Role of Forkhead box protein 3 in the pathogenesis of oral lichen planus: A systematic review

BACKGROUND: The composition and changes of microbiota have a significant impact on overall health and the development of various diseases. Of particular relevance is the problem of changes in the oral microbiota in patients with lichen planus of the oral mucosa. Studying the relationship between the composition of the oral microbiota and the pathogenesis of oral lichen planus will improve the understanding of the mechanisms of this disease. Thus, this topic is of considerable interest to a wide range of specialists in the field of medicine and biology. AIM: Detailed analysis of oral cavity microbiota and establishment of potential pathogenetic microbial associations with oral lichen planus. MATERIALS AND METHODS: The study included samples from patients diagnosed with various forms of oral red squamous lichen planus (lichen planus erosive-ulcerative) and a control group. The investigation was based on analyzing microbial diversity metrics (alpha and beta diversity), relative abundance of bacterial taxa, and identification of unique bacterial taxa in the oral red squamous lichen planus patients. This analysis utilized the 16S rRNA sequencing method. RESULTS: The analysis revealed a rich bacterial composition in patients with oral lichen planus, which was significantly different from that in the control group. Differences were also observed between the subgroups, especially between the typical and erosive-ulcerative forms of the disease. Notably, beta diversity did not show significant differences between the groups, indicating a similar overall microbiota composition despite fluctuations in the relative abundance of species. Nevertheless, the typical clinical form of the disease demonstrated more significant differences in the microbiota structure compared to the hyperkeratotic and erosive-ulcerative forms. Furthermore, analysis of the study groups revealed the presence of 50% shared microbial species, while the other half was represented by unique species associated with oral lichen planus. Regarding the subgroups, it was found that unique microorganisms correlated with the typical and erosive-ulcerative forms, respectively, providing a deeper understanding of the specific microbiological profile in the context of this disease. CONCLUSION: The study confirmed the hypothesis of an association between the microbiota composition and oral lichen planus, which may be of importance for the development of novel therapeutic approaches.

Background: In oral lichen planus (OLP), which is a persistent inflammatory condition of the autoimmune system, cytotoxic T lymphocytes are triggered against epithelial cells. OLP resists treatment more than its cutaneous counterpart and potentially transforms into malignancy as oral squamous cell carcinoma (OSCC). Transforming growth factor β (TGF-β) is produced by various cells, such as leukocytes and epithelial cells, whereby epithelial-mesenchymal-epithelialn (EMT) forms the phenotype of invasive cancerous cells and promotes tumors. Objectives: We investigated the role of TGF-β in the pathogenesis and biological behavior of dysplastic and non-dysplastic OLP. Methods: Thirty samples of erosive/atrophic OLP (15 dysplastic and 15 non-dysplastic) and 10 samples of normal mucosa of the oral cavity were immunohistochemically examined for the expression of TGF-β. Statistical analysis was performed using the Kruskal-Wallis and chi-squared tests. Results: TGF-β expressed to varying degrees in the epithelium of the studied groups. The groups significantly differed in terms of the expression of TGF-β. In pairwise comparisons, the dysplastic OLP group showed significantly higher immunoreactivity than the normal and non-dysplastic groups, although there was no significant difference between the normal and non-dysplastic OLP groups. The expression of TGF-β in the sub-epithelial lymphocytes of the dysplastic and non-dysplastic OLP groups showed a statistically significant difference. Conclusions: According to the results, TGF-β, as a marker of the inflammatory process in chronic inflammatory conditions, was expressed in epithelial cells and sub-epithelial lymphocytes of all OLPs. This suggests a possible role of this marker in the pathogenesis of OLP. In addition, the increased expression of TGF-β, a marker also involved in carcinogenesis, in the epithelial keratinocytes indicates the role it might play in the development of carcinoma in OLP.

Lichen planus is considered a chronic inflammatory disease which affects different sites, such as the skin, mucous membranes, hair, and nails. Based on the evidence, a complex cytokine network plays a crucial role in lichen planus pathogenesis. The study was aimed at assessing the serum IL-23 levels in the patients with cutaneous and oral lichen planus compared to healthy controls. Method. The study included 30 cutaneous lichen planus patients, 20 oral lichen planus patients, and 33 control subjects. Five milliliters of peripheral blood was obtained from each patient, and the serum was separated. IL-23 levels were determined using the ELISA kit, and the data were analyzed using the Mann–Whitney test. Results. IL-23 levels in the patient serum with oral lichen planus (P value ≤ 0.001) were significantly higher than in controls. Furthermore, there were significant differences in IL-23 serum levels in the patients with cutaneous lichen planus compared to the healthy controls (P value ≤ 0.001). Moreover, IL-23 serum levels were statistically different between patients with cutaneous lichen planus and patients with oral lichen planus (P value ≤ 0.001). Based on the mean concentration of interleukin-23, IL-23 levels were higher in the patients with oral lichen planus than in the patients with cutaneous lichen planus. Conclusions. Elevated serum IL-23 levels in the patients with oral lichen planus may indicate that IL-23 plays a crucial role in the pathogenesis of oral lichen planus. However, more research is needed with a larger sample size.

