Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen

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 Erkr...

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1. Verfasser: Baumgartl, Nadja
Beteiligte: Garn, Holger (PD. Dr. rer. nat.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2016
Medizin
Ausgabe:http://dx.doi.org/10.17192/z2016.0377
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topic IFNgamma
T-cells
IL-9
COPD
Zigarettenrauch
IL-9
IFNgamma
Medizin, Gesundheit
COPD
T-Zellen
spellingShingle IFNgamma
T-cells
IL-9
COPD
Zigarettenrauch
IL-9
IFNgamma
Medizin, Gesundheit
COPD
T-Zellen
Baumgartl, Nadja
Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
Chronic obstructive pulmonary disease (COPD) is a highly prevalent inflammatory disease of the lung associated with increasing mortality rates throughout the world. Tobacco smoke exposure has been identified as most common cause of COPD, however, the pathogenetic mechanisms leading to disease development are still poorly understood. Most recently, autoimmune mechanisms probably directed against degraded components of the extracellular matrix and a role of Th1/Th17 have been proposed to be involved in induction and/or perpetuation of the inflammatory processes. Based on these observations we hypothesized that cigarette smoke directly impacts on the differentiation of Th cells. To test this hypothesis, we analyzed the influence of cigarette smoke extract-conditioned medium (CSE) on the development of naïve and differentiating T cells in vitro and proofed these findings in a murine chronic smoke exposure model in vivo. The activation state of Th subsets was determined by intracellular FACS staining, cytokine secretion assays and cytometric bead assays. In vitro CSE delays the proliferation but promotes the differentiation of Th1 cells. The number of IFN + Th1 cells was decreased after 3 days of polarisation with CSE, however, remaining Th1 cells were more active and produced significantly more IFN . In parallel, CSE directly inhibited the development of Tregs. Application of CSE in a late stage of differentiation preferentially stabilized/promoted an already established Th17 phenotype in contrast to a Th1 phenotype. In addition, it could be shown that CSE drives Th2 cells into an IL-9 producing phenotype and significantly increases the production of IL-9 in Th9 cells. These in vitro findings could be verified in the in vivo mouse model. Chronic cigarette smoke exposure resulted systemically in significant less numbers of Tregs and locally to significant more IL-9+ and IL-17+ CD4+ cells. These data demonstrate for the first time that cigarette smoke directly influences differentiation and activity of different Th subtypes and drives them into a potentially more autoimmune associated inflammatory subtype with enhanced Th1 activity, stable Th17 cells, less Tregs and increased IL-9 production.
publishDate 2016
era_facet 2016
title_alt Role of T-cells by COPD: Influence of cigarette smoke components on Th Subtyp Differentiation processes
ref_str_mv references
url http://archiv.ub.uni-marburg.de/diss/z2016/0377/pdf/dnb.pdf
building Medizin
first_indexed 2016-06-16T00:00:00Z
last_indexed 2016-06-16T23:59:59Z
description 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.
institution Medizin
doi_str_mv http://dx.doi.org/10.17192/z2016.0377
edition http://dx.doi.org/10.17192/z2016.0377
author Baumgartl, Nadja
license_str https://creativecommons.org/licenses/by-sa/4.0
oai_set_str_mv open_access
doc-type:doctoralThesis
ddc:610
xMetaDissPlus
physical 191 pages.
