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CLEC7A/Dectin-1 Verringert Die Immunantwort Gegen Sterbende Und Tote Zellen)

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CLEC7A/Dectin-1 Verringert Die Immunantwort Gegen Sterbende Und Tote Zellen) CLEC7A/Dectin-1 attenuates the immune response against dying and dead cells (CLEC7A/Dectin-1 verringert die Immunantwort gegen sterbende und tote Zellen) Der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades Dr. rer. nat. vorgelegt von Connie Hesse aus Eberswalde-Finow Als Dissertation genehmigt von der Naturwissenschaftlichen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Tag der mündlichen Prüfung: 21.12.2010 Vorsitzender der Promotionskommision: Prof. Dr. Rainer Fink Erstberichterstatter: Prof. Dr. Lars Nitschke Zweitberichterstatter: PD Dr. Reinhard Voll Table of Contents Table of Contents Table of Contents ............................................................................................ 1 Abstract ............................................................................................................ 3 Zusammenfassung.......................................................................................... 4 1 Introduction ............................................................................................... 6 1.1 C-type lectins................................................................................................. 8 1.1.1 CLEC4L/DC-SIGN ................................................................................ 11 1.1.2 CLEC7A/Dectin-1.................................................................................. 12 1.1.3 CLEC9A/DNGR1 .................................................................................. 13 1.2 Cell death: apoptosis, primary necrosis, secondary necrosis ...................... 14 1.3 Cell death and clearance............................................................................. 17 1.3.1 “Find-me” signals .................................................................................. 18 1.3.2 “Eat-me” signals (PS dependent).......................................................... 19 1.3.3 “Eat-me” signals (PS independent)....................................................... 19 1.3.4 “Tolerate-me” signals............................................................................ 22 1.4 Clearance deficiency and autoimmunity...................................................... 22 2 Materials & Methods ............................................................................... 26 2.1 Materials...................................................................................................... 26 2.2 Methods....................................................................................................... 30 2.2.1 Cells, culture conditions, isolations and generations............................. 30 2.2.2 Induction and detection of apoptosis and necrosis ............................... 33 2.2.3 Cell stainings......................................................................................... 33 2.2.4 Binding Experiments............................................................................. 34 2.2.5 Phagocytosis Assays............................................................................ 37 2.2.6 In vitro cytokine release assays ............................................................ 38 2.2.7 Immunization experiments .................................................................... 39 2.2.8 Antibody determination ......................................................................... 41 2.2.9 Cytokine determination ......................................................................... 42 2.2.10 Flow cytometry analyses ................................................................... 43 2.2.11 Microscopy anaylses ......................................................................... 44 1 Table of Contents 2.2.12 Statistical analyses ............................................................................ 44 3 Results ..................................................................................................... 45 3.1 Cell death is reflected by characteristic morphological changes ................. 45 3.2 Plant lectin binding ...................................................................................... 47 3.3 C-type lectin CLEC9A/DNGR1 .................................................................... 50 3.4 C-type lectin CLEC4L/DC-SIGN.................................................................. 61 3.5 C-type lectin CLEC7A/Dectin-1 ................................................................... 66 4 Discussion............................................................................................... 82 4.1 Lectin binding is a special feature of late apoptotic cells............................. 82 4.2 C-type lectin CLEC9A/DNGR1 binds late apoptotic PMN endowed with intact membranes........................................................................................................... 84 4.3 C-type lectin CLEC4L/DC-SIGN binds apoptotic cells endowed with intact membranes........................................................................................................... 86 4.4 C-type lectin CLEC7A/Dectin-1 downregulates the response against late apoptotic and primary necrotic cells...................................................................... 88 5 Concluding remarks ............................................................................... 95 6 References............................................................................................... 96 7 List of abbreviations............................................................................. 109 8 List of figures ........................................................................................ 112 Acknowledgements..................................................................................... 114 Curriculum Vitae.......................................................................................... 116 2 Abstract Abstract Analysing apoptotic cell death it has been observed that late apoptotic cells expose internal membranes with heavily altered glycocalyx. The latter is the target for a plethora of sugar-epitope recognizing proteins such as pentraxins, collectins, galectins, and, less physiological, plant lectins. These lectins bind to late apoptotic as well as to primary and secondary necrotic cells. Strong binding to late apoptotic cells with intact membranes was observed for the plant lectins Narcissus pseudonarcissus (NPn) and Griffonia simplicifolia (GSL II). Within this thesis the C-type lectins CLEC4L/DC-SIGN, CLEC9A/DNGR1, CLEC7A/Dectin-1 and their role in recognition, uptake of apoptotic and necrotic cells and/or their influence on the immunogenicity of dead and dying cells has been investigated. Enhanced binding for CLEC4L/DC-SIGN and CLEC9A/DNGR1 to late apoptotic cells was observed. CLEC9A/DNGR1 binding, which until now was only reported for necrotic cells, could also be demonstrated for late apoptotic PMN endowed with intact membranes. CLEC9A/DNGR1 could, therefore, act as recognition receptor of dying cells at the edge of late apoptosis and secondary necrosis. Its physiological role is yet unkown, but might become clear, when CLEC9A/DNGR1 ligands are revealed. For CLEC7A/Dectin-1 no direct binding to apoptotic or necrotic cells was observed. However, a co-operation with other receptors is proposed, since phagocytosis assays revealed differences in uptake and/or degradation in the absence or presence of CLEC7A/Dectin-1 receptor. In vivo studies revealed an attenuated immune response in the presence of CLEC7A/Dectin- 1 against dead and dying cells. This thesis points out that the role of lectin receptors in the clearance process seems to be much more important than assumed. The anti- inflammatory PS-dependent clearance of early apoptotic cells is well characterized. Hence, if apoptotic cells escape clearance, the recognition of their altered surface glycosylation pattern with exposed modified autoantigens by C-type lectin receptors on professional phagocytes and antigen presenting cells is very likely. The role of C- type lectins in immune stimulation in co-operation with other phagocytic receptors is subject to deeper investigation. If involved in the clearance process of late apopotic cells, as the data in this thesis indicate, C-type lectins might be targets for a therapeutic concept for the chronic inflammatory autoimmune diseases SLE, which is linked with clearance deficiencies. 3 Zusammenfassung Zusammenfassung Untersuchungen zum Zelltod haben gezeigt, dass spät apoptotische Zellen innere Membranen mit stark veränderter Glykokalyx exponieren. Letztere ist Zielstruktur für zahlreiche Zucker-Epitop-erkennende Proteine, wie z.B. Pentraxine, Kollektine, Galektine, und weniger physiologisch Pflanzenlektine. Diese Moleküle binden sowohl spät apoptotische als auch primär und sekundär nekrotische Zellen. Starke Bindung an spät apoptotische Zellen mit intakter Zellmembran wurde für die Pflanzenlektine Narcissus pseudonarcissus (NPn) and Griffonia simplicifolia (GSL II) beobachtet. Im Rahmen dieser Arbeit wurde die Rolle der C-typ Lektine CLEC4L/DC-SIGN, CLEC9A/DNGR1, CLEC7A/Dectin-1 bei der Erkennung sowie der Aufnahme apoptotischer und nekrotischer Zellen und/oder ihr Einfluss auf die Immunogenität toter und sterbender Zellen untersucht. Es wurde verstärkte Bindung von CLEC4L/DC-SIGN und CLEC9A/DNGR1 an spät apoptotische Zellen beobachtet. CLEC9A/DNGR1 Bindung, die bisher nur für nekrotische Zellen berichtet wurde, konnte in dieser Arbeit auch für spät apoptotische PMN mit intakter
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