Caveolin-1 expression in oral lichen planus, dysplastic lesions and squamous cell carcinoma

Introduction:Oral lichen planus (OLP) is a chronic inflammatory disease with cell-mediated immune dysregulation. The aetiology of OLP has been studied extensively for decades. Viruses like Hepatitis C Virus (HCV), human papillomavirus (HPV), herpes simplex virus (HSV), and stress have been hypothesized to play a role in the pathogenesis and malignant transformation of OLP. HPV has been proved to be an etiological agent in oropharyngeal cancers and non-tobacco-associated leukoplakia. The role of human papillomavirus in the pathogenesis of OLP has to be studied extensively.Aim:This study aims to detect the presence of HPV 16 and HPV 18 DNA in the biopsy samples of OLP and also to determine the role played by the virus in the pathogenesis and malignant transformation of OLP.Materials and Methods:Biopsy samples comprising 30 OLP tissues were collected. The DNA was extracted by the cetyltrimethylammonium bromide method. Polymerase chain reaction was performed by using general primers to amplify the HPV E6 gene.Results:Twelve out of 30 (40%) OLP cases were positive for HPV DNA. A significant relation was found between HPV, site (buccal mucosa) and the type (reticular) of the lesion (P = 0.007). However, the difference between the percentage of HPV positive males and females was statistically insignificant (P = 0.852).Conclusion:This study confirmed the presence of high-risk HPV 16 and HPV 18 DNA in OLP. The study showed a significantly higher expression of HPV in erosive OLP when compared to reticular OLP, suggesting a possible role of HPV in the malignant transformation of OLP.

The pathogenesis of oral lichen planus (OLP) remains to be fully elucidated; however, certain psychoneurological factors may influence the onset and exacerbation of OLP. The aim of the present study is to evaluate the intensity of negative emotions in patients with OLP. A cross-sectional, questionnaire-based study was performed. The sample consisted of 52 subjects, comprising 26 patients with OLP (OLP group) and 26 controls (CTRL group). The Depression Anxiety Stress Scale 21 (DASS-21) was used for psychometric evaluation. The patients were also asked about their attitude toward the disease, treatment, and interference of the disease on daily life. The mean level of depression was 12.54 ± 6.6 in the OLP group and 7.69 ± 5.22 in the CTRL group (P = 0.006). The mean level of anxiety was 11.15 ± 7.95 in the OLP group and 6.62 ± 4.86 in the CTRL group (P = 0.018). The mean stress levels were 8.69 ± 7.06 and 3.85 ± 3.18 in the OLP and CTRL groups, respectively (P = 0.003). Severe and very severe scores of depression and very severe scores of anxiety and stress were present in the OLP group, whereas these emotions were normal in the majority of controls. Depression, stress, and anxiety may be involved in the pathogenesis and course of OLP.

Some members of the Toll-like receptor (TLR) family, which plays key roles in both innate and adaptive immune responses, are involved in the pathogenesis of autoimmune, chronic inflammatory and infectious diseases. However, the role of TLR in the pathogenesis of oral lichen planus (OLP) has not been investigated. The aim of this study was to understand the roles of TLR in OLP. The expression of TLR genes in OLP tissues was analyzed by cDNA microarray and reverse transcription polymerase chain reaction, and TLR protein expression in OLP tissues and peripheral blood monocytes was examined by immunohistochemical analysis and flow cytometry, respectively. Furthermore, TLR ligand-induced cytokine production from peripheral blood monocytes was measured by enzyme-linked immunosorbent assay. Among 10 TLR genes, the average expression ratio of the genes for TLR1, 2, 3, 5, 6 and 10 in OLP tissues compared to that in the normal buccal mucosae was more than 1.0. In contrast, the average ratio of the genes for TLR7, 8 and 9 was less than 1.0. TLR2 but not TLR4 was highly expressed in the cells of the spinous layer and infiltrating monocytes in OLP tissues, and the mean fluorescence intensity of TLR2 on peripheral blood monocytes was significantly higher in OLP patients than in healthy controls. Furthermore, the peripheral blood monocytes from OLP patients produced considerably higher amounts of interleukin (IL)-12 and lower amounts of IL-10 than those from healthy controls. In OLP, the T-helper cell (Th)1/Th2 balance appears to shift toward Th1 dominance, probably depending on the upregulation of TLR2 expression and these alterations in TLR2-mediated immunity may be involved in the pathogenesis and maintenance of OLP.

