|dc.description.abstract||This thesis aimed to study the inter-relationship between the oral health status, aspects of the adaptive and innate immune response, and the oral microbiome of a well-defined cohort of Behçet’s syndrome (BS) patients.
Patients thought to have BS were referred to one of the two centres participating in this study (St Thomas’ Hospital and Royal London Hospital). Diagnosis was based on the International Study Group (ISG) criteria. Information about the frequency of the different symptoms of the disease along with the treatment protocol was collected on a data sheet and stored electronically in a database, in the period between January 2006 and August 2012. The data were then analysed at the end of the study period.
The quality of life (QoL) and oral health status of BS patients in the UK was compared to those from Turkey. Furthermore, the oral health status of BS patients in the UK was compared to that of healthy control (HC) volunteers and recurrent aphthous stomatitis (RAS) patients. Saliva and oral swabs were cultured and purified to homogeneity and bacteria were identified by matrix-assisted laser desorption/ionisation-time of flight (MALDI-TOF). Salivary viral load and the serum immunoglobulin (Ig) G of the different herpes viruses were also examined.
In order to determine whether there were differences in the innate response efficacy in BS patients, the expression of key molecular determinants of pathogen recognition was also analysed. Total ribonucleic acid (RNA) was purified from non-ulcerated buccal mucosal brush biopsies and analysed by real time polymerase chain reaction (qPCR) for the presence of toll-like receptor (TLR) 2 messenger RNA (mRNA) and TLR4 mRNA, and their splice variants. The functions of TLR2 and TLR4 were also investigated.
In the investigated cohort of UK BS patients, all patients had a history of recurrent oral ulceration, 85.6% had dermatological lesions, 79.1% had rheumatological manifestations, 73.9% had genital ulceration, 68.6% had ocular involvement, 15% had neurological manifestations, and 10.5% had vascular involvement. The most frequent treatment was colchicine (54.2%), followed by topical corticosteroid therapy (53.6%) then azathioprine (43.8%).
The QoL of BS patients from the UK and Turkey was affected to a similar extent. The Turkish BS patients had generally poorer oral health status in comparison to the UK BS patients. Nevertheless, the UK BS patients had also generally poorer oral health status in comparison to HC volunteers. The oral health status of the UK BS patients was comparable to those suffering from RAS.
The oral mucosal and salivary microbial profile was variable between individuals in the same group and between individuals in different groups. The orally active BS patients’ oral mucosa showed the highest microbial community complexity and diversity compared to all the other investigated groups. Moreover, the BS patients had statistically higher salivary Epstein-Barr virus (EBV) shedding compared to HC volunteers, but not to RAS patients.
Relapsed BS patients’ oral mucosa expressed higher levels of TLR2 and TLR4 mRNA. Investigation of the known splice variants of both receptors revealed that TLR2 mRNA variants b, d and e, and TLR4 variants 3 and 4 are significantly elevated in relapsed BS patients. A significant defect in the response to cognate agonists of TLR1/2 heterodimer and TLR4 was also observed in the whole BS patient cohort. Furthermore, BS patients expressed a lower cytomegalovirus (CMV) IgG level in comparison to all the investigated groups.
In conclusion, BS patients show higher levels of expression of some of the unusual splice variants of TLR2 and TLR4 mRNA, which might contribute to the observed functional defect in TLR1/2 heterodimer and TLR4. This defect in the key molecular determinants of pathogen recognition can lead to a failure in the adaptive immune responses’ modulation, resulting in the observed decrease in the expression of CMV IgG in BS patients and indeed the increase in susceptibility to oral infections. Furthermore, it is envisaged that the reported discrepancy in the oral microbiome of BS patients can be targeted in the future by probiotics to restore the balance of the oral microbial community, leading to better oral health which in turn will enable a better control of the BS immune response.||en_US