Immunopathogenesis Of Oral Lichen Planus Research Articles

Abstracts from the World Federation for Laser Dentistry—Asia Pacific Division Virtual Conference July 16–17, 2021

Abstracts from the World Federation for Laser Dentistry—Asia Pacific Division Virtual Conference July 16–17, 2021

The role of CD68+ and CD163+ macrophages in immunopathogenesis of oral lichen planus and oral lichenoid lesions

Macrophages are phagocytic cells with essential participation in immunological events of the oral cavity. However, the role of these cells in oral lichen planus (OLP) and oral lichenoid lesions (OLL) remains unclear. The present study aimed to evaluate the density of macrophages in OLP and OLL, and to compare it with that of oral inflammatory fibrous hyperplasia (OIFH) (control group). 14 cases of OLP, 14 cases of OLL and 14 cases of OIFH were selected for immunohistochemical analysis of CD68+ (M1) and CD163+ (M2) macrophage expression. CD68+ and CD163+ macrophages densities were measured in the intraepithelial and subepithelial areas. The statistical tests used were multivariate analysis of variance, as well as a correlation and linear regression. OLP has more CD68+ macrophages when comparing with OLL (p = 0.001) and OIFH (p = 0.045). There is a very strong relationship between the macrophages types (p < 0.0001) in OLP and OLL. The linear regression showed that to OLL development (p < 0.0001/R2′ = 0.9584), the presence of different types of macrophages are more essential than to OLP (p < 0.0001/R2′ = 0.8983). However, in the OLP these dependencies are also largely. CD68+ macrophages may be associated with immunopathogenesis of OLP, indicating a pro-inflammatory activity and regulatory role in the type of T-cell response. Besides, CD68+ macrophages can cooperate in the diagnosis of OLP. These results are essential to future studies that seek a therapeutic target for OLP and OLL.

MiR-29b interacts with IFN-γ and induces DNA hypomethylation in CD4+ T cells of oral lichen planus

Oral lichen planus (OLP) is an autoimmune inflammatory disease mediated by T cells, in whose pathogenesis CD4+ T helper cells are supposed to play vital roles. MiR-29b has recently been recognized as a crucial regulator in immune response and inflammation. The current research focuses on exploring how miR-29b functions in the immunopathogenesis of OLP. Our findings showed that miR-29b expression in CD4+ T cells was upregulated in OLP, especially in its erosive form. MiR-29b in CD4+ T cells repressed IFN-γ mRNA and IFN-γ secretion, but not T-bet and EOMES; in turn, IFN-γ increased the expression of STAT1 and miR-29b in CD4+ T cells. Moreover, miR-29b in CD4+ T cells suppressed DNMT1 expression and induced global DNA hypomethylation. In conclusion, elevated miR-29b interacts with IFN-γ via a regulatory feedback loop and induces global DNA hypomethylation in CD4+ T cells, which consequently modulates Type 1 T helper immune response, thus contributing to the immune dysregulation of OLP.

Enhanced T-cell proliferation and IL-6 secretion mediated by overexpression of TRIM21 in oral lesions of patients with oral lichen planus.

To explore the expression and functions of the tripartite motif-containing protein 21 (TRIM21) in oral lichen planus(OLP) lesions. Paraffin sections of buccal mucosa samples from 15 cases of reticular oral lichen planus (OLP) patients and 10 healthy controls were used for immunohistochemistry to determine expression and distribution of TRIM21. Buccal mucosae from 11 OLP patients and seven healthy controls were analyzed by qPCR to quantify its gene expression. Peripheral blood mononuclear cells and CD3+ cells from four pairs of age- and sex-matched OLP patients and healthy controls were isolated for immunocytochemistry and culture. Following lentivirus-mediated overexpression of TRIM21 gene in CD3+ cells, CCK-8 was applied to evaluate cell proliferation. Cytokines including IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, and IFN-γ in the supernatants were measured by the cytometric bead array and verified by ELISA. A larger number of TRIM21-positive cells infiltrating the lamina propria were observed in OLP lesions by immunohistochemistry than those of healthy controls. Significantly higher transcription of TRIM21 was revealed by qPCR. TRIM21 overexpression in CD3+ cells significantly enhanced the proliferation and IL-6 secretion in CD3+ cells from 12 to 72hours. Overexpressed TRIM21 in OLP may be a primary proinflammatory molecule rather than a secondary and inducible regulatory factor in immunopathogenesis of OLP.