Objective: To explore the expression of autophagy related factors microtubule associated protein 1 light chain 3B (LC3B), p62, autophagy key factor Beclin1 in oral lichen planus (OLP) tissues and their relationships with the clinicopathological characteristics of OLP, investigating the function and significance of autophagy in pathogenesis of OLP. Methods: Forty-one lesion tissues (OLP group, twenty-one cases of erosive OLP and twenty cases of non-erosive OLP) were selected from OLP patients visiting the Department of Periodontal and Oral Medicine, School and Hospital of Stomatology, Guizhou Medical University from October 2017 to December 2019. Fifteen cases of normal oral mucosal tissues (control group) were collected from oral and maxillofacial surgery at The Affiliated Stomatology Hospital of Guizhou Medical University during the same period. Protein and mRNA expression levels of LC3B, p62 and Beclin1 were detected by immunohistochemistry (IHC) and real-time quantitative PCR (RT-qPCR) in OLP lesions respectively. The protein expression levels of LC3B, p62, Beclin1 and ratio of LC3B-Ⅱ/LC3B-Ⅰ in sixteen cases (eight cases of erosive OLP and eight cases of non-erosive OLP) from the OLP group were detected by Western blotting (WB). The potential relationship between LC3B, p62, Beclin1, LC3B-Ⅱ/LC3B-Ⅰ ratio and clinical features of OLP were analyzed. Results: IHC results showed that the positive expression rates of LC3B and p62 proteins in OLP lesion tissues [LC3B: 68% (28/41); p62: 59% (24/41)] were higher than those in the control group [LC3B: 5/15; p62: 3/15] (LC3B: χ2=5.55, P=0.019; p62: χ2=5.55, P=0.015). The positive expression rates of LC3B and p62 proteins in the erosive OLP group [LC3B: 86% (18/21); p62: 76% (16/21)] were higher than those in the non-erosive OLP group [LC3B: 50% (10/20); p62: 40% (8/20)] (LC3B: χ2=4.50, P=0.034; p62:χ2=5.53, P=0.019). The positive expression rate of Beclin1 protein in the OLP lesions[20% (8/41)] was lower than that in the control group (7/15) (χ2=4.13, P=0.042), but was not statistically different between the two types of OLP (P>0.05). The RT-qPCR results showed that the mRNA expression levels of LC3B and p62 in OLP lesions [LC3B: 2.78 (1.59, 6.15); p62: 4.30 (2.34, 6.29)] were higher than those in the control group [LC3B: 1.05 (0.88, 1.21); p62: 1.12 (0.89, 1.36)] (LC3B: Z=-4.56, P<0.001; p62: Z=-4.78, P<0.001), and the mRNA expression levels of LC3B and p62 in the erosive OLP group were higher than those in the non-erosive OLP group (LC3B: Z=-2.87, P=0.004; p62: Z=-2.95, P=0.003). The mRNA expression level of Beclin1 in OLP tissues was lower than that in the control group (Z=-2.43, P=0.015), but the difference was not statistically significant between the two types of OLP (P>0.05). WB results showed that the LC3B-Ⅱ/LC3B-Ⅰ ratio was higher in the OLP lesions than that in the control group (t=-2.45, P=0.021), and the LC3B-Ⅱ/LC3B-Ⅰ ratio was higher in the non-erosive OLP group than in the erosive OLP group (t=-2.38, P=0.032). Spearman's correlation analysis showed that the ratio was negatively correlated with the clinical staging and the degree of basal cell liquefaction in OLP (clinical staging: r=-0.57, P=0.021; basal cell liquefaction: r=-0.54, P=0.032), but not with the disease duration and the degree of lymphocytic infiltration (P>0.05). Conclusions: Autophagy related factors LC3B, p62 and Beclin1 may play a role in the formation and progression of OLP lesions. The autophagy level was relatively lack in erosive OLP compared to non-erosive OLP, contributing to the increased local lesion destruction in erosive OLP. Abnormal cellular autophagy may play an important role in the formation of OLP lesions.

