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Rheumatoide Arthritis Im Mausmodell - Immunologische Und Strukturelle Verän- Derungen Im Darm

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Rheumatoide Arthritis Im Mausmodell - Immunologische Und Strukturelle Verän- Derungen Im Darm Rheumatoide Arthritis im Mausmodell - immunologische und strukturelle Verän- derungen im Darm in Medizin 3 Rheumatologie/ Immunologie des Universitätsklinikums Erlangen Klinikdirektor: Prof. Dr. med. univ. Georg Schett Dissertation der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg zur Erlangung des Doktorgrades Dr. med. vorgelegt von Oscar Theodor Schulz aus Burgwedel Als Dissertation genehmigt von der Medizinischen Fakultät der Friedrich-Alexander-Universität Erlangen-Nürnberg Vorsitzender des Promotionsorgans: Prof. Dr. Markus F Neurath Gutachter: Prof. Dr. Mario Zaiss Gutachter: Prof. Dr. Gerhard Krönke Tag der mündlichen Prüfung: 16. März 2021 Inhaltsverzeichnis 1. Zusammenfassung / Abstract ...................................................................... - 1 - 1.1.1 Hintergrund und Ziele ......................................................................... - 1 - 1.1.2 Methoden (Patienten, Material und Untersuchungsmethoden) .......... - 1 - 1.1.3 Ergebnisse und Beobachtungen ......................................................... - 2 - 1.1.4 Schlussfolgerung ................................................................................ - 3 - 1.2.1 Background and aims ......................................................................... - 4 - 1.2.2 Methods (patients, material and examination methods) ..................... - 4 - 1.2.3 Results ................................................................................................ - 5 - 1.3.4 Conclusion .......................................................................................... - 6 - 2. Einleitung ..................................................................................................... - 6 - 2.1 Rheumatoide Arthritis ............................................................................. - 6 - 2.2 Rheumatoide Arthritis und der Gastrointestinaltrakt .............................. - 8 - 2.3 Immunisierung im Darm ......................................................................... - 9 - 2.4 Das Immunsystem bei der rheumatoiden Arthritis ............................... - 11 - 2.5 Behandlung der rheumatoiden Arthritis ............................................... - 15 - 2.6 Medikamentöse Therapieansätze ........................................................ - 17 - 3. Fragestellung und Zielsetzung .................................................................. - 19 - 4. Material und Methoden .............................................................................. - 20 - 4.1. Mausstudien ........................................................................................ - 20 - 4.2 Materialgewinnung ............................................................................... - 21 - 4.3 Durchflusszytometrie (FACS) ............................................................... - 23 - 4.4 Darmhistologie ..................................................................................... - 28 - 4.5 Immunofluoreszenzhistologie für Neutrophile ...................................... - 29 - 4.6 In vivo Permeabilitätsmessung ............................................................ - 31 - 4.7 Zellkultur ............................................................................................... - 32 - 4.8 LEGENDplex™ .................................................................................... - 32 - 4.9 qRT-PCR .............................................................................................. - 34 - 4.10 Knochendichtemessung mit µCT ....................................................... - 39 - 4.11. Osteomeasure ................................................................................... - 40 - 4.12 Zonulin ELISA .................................................................................... - 41 - 4.13 Behandlungen .................................................................................... - 42 - 4.13.1 Butyrate ....................................................................................... - 42 - 4.13.2 ACEA ........................................................................................... - 42 - 4.13.3 Larazotide .................................................................................... - 43 - 4.13.4 α4ß7-Antikörper ........................................................................... - 43 - 4.14 Humanstudie: Zonulin-Serumlevel ..................................................... - 43 - 4.15 Statistik ............................................................................................... - 44 - 5. Ergebnisse ................................................................................................ - 45 - 5.1 Verlaufsstudie der CIA ......................................................................... - 45 - 5.1.1 Längenmessung des Darms .......................................................... - 45 - 5.1.2 FACS ............................................................................................. - 47 - 5.1.3 Histologie ....................................................................................... - 53 - 5.1.4 LEGENDplex™. ............................................................................. - 55 - 5.1.5 in vivo Permeabilitätsmessung ...................................................... - 56 - 5.1.6 qRT-PCR ....................................................................................... - 57 - 5.1.7 Zonulin ELISA ................................................................................ - 59 - 5.2 Butyrate ................................................................................................ - 60 - 5.3 ACEA + α4ß7 ....................................................................................... - 60 - 5.3.1 Behandlungserfolg anhand von Score und Gewicht ...................... - 61 - 5.3.2 Längenmessung ............................................................................ - 62 - 5.3.3 FACS ............................................................................................. - 62 - 5.3.4 Knochendichte im µCT .................................................................. - 65 - 5.3.5 Zonulin ELISA ................................................................................ - 66 - 5.4 Larazotide ............................................................................................ - 67 - 5.4.1 Behandlungserfolg anhand von Score und Gewicht ...................... - 67 - 5.4.2 Längenmessung ............................................................................ - 68 - 5.4.3 FACS ............................................................................................. - 68 - 5.4.4 Knochendichte im µCT .................................................................. - 71 - 5.4.5 Osteomeasure ............................................................................... - 72 - 5.4.5 Zonulin ELISA ................................................................................ - 75 - 5.5 Zonulin Humanstudie ........................................................................... - 76 - 6. Diskussion ................................................................................................. - 78 - 6.1 Verlaufsstudie der CIA ......................................................................... - 78 - 6.2 Butyrate, ACEA, α4ß7-Antikörper ........................................................ - 82 - 6.2.1 Butyrate ......................................................................................... - 82 - 6.2.2. ACEA ............................................................................................ - 83 - 6.2.3 α4ß7-Antikörper ............................................................................. - 84 - 6.3 Zonulin und Darmpermeabilität ............................................................ - 86 - 6.4 Larazotide ............................................................................................ - 88 - 6.5 Generelle Kritik ..................................................................................... - 90 - 6.5.1 FACS ............................................................................................. - 90 - 6.5.2 Histologie ....................................................................................... - 91 - 6.5.3 Zellkultur ........................................................................................ - 92 - 6.5.4 Darmpermeabilität ......................................................................... - 92 - 6.5.5 Osteomeasure ............................................................................... - 92 - 6.6 Fazit ..................................................................................................... - 93 - 6.7 Ausblick ................................................................................................ - 94 - 6.7.1 Durchlässigkeit .............................................................................. - 94 - 6.7.2 Immunisierungsort Darm ............................................................... - 95 - 7. Literaturverzeichnis ................................................................................... - 96 - 8. Anhang .................................................................................................... - 127 - 8.1 Abbildungen zu Kapitel 5.1.3 Histologie (Zeitverlauf CIA) ................. - 127 - 8.2 Abbildungen zu Kapitel 5.1.4 LegendplexTM (Zeitverlauf CIA) ........... - 129 - 8.3 Abbildungen zu Kapitel 5.3.3 FACS (ACEA und α4ß7)
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