Delineating the immunological links between periodontitis and rheumatoid arthritis

Abstract

Periodontitis (PD) and rheumatoid arthritis (RA) are multifactorial chronic inflammatory diseases driven by dysregulation of the immune response. Combined PD and RA are incredibly detrimental to global health as PD is the most prevalent disease of mankind affecting almost half of the adult population, and RA inflicts severe disability and treatment is extremely costly with poor efficacy. A review of the literature indicates a link between PD and RA exists, but studies have focused on the role of bacteria, whilst disregarding possible immunological links. In both PD and RA, Th17 cells become dysregulated and drive pathology; therefore, this thesis aims to investigate the role of gingival Th17 cells in pathology of RA. Utilising the ligature-induced periodontitis (LIP) model, results presented in this thesis have revealed that PD induced changes to systemic populations of Th17 cells, demonstrating a potential mechanism linking PD to systemic comorbidities. Further experiments utilising the antigen-induced arthritis (AIA) model have shown that manipulating the frequency of damage- induced gingival Th17 cells implicated RA pathology and this was mediated through IL-17. Moreover, experiments using transgenic IL17-reporter mice revealed a unique LIP-driven plasticity of Th17 cells occurring in the gingival-draining lymph nodes. Data reveal that Th17 cells can convert into Tfh cells and this conversion is driven by IL-6 and possibly bacteria. Utilising Il17- Bcl6-/- KO mice (in which Th17 cells cannot convert into Tfh cells) to investigate the role of Th17- to-Tfh conversion has revealed that Th17-derived Tfh cells do not drive pathology but could mediate a protective role by enhancing antibody class-switching to limit bacterial growth. Taken together, these data highlight a previously unappreciated role of Th17 cells in the systemic effects of LIP, and a further role for gingival-Th17 cells in implicating pathology of RA. These data highlight the importance of studying the immunological links between PD and its associated comorbidities. Finally, this thesis has highlighted a previously unknown plasticity of Th17 cells, exclusive to PD, which could mediate a protective role in disease. This type of work could be used to improve patient stratification methods and therapeutic outcomes for RA patients.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Anne Barton (Supervisor), John Grainger (Supervisor) & Joanne Konkel (Supervisor)