Oral lichen planus (OLP) is considered a T cell-mediated autoimmune disease with unknown aetiology. T helper cells appear to play an important role in the pathogenesis of OLP. We investigated the possible role of T helper cells, Th1 and Th17, in the lesions and circulation of patients with OLP. Forty patients with OLP and 15 healthy volunteers were recruited. Double immunofluorescence staining was used to detect Th1 and Th17 cells in the OLP lesions, and intracellular cytokine staining and flow cytometry to evaluate the proportion of Th1 and Th17 cells in peripheral blood. The levels of serum interferon (IFN)-γ and interleukin (IL)-17 were assessed by using an enzyme-linked immunosorbent assay. It was found that Th17 cells, as well as Th1 cells, were present in OLP lesions. The proportion of peripheral Th1 and Th17 cells was significantly increased in patients with OLP. The proportion of Th17 cells in atrophic-erosive OLP was elevated as compared with that in reticular OLP. Serum IL-17 levels in OLP patients were significantly higher than in controls, and those in the atrophic-erosive OLP group were increased as compared with the reticular OLP group. However, the levels of serum IFN-γ were slightly decreased in OLP patients. Our data suggested that Th1 and Th17 cells in the local lesions and peripheral blood may be associated with the pathogenesis of OLP, and that IL-17 may be an important proinflammatory cytokine in OLP. These findings enhance our understanding of OLP pathogenesis.

Background:Macrophages are essential cellular elements of innate and adaptive immunity and one of the most common cell types in chronic inflammatory conditions such as oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC). However, the roles of M1 and M2 macrophages in the pathogenesis of erosive OLP (E-OLP) which has the highest malignant potential remain unclear.Objective:To evaluate and compare the immunohistochemical expression of M1 and M2 macrophages in OLP and OSCC.Materials and Methods:Paraffin-embedded tissue sections of 20 OLP (9 erosive, 11 non-erosive) and 30 OSCC (16 well, 8 moderate, and 6 poorly differentiated) cases were subjected to immunohistochemical staining for CD68 (M1) and CD163 (M2). The slides were examined for distribution, intensity, and localisation of CD68 and CD163 expression. Quantitative assessment of the staining was done with the help of Image Pro Plus software. Statistical analysis using Fisher exact test for qualitative assessment and Student t-test and one-way ANOVA for quantitative analysis were done.Results:Although there was an increase in the density of CD68+ and CD163+ macrophages in E-OLP, a statistically significant difference was not observed between the subgroups of OLP. However, the density of CD68 and CD163-positive macrophages was relatively higher in moderately differentiated OSCC with no statistically significant difference. However, the staining pattern, intensity, and localisation between CD68 and CD163 in OLP and OSCC showed significant difference.Conclusion:An increase in the density of CD68+ and CD163+ macrophages in E-OLP may be associated with the pathogenesis of OLP into malignant transformation.

Oral lichen planus (OLP) is frequently seen in patients with hepatitis C virus (HCV) infection. To clarify the role of HCV in OLP pathogenesis, we investigated the occurrence and progression of oral lesions in chronic hepatitis C patients treated with interferon. Oral surgeons examined 24 hepatitis C patients (15 men, nine women; mean age 48.1 years) for oral lesions before, during and after interferon (IFN) treatment. OLP was observed in 16.7% (4/24). Two patients had OLP before treatment, one during and one after treatment. Those who developed OLP during or after treatment had neither improvement nor disappearance of OLP even when serum HCV RNA became negative. Leucoplakia was seen in four patients before treatment and oral cancer in one patient 6 months after completing treatment. OLP can occur, exacerbate and persist during IFN treatment for hepatitis C, even when serum HCV RNA becomes negative. The present study suggested that OLP pathogenesis in hepatitis C is due to host factors induced by HCV infection rather than direct HCV participation. Treating physicians should be aware of OLP occurrence or exacerbation by IFN treatment with hepatitis C patients, but IFN therapy is not necessarily contraindicated in these patients.

Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory disorder with multifactorial aetiology and malignant transformation potential. Despite the treatments so far identified, new tailored and safe specific measures are needed. Recently, human microbiota imbalance has been linked to several immune-mediated diseases, opening new therapeutic perspectives for probiotics; besides their ability to directly interact with the host microbiota, they also display a strain-specific immune-modulatory effect. Thus, this non-systematic review aims to elucidate the molecular pathways underlying probiotic activity, mainly those of Lactobacilli and Bifidobacteria and their metabolites in OLP pathogenesis and malignant transformation, focusing on the most recent in vitro and in vivo research evidence. Findings related to their activity in other immune-mediated diseases are here included, suggesting a probiotic translational use in OLP. Probiotics show immune-modulatory and microbiota-balancing activities; they protect the host from pathogens, hamper an excessive effector T cell response, reduce nuclear factor-kappa B (NF-kB) signalling and basal keratinocytes abnormal apoptosis, shifting the mucosal response towards the production of anti-inflammatory cytokines, thus preventing uncontrolled damage. Therefore, probiotics could be a highly encouraging prevention and immunotherapeutic approach for a safer and more sustainable OLP management.

