. This contact activates the T cells to penetrate deep into the CNS parenchyma, where the infiltrated T cells again can find antigen, be further activated, and produce cytokines, resulting in massive immune cell recruitment and clinical disease."],["dc.identifier.doi","10.1007/s00281-010-0216-x"],["dc.identifier.isi","000281740500006"],["dc.identifier.pmid","20623286"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/5155"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/19167"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","1863-2297"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Knocking at the brain's door: intravital two-photon imaging of autoreactive T cell interactions with CNS structures"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]