Potential roles of the CCL17-CCR4 axis in immunopathogenesis of oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory disease. C-C chemokine receptor type 4 (CCR4) and its cognate C-C motif chemokine ligand 17 (CCL17) play a key role in T-cell activation and trafficking, but their implication in OLP pathogenesis has not been explored. Our study was designed to analyze the expression and function of the CCL17-CCR4 axis in OLP. The mRNA expression levels of CCL17 and CCR4 in the circulating T cells of OLP subjects were examined by quantitative real-time PCR. The protein levels of CCL17 and CCR4 in the peripheral blood of OLP subjects were detected by enzyme-linked immunosorbent assay (ELISA) and Simple Western assay, respectively. The functional relevance of increased expression of CCL17 and CCR4 in OLP was demonstrated in proliferation, apoptosis, and migration assays. The mRNA and protein expression levels of CCL17 and CCR4 in the peripheral blood of patients with OLP were significantly upregulated compared with those of controls. CCL17 induced the migration of OLP T cells. In addition, blocking CCR4 with a small molecule CCR4 antagonist not only inhibited the proliferation and migration of OLP T cells but also promoted the apoptosis of OLP T cells. Our findings indicate that the CCL17-CCR4 axis might be responsible for the inflammatory infiltration of T cells in OLP.

The immunopathogenesis of oral lichen planus-Is there a role for mucosal associated invariant T cells?

Oral lichen planus (OLP) is a chronic, T-cell-mediated, immune condition of unknown cause. OLP may present with painful symptoms requiring treatment, as well as lesions outside the oral cavity. It is likely that what initiates the OLP disease process is a complex interaction of host susceptibility and environmental triggers. While it is possible that OLP represents a true autoimmune condition against an epithelial autoantigen, the mechanisms that lead to this immune dysregulation are still poorly understood. In this review article, we discuss current concepts relating to the immunopathogenesis of OLP, as well as the potential contributory roles the oral microbiota and mucosal-associated invariant T (MAIT) cells.

Evaluation of the miRNA-146a and miRNA-155 Expression Levels in Patients with Oral Lichen Planus.

Oral Lichen Planus (OLP) is a chronic autoimmune disease that could be considered as a potential premalignant status. To evaluate the miRNA-146a and miRNA-155 expression levels in patients with oral Lichen planus lesions compared to healthy subjects with normal oral mucosa. Forty patients with oral lichen planus and 18 healthy age and gender-matched controls were recruited in this case-control study. Oral lichen planus was diagnosed clinically and pathologically. The expression levels of two miRNAs in peripheral blood samples were determined using commercial TaqMan MicroRNA Assays. Relative quantification of gene expression was calculated by the 2-ΔΔct method. The expression levels of miRNA-146a and miRNA-155 in patients with oral Lichen planus were significantly higher than those of healthy controls. Also, a direct but insignificant correlation was found between miRNA-155 and miRNA-146a expression levels among the patient group. Our findings indicate that miRNA-146a and miRNA-155 could be potential biomarkers for the immunopathogenesis of oral lichen planus.

Understanding the Pathobiology of Oral Lichen Planus

Oral lichen planus (OLP) is a relatively common chronic inflammatory disease. A consistent body of evidence suggests that OLP is a predominantly T-cell mediated disease that shares clinical and histological features with chronic graft versus host disease. A putative genetic predisposition linked to cytokine polymorphisms has been revealed and some possible etiologic factors such as amalgam and hepatitis C virus have been studied in detail. In this review, an overview on the immunopathogenesis of OLP will be provided and a putative comprehensive hypothesis will be discussed in detail. Despite significant advances, many questions still remain concerning the etiology and pathogenesis of OLP.

Inflammation‐related cytokines in oral lichen planus: an overview

Cytokines are powerful mediators which play a central role in both innate and adapted immune responses. Aberrant productions of cytokines may lead to the onset of immune deficiency, allergy or autoimmunity, which are involved in the mechanisms of various immune-mediated inflammatory diseases. Oral lichen planus (OLP) is a chronic inflammation disease affecting the oral mucosa with unknown aetiology. Previous studies have described the abnormal expression patterns of various inflammation-related cytokines, such as IL-1, 2, 4, 5, 6, 8, 10, 12, 17, 18, TGF-β, IFN-γ and TNF-α, in lesions, saliva, serum and peripheral blood mononuclear cells from patients with OLP, which may reflect the immune dysregulation status and emerge as central players in the immunopathogenesis of OLP. Besides, the gene polymorphisms of several cytokines such as IFN-γ, TNF-α, IL-4, IL-10 have been found to be involved in the susceptibility of OLP. In this review, we gave a brief introduction of the characteristics and biological functions of these inflammation-related cytokines and summarized for the first time the current knowledge on the involvement of inflammation-related cytokines in OLP. Further research on the exact roles of these cytokines will aid the understanding of the pathogenesis and the identification of novel therapeutic approaches of OLP.

