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Unterschiedliche Immunkapazitäten Beim Rind Nach Polyklonaler

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Unterschiedliche Immunkapazitäten Beim Rind Nach Polyklonaler Inaugural-Dissertation zur Erlangung der Doktorwürde der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Unterschiedliche Immunkapazitäten beim Rind nach polyklonaler Stimulation von Karina Lutterberg aus Leinefelde München 2017 Aus dem Veterinärwissenschaftlichen Department der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Lehrstuhl für Tierphysiologie Arbeit angefertigt unter Leitung von Univ.-Prof. Dr. Cornelia A. Deeg Gedruckt mit Genehmigung der Tierärztlichen Fakultät der Ludwig-Maximilians-Universität München Dekan: Univ.-Prof. Dr. Joachim Braun Berichterstatter Univ.-Prof. Dr. Cornelia A. Deeg Korreferent/en: Univ.-Prof. Gabriela Knubben-Schweizer Tag der Promotion: 11. Februar 2017 Oma Frieda und Tante Lisa Inhaltsverzeichnis 1 EINLEITUNG..................................................................................................... 1 2 LITERATUR ...................................................................................................... 2 2.1 Bovine Neonatale Panzytopenie............................................................................... 2 2.1.1 Auftreten und Krankheitsbild der BNP ................................................................... 2 2.1.2 Ätiologie der BNP .................................................................................................. 3 2.1.3 Pathogenese der BNP .......................................................................................... 4 2.1.4 MHCI als mögliches Alloantigen ............................................................................ 8 2.1.5 MHCI als auslösendes BNP-Alloantigen konnte nicht abschließend bestätigt werden ...................................................................................................11 2.2 Immunreaktionen beim Rind ...................................................................................15 2.2.1 Unterschiedliche T-Zellantworten .........................................................................15 2.2.1.1 T-Zell-mediierte Autoimmunerkrankungen beim Menschen ......................17 2.2.2 Immunreaktionen beim Rind ................................................................................17 2.2.2.1 Unterschiedliche T-Zellantworten beim Rind ............................................17 2.2.2.2 Verschiedene Immunreaktionen bei Rindern ............................................18 2.2.2.3 Rinder mit funktionellen Unterschieden in der Immunantwort ...................20 3 MATERIAL UND METHODEN ........................................................................ 22 3.1 Probenmaterial .........................................................................................................22 3.1.1 Puffer und Lösungen zur Gewinnung und Aufbereitung von PBL .........................24 3.1.2 Gewinnung der Blutproben...................................................................................24 3.1.3 Gewinnung der peripheren Blutlymphozyten mittels Dichtegradientenzentrifugation .............................................................................25 3.1.4 Zählung der gewonnenen Zellen ..........................................................................25 3.2 Zellproliferationsassay ............................................................................................26 3.2.1 Lösungen für die Zellproliferation .........................................................................26 3.2.2 In vitro Stimulation und radioaktive Markierung von Lymphozyten .......................26 3.2.3 Statistische Auswertung der Zellproliferationsraten ..............................................29 3.3 Stimulation und Fraktionierung von Zellen für die differenzielle Proteomanalyse ........................................................................................................30 Inhaltsverzeichnis 3.3.1 Puffer und Lösungen zur Anreicherung von Oberflächenproteinen und zur Zellfraktionierung .....................................................................................30 3.3.2 Stimulation von Zellen für die Proteomanalyse .....................................................35 3.3.3 Fraktionierung der stimulierten Zellen für die Proteomanalyse .............................35 3.3.3.1 Biotinylierung der Plasmazellmembranproteine ........................................35 3.3.3.2 Anreicherung der Plasmazellmembranproteine und Gewinnung der zytosolischen Fraktion ..........................................................36 3.3.3.3 Ablösen der Proteine von den Beads und Verdau der Plasmazellmembran-Fraktion ........................................................................37 3.3.3.4 Aufbereitung der Zellkern-Fraktion ...........................................................37 3.4 Massenspektrometrische Identifikation von Proteinen .........................................38 3.4.1 Puffer und Lösungen für den FASP-Verdau .........................................................38 3.4.2 Puffer und Lösungen für die massenspektrometrische Analyse ...........................40 3.4.3 FASP-Verdau der Fraktionen Zytosol und Nukleus ..............................................41 3.4.4 LC-MS/MS ...........................................................................................................41 3.4.5 Quantitative Auswertung mit Progenisis ...............................................................43 3.4.6 Datenbanksuche für die mittels LC-MS/MS identifizierten Peptide .......................43 3.4.7 Suche von Orthologen und Paralogen .................................................................44 3.4.8 Auswertung der Proteinabundanzen ....................................................................45 3.5 SDS-Page ..................................................................................................................45 3.5.1 Puffer und Lösungen zur Lymphozytenstimulation und Lymphozytenaufbereitung ....................................................................................45 3.5.2 Puffer und Lösungen zur Proteinbestimmung.......................................................46 3.5.3 Puffer und Lösungen für die SDS-Page ...............................................................47 3.5.4 Puffer und Lösungen für den Western Blot ...........................................................50 3.5.5 Stimulation von Zellen für den Western Blot .........................................................53 3.5.6 Bestimmung der Proteinkonzentration der Lysate ................................................53 3.5.7 1D Gelelektrophorese ..........................................................................................54 3.5.8 Durchführung des Western Blots..........................................................................55 3.5.9 Überprüfung des Proteintransfers mittels Ponceau-Färbung ................................56 3.5.10 Immunblot ............................................................................................................56 3.5.11 Statistische Auswertung .......................................................................................59 3.6 Immunhistochemie ...................................................................................................59 Inhaltsverzeichnis 3.6.1 Puffer und Lösungen für die Immunhistochemie ..................................................59 3.6.2 Herstellung der Paraffinschnitte ...........................................................................61 3.6.3 Entparaffinieren der Paraffinschnitte ....................................................................61 3.6.4 Immunhistochemische Färbung ...........................................................................62 3.7 Auswertung der Leistungs- und Gesundheitsdaten ..............................................63 4 ERGEBNISSE ................................................................................................. 65 4.1 Abweichende Immunreaktion von BNP-Überträgerlymphozyten nach polyklonaler Stimulation ..........................................................................................65 4.1.1 BNP-Lymphozyten reagieren nach polyklonaler ConA-Stimulation hyperproliferativ ...................................................................................................65 4.2 Proteine von Kontroll- und BNP-Überträgerlymphozyten werden nach ConA- Stimulation unterschiedlich exprimiert ...................................................................67 4.2.1 Auf der Plasmazellmembranoberfläche von Kontrolllymphozyten nach ConA-Stimulation stärker exprimierte Proteine .....................................................67 4.2.2 Auf der Plasmazellmembranoberfläche von BNP-Überträgerlymphozyten nach ConA-Stimulation stärker exprimierte Proteine ............................................68 4.2.3 Im Zytosol von Kontrolllymphozyten nach ConA-Stimulation stärker exprimierte Proteine .............................................................................................71 4.2.4 Im Zytosol von BNP-Überträgerlymphozyten nach ConA-Stimulation stärker exprimierte Proteine .................................................................................77 4.2.5 Im Nukleus von Kontrolllymphozyten nach ConA-Stimulation stärker exprimierte Proteine .............................................................................................88 4.2.6 Im Nukleus von BNP-Überträgerlymphozyten nach ConA-Stimulation stärker exprimierte Proteine .................................................................................95 4.3 Untersuchungen
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