| Popis: |
The Th17/IL-17 pathway is increasingly implicated in the pathogenesis of periodontitis. However the mechanisms that drive this pathway in humans and the relationship of this pathway to disease severity are not fully understood. The first aim of this thesis was to investigate whether the periodontal pathogens Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa) promote a Th17/IL-17 response in vitro, and to investigate the underlying mechanisms. The second aim was to determine the frequencies of IL-17+ CD4+ T cells in gingival tissue and peripheral blood from patients with periodontitis versus periodontally healthy control subjects. My results show that Pg and Aa activate monocytes, which can subsequently induce an IL-17/Th17 response in CD4+ T cells in vitro. The underlying mechanism involves the recognition of Pg by TLR2/4 on monocytes leading to an IL-1β/IL-23 dependent induction of IL-17 production by CD4+ T cells, which is further dependent in part on costimulation. The data also show that gingival tissue from patients with periodontitis contains increased frequencies of IL-17+ cells (predominantly CD4+ T cells) as well as IFNγ+ and TNFα+ cells relative to healthy subjects. IL-17+ CD4+ T cells and IL-17 protein are clearly detectable however in both diseased and healthy gingival tissue and GCF. No differences are observed in IL-17+ CD4+ T cell frequencies in peripheral blood from patients or healthy subjects. However, in vitro, Pg induces significantly higher IL- 17 production in anti-CD3 mAb-stimulated monocyte/CD4+ T cell co-cultures from patients with periodontitis compared to healthy controls. |