Evaluation of Serum TNF-α and TGF-β in Patients with Oral Lichen Planus.

Background and aims The role of cytokines in the immunopathogenesis of oral lichen planus (OLP) has received much attention. The aim of this study was to evaluate the serum levels of TNF-α and TGF-β in patients with OLP in an Iranian population. Materials and methods Thirty-two patients with OLP and 32 age-matched healthy volunteers as a control group were included in this study. Serum tests including TNF-α and TGF-β was performed in both groups. Data analysis was performed using descriptive statistics and Mann–Whitney U test using SPSS software version 16.0. Results The mean of TNF-α in study and control groups were 157 ± 115 pg/ml and 14 ± 10 pg/ml, respectively. The difference between the two means was statistically significant (P < 0.001). Moreover, the mean of TGF-β in study and control groups were 155 ± 26 pg/ml and 175 ± 57 pg/ml, respectively. The difference between the two means was statistically significant (P = 0.03). Conclusion According to the results of the present study, there was a significant decrease in the serum levels of TGF-β and a significant increase in the serum levels of TNF-α in patients with oral lichen planus. The increase in TNF-α serum levels in patients with OLP explains the inflammatory process in the course of the disease.

The Possible Roles of OPN-Regulated CEACAM1 Expression in Promoting the Survival of Activated T Cells and the Apoptosis of Oral Keratinocytes in Oral Lichen Planus Patients

Oral lichen planus is a chronic inflammatory disorder of the oral mucosa that represents T cell-mediated autoimmune diseases. The regulation and roles of carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1), a novel immune molecule, in the immunopathogenesis of T cell-mediated autoimmune diseases remain unclear. In the current paper, CEACAM1 was found to be overexpressed in peripheral T cells and epithelial cells in oral lichen planus patients. A fraction of infiltrating inflammatory mononuclear cells in the lamina propria of the oral lichen planus mucosa also expressed CEACAM1. Importantly, for the first time, CEACAM1 expression in T cells and in normal human oral keratinocytes was demonstrated to be regulated differently by osteopontin in vitro. Furthermore, the apoptosis of oral keratinocytes and activated T cells can be markedly suppressed by CEACAM1-specific monoclonal antibodies. In conclusion, OPN-regulated CEACAM1 expression may play a critical role in the immunopathogenesis of oral lichen planus.

Expression of TNF‐α in oral lichen planus treated with fluocinolone acetonide 0.1%

Oral lichen planus (OLP) is a common chronic inflammatory disease involving T cells-mediated immunity. Tumor necrosis factor (TNF)-alpha has been reported to be involved in the disease process. The purpose of this study was to investigate the effect of fluocinolone acetonide in orabase (FAO) 0.1% on the expression of TNF-alpha in patients with OLP. Eighteen Thai patients with atrophic or erosive OLP were recruited. Biopsy specimens were taken before and 1 month after treatment with FAO 0.1% and sent for histopathologic examination where they were immunohistochemically stained with antibody to TNF-alpha. Twenty normal mucosa specimens were identically processed. Oral squamous cell carcinoma tissue was used as a positive control for TNF-alpha expression, whereas OLP sections without primary antibody were served as negative control. Sixteen of 18 cases (88.89%) of OLP exhibited positive staining for TNF-alpha. Most of the TNF-alpha was observed in the mononuclear cells. Ten cases (55.56%) of OLP demonstrated TNF-alpha expression in keratinocytes. The number of mononuclear cells positive for TNF-alpha before the treatment with FAO 0.1% in orabase was statistically higher than that after the treatment (P=0.000) and in the normal mucosa (P=0.000). Moreover, the number of mononuclear cells after treatment with FAO 0.1% in orabase was statistically lower than before the treatment (P=0.000). Our study exhibited that TNF-alpha may be associated with the immunopathogenesis of OLP in Thai patients and FAO 0.1% had an effect on the reduction of TNF-alpha expression.

Current controversies in oral lichen planus: Report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis

Despite recent advances in understanding the immunopathogenesis of oral lichen planus (LP), the initial triggers of lesion formation and the essential pathogenic pathways are unknown. It is therefore not surprising that the clinical management of oral LP poses considerable difficulties to the dermatologist and the oral physician. A consensus meeting was held in France in March 2003 to discuss the most controversial aspects of oral LP. Part 1 of the meeting report focuses on (1) the relationship between oral LP and viral infection with special emphasis on hepatitis C virus (HCV), and (2) oral LP pathogenesis, in particular the immune mechanisms resulting in lymphocyte infiltration and keratinocyte apoptosis. Part 2 focuses on patient management and therapeutic approaches and includes discussion on malignant transformation of oral LP.

