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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
1. Verfasser: Baumgartl, Nadja
Beteiligte: Garn, Holger (PD. Dr. rer. nat.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Deutsch
Veröffentlicht: Philipps-Universität Marburg 2016
Medizin
Schlagworte:
Online Zugang:PDF-Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Inhaltsangabe: 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.