Introduction: Oral Lichen Planus (OLP) is a chronic inflammatory disease of cell-mediated dysregulation characterized by relapses and remissions. The aetiology of OLP has been extensively studied for decades. The pathogenesis is unclear with a debatable malignant transformation. The pathogenesis and malignant transformation of OLP may be affected by viruses such as Hepatitis C Virus (HCV), Human Papillomavirus (HPV), Herpes Simplex Virus (HSV), and stress. HPV has been proved to be an etiological agent in oropharyngeal cancers and non-tobacco-associated leukoplakia. The role of human papillomavirus in the pathogenesis of OLP and its malignant transformation has to be studied extensively. Aim: This study aims to detect the presence of HPV DNA in the biopsy samples of dysplastic and non-dysplastic OLP and thus determine the role the virus played in the malignant transformation of OLP. Materials and Methods: Biopsy samples comprising 250 OLP tissues were collected. The DNA was extracted from the fixed tissue by using the Cetyltrimethylammonium bromide (CTAB) method. Polymerase Chain Reaction (PCR) was performed using primers to amplify the HPV E6 gene. Results: Hundred and three out of 250 (41.2%) OLP cases were positive for HPV DNA.

The aim of this study was to determine the correlation between the number of FOXP3(+) T cell in lesions and the disease activity of patients with oral lichen planus (OLP). The expression of FOXP3 was investigated using immunohistochemical staining and real-time RT-PCR in 23 OLP lesions and 12 controls. Changes of FOXP3(+) Treg in peripheral blood from three patients' pre and post-treatment were assessed using flow cytometry. Few FOXP3(+) cells were detected in controls, but an increased number of FOXP3(+) cells were observed in lesions (n = 20, 40.99 +/- 24.68 cells per high-power field - hpf). Furthermore, the frequency of FOXP3(+) Treg in reticular OLP (n = 7, 63.6 +/- 23.2 cells per hpf) was significantly higher than that in erythematous/erosive OLP (n = 13, 28.8 +/- 16.8 cells per hpf, P = 0.001). In addition, negative correlation was found between the number of FOXP3(+) Treg and disease activity (correlation oefficient = -0.557, P = 0.013). The proportion of FOXP3(+) Treg showed remarkable increase in peripheral blood from patients after treatment (1.39 +/- 0.71%vs 4.91 +/- 1.59%). These data indicated that FOXP3(+) Treg were involved in the pathogenesis of OLP and correlated with disease's subtype and activity.

To investigate the expression and clinical significance of miRNA-155 and miRNA-146a in peripheral blood mononuclear cells (PBMC) and plasma of oral lichen planus (OLP) patients. Twenty-five female and seven male OLP patients (OLP group) aged 25 to 54 years were selected from January 2012 to May 2013. The diagnosis was confirmed by pathology and the lesions were divided into two non-erosive OLP group (18 cases) and erosive OLP group (14 cases). Twenty healthy sex and age matched volunteers served as control. miRNA-155 and miRNA-146a expressions in PBMC and plasma were examined by real-time PCR. The difference between OLP group and control group was statistically analyzed. The expressions of PBMC and plasma miRNA-155 were higher in OLP patients than those in the healthy control (median, 0.07 vs 0.03, P < 0.05; 5.84 vs 1.32, P < 0.01). The median expression level of miRNA-146a in PBMC and plasma of OLP patients and healthy controls were (1.26 vs 0.58, P < 0.05) and (412.60 vs 238.42, P < 0.01). The plasma miRNA-155 and miRNA-146a expressions were significantly higher in erosive OLP group than those in non-erosive OLP group. There were no significant differences in the expression of PBMC miRNA-155 and miRNA-146a between the two groups. The expressions of PBMC and plasma miRNA-155 and miRNA-146a are higher in OLP patients. The expressions of plasma miRNA-155 and miRNA-146a are associated with OLP severity. The over expression of miRNA-155 and miRNA-146a in OLP may play a role in the pathogenesis of OLP.