Abstract
Oral lichen planus (OLP) and oral lichenoid lesions (OLL) are chronic immune-mediated inflammatory diseases of oral mucosa. The precise aetiology of OLP is unknown but many potential triggers are recognised and OLL is linked to drugs or restorative materials. The immunopathogenesis of OLP and OLL involves antigen presentation leading to the activation and migration of T cells, which in turn induce apoptotic dysregulation of keratinocytes. Endoplasmic reticulum (ER) stress is known to play a significant role in many immune-mediated conditions by activating the unfolded protein response (UPR). The UPR aims to restore ER homeostasis along with engaging in inflammatory pathways. Understanding UPR pathways in the context of OLP and OLL is therefore crucial given their relation to inflammation and T cell homeostasis. In this thesis, it is postulated that UPR contributes to cellular stress, immune dysregulation, and keratinocyte apoptosis in OLP and OLL suggesting a significant link between ER stress and these inflammatory conditions.
To investigate the expression of genes and proteins associated with UPR in OLP and OLL, the research aimed to profile UPR expression by evaluating the differential expression of 84 key UPR genes in OLP, OLL, and control oral mucosal tissue samples through quantitative real-time polymerase chain reaction (qRT2-PCR). Additionally, the study assessed the expression of selected proteins in these tissue samples using immunohistochemistry techniques.
The study involved 36 cases including non-specific inflammatory controls, and cases of OLP and OLL. After RNA extraction from formalin fixed paraffin embedded (FFPE) tissue samples, the converted cDNA was profiled for 84 key UPR genes with a human UPR RT² Profiler Array with subsequent assessment of expression of five corresponding proteins (ATF4, CANX, MCM4, PDIA3, and RRM2).
Gene expression analysis revealed significant downregulation of genes in both OLP and OLL compared to controls, with OLP showing 7 genes and OLL showing 16 genes affected. In the drug-induced OLL subgroup, one gene was notably downregulated, while the restoration-associated OLL subgroup had 7 genes significantly downregulated. The downregulation in OLP indicates compromised UPR pathways, leading to increased apoptosis and chronic DNA replication stress, while OLL also showed impaired protein handling, inflammation, and dysregulated lipid metabolism.
The data suggests that OLP and OLL are influenced by a complicated and prolonged state of cellular stress. Gene analysis reveals a malfunction in the UPR machinery, specifically involving the genes ATF4, CANX, and PDIA3. In contrast, protein level assessments present a more intricate and occasionally compensatory response. The heightened protein expression of PDIA3 in OLL may indicate a targeted hypersensitivity reaction. Furthermore, the overexpression of proliferation markers including MCM4 and RRM2 in both conditions may signify a condition of chronic replication stress accompanied by an unregulated, pro-inflammatory cellular environment. Finally, it can be speculated that combination of ineffective stress responses and persistent cellular adaptation efforts may contribute to the ongoing inflammation and epithelial basal cell lysis that characterize these diseases.