Publikationsserver der Universitätsbibliothek Marburg

Titel:Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
Autor:Baumgartl, Nadja
Weitere Beteiligte: Garn, Holger (PD. Dr. rer. nat.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0377
DOI: https://doi.org/10.17192/z2016.0377
URN: urn:nbn:de:hebis:04-z2016-03776
DDC:610 Medizin
Titel (trans.):Role of T-cells by COPD: Influence of cigarette smoke components on Th Subtyp Differentiation processes
Publikationsdatum:2016-06-16
Lizenz:https://creativecommons.org/licenses/by-sa/4.0

Dokument

Schlagwörter:
COPD, IFNgamma, COPD, IL-9, T-Zellen, IL-9, T-cells, Zigarettenrauch, IFNgamma

Zusammenfassung:
Die chronisch obstruktive Lungenerkrankung (COPD) ist eine weit verbreitete chronisch-entzündliche Erkrankung der Lunge, die mit weltweit steigenden Mortalitätsraten assoziiert ist. Die häufigste Ursache der COPD ist chronische Rauchexposition. Die pathogenen Mechanismen, die zur Ausprägung der Erkrankung führen, sind bisher noch weitgehend unklar. Allerdings wird aktuell diskutiert, dass autoimmune Prozesse, wahrscheinlich gerichtet gegen degradierte Komponenten der extrazellulären Matrix und dabei Th1/Th17 Zellen an der Induktion und/oder Perpetuierung der Erkrankung beteiligt sind. Vor diesem Hintergrund verfolgen wir die Hypothese, dass Zigarettenrauch einen direkten modifizierenden Einfluss auf die Differenzierung von T-Helferzellen hat. Um diese Hypothese zu testen, wurde der Einfluss von Zigarettenrauch- konditioniertem Medium (CSE) auf die Entwicklung von naїven und differenzierten T-Zellen in vitro untersucht. Diese Ergebnisse wurden anhand eines murinen chronischen Rauchexpositionsmodells in vivo evaluiert. Die Aktivität verschiedener Th Subtypen wurde mithilfe von mRNA Expressionsanalysen, intrazellulären FACS Messungen, Sekretionsassay und cytokine cytometric bead assay bestimmt. In vitro verzögert CSE die Proliferation von Th1 Zellen, unterstützt aber gleichzeitig deren Differenzierung nachgewiesen durch eine signifikant höhere IFN+ Produktion. Gleichzeitig inhibiert CSE die Differenzierung von Tregs deutlich. Die Gabe von CSE auf bereits differenzierte Th Subtypen zeigte, dass im Gegensatz zu Th1 Zellen bereits differenzierte Th17 Zellen stabilisiert bzw. unterstützt werden. Außerdem konnte gezeigt werden, dass CSE während der Th2 Polarisation zu einem Wechsel zu einem IL-9 produzierenden Phänotyp führt und die IL-9 Produktion in Th9 Zellen signifikant induziert bzw. verstärkt. Diese in vitro Ergebnisse konnten in vivo verifiziert werden. Die chronische Exposition von Zigarettenrauch führte systemisch zu einer signifikant reduzierten relativen Zellzahl von Tregs und lokal (Lunge) zu einer signifikant gesteigerten relativen Zellzahl von IL-17+ und IL-9+ CD4+-Zellen. Mit diesen Ergebnissen kann erstmalig gezeigt werden, dass Zigarettenrauch-Komponenten einen direkten Einfluss auf die Differenzierung und Aktivierung von verschiedenen Th Subtypen hat. Dabei wird ein potentiell autoimmun-assoziierter inflammatorischer Phänotyp mit verstärkter Th1 Aktivität, stabilen Th17 Zellen, weniger Tregs und einer gesteigerten IL-9 Produktion generiert. Somit führt Zigarettenrauch-Exposition zu Änderungen des lokalen Zytokin-Milieus, welches eine chronische Inflammation und autoimmune Prozesse unterstützen und so einen wesentlichen Einfluss auf die Pathogenese in der COPD haben kann.

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