The role of PAD4 in periodontal disease, autoimmunity and inflammation

Adrados Planell, Ana (2017) The role of PAD4 in periodontal disease, autoimmunity and inflammation. PhD thesis, University of Glasgow.

Abstract

Periodontal disease (PD) and rheumatoid arthritis (RA) are multifactorial chronic inflammatory diseases with high prevalence among the global population. There is evidence of a bidirectional relationship between PD and RA, although the underlying mechanisms remain undefined. Both PD and RA are associated with a dysregulated immune response and citrullination, a post-translational modification of proteins catalysed by peptidylarginine deiminases (PADs). PADs, in particular PAD4, are involved in formation of neutrophil extracellular traps (NETs) and may play a role both in generating potential auto-antigens and in host defence against bacterial infections. RA onset is preceded by a breach of self-tolerance and presence of anti-citrullinated protein antibodies (ACPAs). These ACPA have also been found in PD patients. Porphyromonas gingivalis is a key pathogen in PD and uniquely among prokaryotes expresses a PAD enzyme (PPAD), which is also potential source of citrullinated self-antigens. One hypothesis linking PD and RA suggests that the combination of PPAD and PAD4 activity in an inflamed environment may predispose to autoimmunity to citrullinated proteins and generation of ACPAs. This project aimed to determine the effect of PAD4 activity in PD and RA disease progression. Using PAD4 deficient animals or wild type controls, PAD4 was confirmed to be essential for NETs formation as bone marrow derived neutrophils from PADi4 knockout (KO) mice were unable to generate NETs in vitro. Experimental PD was initiated by oral infection with P. gingivalis and animals demonstrated a robust antibody response to P. gingivalis. However, there was limited evidence of bone loss in the animals, possibly due to inherent resistance in the strain. The immune response to P. gingivalis appeared unaffected by absence of PAD4, implying that NETS do not play a substantial role in the response to oral infection in this system. In experimental arthritis (EA) models, inflammation in EA was greater in absence of PAD4. Further investigation of the underlying mechanisms of PAD4 modulation of inflammation showed no direct impact in the innate response mediated by neutrophils, but confirmed a sexually dimorphic behaviour in PAD4 regulation of T-cell mediated inflammation. Pharmacological inhibition of PAD4 has been proposed and trialled as an RA therapy. These data suggest that PAD4 may impart subtle modulations on inflammation, which may impact on the outcome of such intervention.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: PD, RA, PAD4, knockout, citrullination, P. gingivalis, neutrophils, NETs, T cells, inflammation, DTH, sexual dimorphism.
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Funder's Name: European Commission (EC)
• Supervisor's Name: Culshaw, Dr. Shauna
• Date of Award: 2017
• Depositing User: Miss Ana Adrados Planell
• Unique ID: glathesis:2017-8253
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 16 Jun 2017 07:10
• Last Modified: 07 Jul 2017 08:59
• URI: https://theses.gla.ac.uk/id/eprint/8253