The immune response to periodontitis and its relevance to cerebral ischaemia

  • Conor O'Boyle

Student thesis: Phd


Periodontitis is a prevalent chronic inflammatory disease that involves the destruction of the supporting structures of the teeth. In addition to local tissue damage and bone loss, periodontitis has been shown to have adverse consequences at sites distant from the oral cavity. Growing epidemiological and experimental data has associated periodontitis with the development and/or exacerbation of a myriad of clinically-important diseases, from rheumatoid arthritis to Alzheimer’s disease to ischaemic stroke. The objective of this thesis was to provide an insight into the local and systemic immune responses during experimental periodontitis which could potentially affect peripheral tissue sites, with a particular focus on the impact on stroke severity. Using an acute bilateral ligature model in mice, we found that experimental periodontitis led to bone loss, bacterial growth, and increased local inflammatory cell mobilisation. Systemically, periodontitis altered the frequencies of monocytes and neutrophils in the bone marrow and small intestine, increased circulating levels of the pro-inflammatory cytokines, interleukin (IL)-1β and IL-17A, and increased tumour necrosis factor (TNF)α production in bone marrow monocytes. In order to evaluate the impact of periodontitis on stroke outcome, we applied this ligature-induced model and induced experimental strokes by transient or permanent occlusion of the middle cerebral artery. In tandem with ligature placement, we systemically challenged with an oral-specific lipopolysaccharide (LPS) in an effort to imitate the systemic aspects of the clinical disease. However, periodontitis alone or in tandem with LPS, did not alter systemic immune trafficking, blood-brain barrier disruption, or brain damage after stroke. In addition to the systemic reaches of periodontitis, we also focused on local immune regulation during disease. In this way, we identified the gingiva as a novel site of extramedullary haematopoiesis that harbours a population of haematopoietic stem and progenitor cells in the tissue which can give rise to multiple lineages of myeloid immune cells, including tissue monocytes. We also describe that these stem cells are differentially modulated by induced or natural bone loss and provide evidence that stromal cells and the surrounding matrix may be important in retaining these progenitors in the gingival niche. Overall, these findings give insight into the fundamental immunological mechanisms during periodontitis, both in a local context, within the oral cavity, as well as the implications at distant tissues sites. We specifically provide evidence that periodontitis does not alter outcome after acute ischaemic stroke, and thus add an important counterpoint to the growing body of literature associating periodontitis with a negative impact on stroke.
Date of Award1 Aug 2019
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorStuart Allan (Supervisor), Catherine Lawrence (Supervisor), Craig Smith (Supervisor) & Joanne Konkel (Supervisor)

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