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Title: Oral ulceration in Behçet's disease : an investigation of neutrophil elastase and its inhibitors
Author: Novak, Tanya
ISNI:       0000 0004 5359 798X
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2014
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Behçet’s disease (BD) is a vasculitis of unknown aetiology typified by recurrent oral and genital ulcers, skin and ocular lesions. Debilitating manifestations can also affect vascular, gastrointestinal and neurological systems. Previous BD investigations showed increased circulating neutrophils and neutrophil elastase (NE), a serine protease. NE can digest connective tissues compromising their integrity if not regulated. In this study, NE and its two main inhibitors, secretory leukocyte protease inhibitor (SLPI) and alpha1- antitrypsin (α1AT), were investigated to determine if NE dysregulation is triggering oral mucosal damage. Findings were compared to healthy controls (HC) and recurrent aphthous stomatitis (RAS) patients, a disorder of episodic oral ulceration. FlowCytoMixTMmultiplex-assays compared saliva and serum inflammatory cytokines measurements where salivary levels reflected disease activity and correlated with published serum levels. Salivary NE, SLPI, and α1AT were measured by ELISA. Patients with oral ulcers had increased NE. Unexpectedly, BDq (quiescent, without ulceration) had increased NE, but SLPI was significantly lower than RASq and HC. RASq NE levels were similar to HC. Overall, NE correlated with α1AT levels, but showed an inverse relationship with SLPI. Quantitative PCR revealed significantly increased SLPI mRNA expression in both BDq and RASq buccal epithelium. High mRNA/low SLPI protein expression during ulceration could be explained by deficient translation, blocked ELISA antibody binding, or SLPI depletion. Despite high α1AT, all study groups had enzymatically active salivary NE which was successfully inhibited by recombinant SLPI. Confocal microscopy revealed BD patients’ blood neutrophils readily release neutrophil extracellular traps (NETs) in vitro compared to HCs. Antimicrobial NETs have mixed granule contents coating decondensed chromatin fibres and are associated with autoimmunity. During NET production, our novel observation that intracellular SLPI but not α1AT co-localised with NE suggests a regulatory role. This study supports the theory that a protease-antiprotease imbalance may play a role in BD oral and systemic pathology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Dentistry ; Behçet's Disease ; Oral Ulceration