Current controversies in oral lichen planus: Report of an international consensus meeting. Part 2. Clinical management and malignant transformation

Despite recent advances in understanding the immunopathogenesis of oral lichen planus (LP), the initial triggers of lesion formation and the essential pathogenic pathways are unknown. It is therefore not surprising that the clinical management of oral LP poses considerable difficulties to the dermatologist and the oral physician. A consensus meeting was held in France in March 2003 to discuss the most controversial aspects of oral LP. Part 1 of the meeting report focused on (1) the relationship between oral LP and viral infection, with special emphasis on hepatitis C virus (HCV), and (2) oral LP pathogenesis, in particular the immune mechanisms resulting in lymphocyte infiltration and keratinocyte apoptosis. Part 2 focuses on patient management and therapeutic approaches and includes discussion on malignant transformation of oral LP.

Immunopathogenesis of oral lichen planus and recurrent aphthous stomatitis.

Oral mucosal bullous/desquamative/ulcerative diseases involve immunopathological mechanisms that account for loss of adhesion between contiguous keratinocytes or to structures within the basal lamina. Some are antibody mediated, in which specific adhesion molecules of the desmosome, hemidesmosome, and basement membrane become antigenic targets. Oral lichen planus and recurrent apthous ulcers, although manifesting disparate clinical appearances and natural history, share immunopathological features that involve T cell-mediated immunity. Although the antigens, haptens, or autoantigens are not usually apparent, current research poses the hypothesis that both of these common oral mucosal diseases are a delayed-type hypersensitivity or cell-mediated response to an antigenic stimulus residing within the epithelium. This article reviews the research evidence for this hypothesis.

Immunohistochemical localization of mast cells and mast cell-nerve interactions in oral lichen planus.

Mast cell mediators are likely to be involved in at least some aspects of the immunopathogenesis of oral lichen planus (OLP). The aim of this project was to map mast cell populations in OLP and identify possible sites of mast cell-nerve interactions. Monoclonal antibodies specific for tryptase and neurofilaments were used to identify mast cells and nerves respectively in an immunohistochemical study of OLP (n = 25) and normal oral buccal mucosa (NOBM) (n = 13) using a double-labelling protocol. Data analysis used paired t-test, multiway analysis of variance and Wilcoxon rank tests. Morphometric analyses showed the greatest mast cell density in the most superficial of the three depth layers examined in OLP, an increase of 130% compared with NOBM. Mast cells associated with neurofilaments ranged from 21.9% in OLP to 10.2% in NOBM. Mean epithelial thickness was significantly lower in OLP (P < 0.001) but without a strong correlation with mast cell density. Increased mast cell and mast cell-nerve interactions in OLP suggest both a controlling role over the lesional cell populations and a secondary role to the immune response once this becomes established.

Is there a role for tumor necrosis factor-alpha (TNF-alpha) in oral lichen planus?

Oral lichen planus (OLP) is a T cell-mediated inflammatory disease of the oral mucosa. T lymphocytes accumulate within OLP lesions by extravasation from the local microvasculature and subsequent migration to the oral epithelium. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine involved primarily in T cell-mediated immunopathological reactions, and it is implicated in diseases which bear clinical and histological similarities to OLP. This review examines the role of TNF-alpha in the initiation and progression of OLP, and summarises evidence for a key role for TNF-alpha in this disease. A unifying hypothesis for the involvement of TNF-alpha in the immunopathogenesis of OLP is presented. Based on this model, a variety of current therapies are explained and several alternative approaches suggested.

Immunopathogenesis of oral lichen planus : Walsh LJ, Savage NW, Ishii T, et al. J Oral Pathol Med 19:389, 1990

Immunopathogenesis of oral lichen planus : Walsh LJ, Savage NW, Ishii T, et al. J Oral Pathol Med 19:389, 1990

Immunopathogenesis of oral lichen planus

Oral lichen planus (LP) is a common mucosal disorder in which cell mediated immunity is thought to play a major role. In this paper, a unifying hypothesis which attempts to integrate cellular and molecular signals in the local immune response in oral LP is presented. In this model, modified keratinocyte surface antigens are the target for the cytotoxic cell response which characterizes oral LP, whereas mast cells and antigen presenting Langerhans cells are key cellular elements in the evolving lesion. It has been established that mast cell degranulation induces adhesion molecule expression on endothelium which facilitates lymphocyte homing to the tissues. These adhesive interactions between lymphocytes and keratinocytes are postulated to be important determinants in the effector phase of the lesion. Cytokines produced by both lymphocytes and keratinocytes which influence the local immune response could promote chronicity. Accordingly, modulation of immunologic events is a potential therapeutic approach for oral LP.