format Dissertation
title Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
title_short Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
title_full Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
title_fullStr Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
title_full_unstemmed Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
title_sort Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen
dewey-raw 610
dewey-search 610
genre Medical sciences, Medicine
genre_facet Medical sciences, Medicine
topic_facet Medizin, Gesundheit
contents Chronic obstructive pulmonary disease (COPD) is a highly prevalent inflammatory disease of the lung associated with increasing mortality rates throughout the world. Tobacco smoke exposure has been identified as most common cause of COPD, however, the pathogenetic mechanisms leading to disease development are still poorly understood. Most recently, autoimmune mechanisms probably directed against degraded components of the extracellular matrix and a role of Th1/Th17 have been proposed to be involved in induction and/or perpetuation of the inflammatory processes. Based on these observations we hypothesized that cigarette smoke directly impacts on the differentiation of Th cells. To test this hypothesis, we analyzed the influence of cigarette smoke extract-conditioned medium (CSE) on the development of naïve and differentiating T cells in vitro and proofed these findings in a murine chronic smoke exposure model in vivo. The activation state of Th subsets was determined by intracellular FACS staining, cytokine secretion assays and cytometric bead assays. In vitro CSE delays the proliferation but promotes the differentiation of Th1 cells. The number of IFN + Th1 cells was decreased after 3 days of polarisation with CSE, however, remaining Th1 cells were more active and produced significantly more IFN . In parallel, CSE directly inhibited the development of Tregs. Application of CSE in a late stage of differentiation preferentially stabilized/promoted an already established Th17 phenotype in contrast to a Th1 phenotype. In addition, it could be shown that CSE drives Th2 cells into an IL-9 producing phenotype and significantly increases the production of IL-9 in Th9 cells. These in vitro findings could be verified in the in vivo mouse model. Chronic cigarette smoke exposure resulted systemically in significant less numbers of Tregs and locally to significant more IL-9+ and IL-17+ CD4+ cells. These data demonstrate for the first time that cigarette smoke directly influences differentiation and activity of different Th subtypes and drives them into a potentially more autoimmune associated inflammatory subtype with enhanced Th1 activity, stable Th17 cells, less Tregs and increased IL-9 production.
author2 Garn, Holger (PD. Dr. rer. nat.)
author2_role ths
language German
publisher Philipps-Universität Marburg
thumbnail http://archiv.ub.uni-marburg.de/diss/z2016/0377/cover.png
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In: Thorax 67 (8), S. 694–700. 2012 Antielastin B-cell and Tcell immunity in patients with chronic obstructive pulmonary disease 2016-06-16 urn:nbn:de:hebis:04-z2016-03776 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. http://dx.doi.org/10.17192/z2016.0377 2016-06-09 Rolle von T-Zellen bei COPD: Einfluss von Zigarettenrauch-Komponenten auf Differenzierungsprozesse von Th-Subpopulationen Chronic obstructive pulmonary disease (COPD) is a highly prevalent inflammatory disease of the lung associated with increasing mortality rates throughout the world. Tobacco smoke exposure has been identified as most common cause of COPD, however, the pathogenetic mechanisms leading to disease development are still poorly understood. Most recently, autoimmune mechanisms probably directed against degraded components of the extracellular matrix and a role of Th1/Th17 have been proposed to be involved in induction and/or perpetuation of the inflammatory processes. Based on these observations we hypothesized that cigarette smoke directly impacts on the differentiation of Th cells. To test this hypothesis, we analyzed the influence of cigarette smoke extract-conditioned medium (CSE) on the development of naïve and differentiating T cells in vitro and proofed these findings in a murine chronic smoke exposure model in vivo. The activation state of Th subsets was determined by intracellular FACS staining, cytokine secretion assays and cytometric bead assays. In vitro CSE delays the proliferation but promotes the differentiation of Th1 cells. The number of IFN + Th1 cells was decreased after 3 days of polarisation with CSE, however, remaining Th1 cells were more active and produced significantly more IFN . In parallel, CSE directly inhibited the development of Tregs. Application of CSE in a late stage of differentiation preferentially stabilized/promoted an already established Th17 phenotype in contrast to a Th1 phenotype. In addition, it could be shown that CSE drives Th2 cells into an IL-9 producing phenotype and significantly increases the production of IL-9 in Th9 cells. These in vitro findings could be verified in the in vivo mouse model. Chronic cigarette smoke exposure resulted systemically in significant less numbers of Tregs and locally to significant more IL-9+ and IL-17+ CD4+ cells. These data demonstrate for the first time that cigarette smoke directly influences differentiation and activity of different Th subtypes and drives them into a potentially more autoimmune associated inflammatory subtype with enhanced Th1 activity, stable Th17 cells, less Tregs and increased IL-9 production. Baumgartl, Nadja Baumgartl Nadja ths PD. Dr. rer. nat. Garn Holger Garn, Holger (PD. Dr. rer. nat.) Philipps-Universität Marburg
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