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Oral Lichen Planus (OLP) is a chronic inflammatory mucocutaneous disorder of the oral mucosa. Th9 cells secrete IL9, which induces elevated levels of MMP9, exacerbating OLP disease severity. IL9 also increases Th17 levels in OLP lesions. This study aimed to detect IL9 tissue expression in patients with OLP compared to normal controls and to correlate its expression with disease severity and response to intralesional steroid therapy. This study involved 18 patients with OLP and 18 healthy, age- and sex-matched volunteers. The REU scoring system was used to monitor OLP lesions before and after treatment with 20 mg/mL intralesional triamcinolone acetonide every 2 weeks for four sessions. Biopsies for H&E and IL-9 expression were taken from patients and controls, with repeat biopsies after the fourth session for patients. A highly statistically significant increase in IL9 expression was observed in the patient group compared with the control group. A highly statistically significant decrease in both the REU score and post-treatment IL-9 expression was detected in the patient group. We can conclude that IL9 is a tissue marker of OLP activity. Future studies on therapies targeting IL-9 in OLP are needed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Neutrophil extracellular traps (NETs) are produced by polymorphonuclear neutrophils (PMNs) stimulated by interleukin-17 (IL-17) and tumor necrosis factor α (TNF-α). However, the level and role of NETs in oral lichen planus (OLP) remain poorly understood., Objective: This study aimed to investigate the expression of NETs in OLP and explore the correlation between NETs and the levels of IL-17 and TNF-α., Methods: The expression and distribution of NET-related proteins in tissue samples from each group were assessed using hematoxylin-eosin (HE) staining and immunofluorescence (IF). Additionally, the expression of NET-related proteins in peripheral blood samples from each group was evaluated using cell IF technique and fluorescence spectrophotometry. The relative formation level of NETs in each group was determined by fluorescence spectrophotometry via plasma co-culture. Furthermore, the levels of inflammatory cytokines IL-17 and TNF-α in plasma and culture supernatant were measured using enzyme-linked immunosorbent assay (ELISA)., Results: NET-related proteins were located in the subepithelial and lamina propria layers of OLP lesions. OLP had significantly higher expression of NET-related proteins in lesion tissues and peripheral blood compared to the healthy control (HC) group ( p < 0.05). The rate of NETs formation in the erosive-stage OLP (EOLP) group was significantly higher than that in the HC group ( p < 0.05), in contrast, no significant increase was observed in the non-erosive OLP (NEOLP) group ( p > 0.05). Furthermore, the levels of IL-17 and TNF-α in the EOLP group were significantly elevated compared to those in the NEOLP group and HC group ( p < 0.05), while the levels in the NEOLP group did not significantly differ from those in the HC group ( p > 0.05). The rate of NETs formation showed a positive correlation with the levels of IL-17 and TNF-α in plasma., Conclusion: The expression of NET-related proteins was upregulated in OLP lesion tissues and peripheral blood. Elevated levels of IL-17 and TNF-α in peripheral blood plasma positively correlated with the rate of NETs formation, suggesting that IL-17 and TNF-α mediate the formation of NETs in OLP patients, and may thereby contribute to the development of OLP., Competing Interests: The authors declare that they have no competing interests., (© 2024 Cheng et al.)

Background: Mucosal-associated invariant T (MAIT) cells play key roles in many inflammatory diseases. However, their effects on the long-term course of oral lichen planus (OLP) and recent-onset OLP remain unclear. In this study, we aimed to investigate the function of MAIT cells in the different processes of OLP and to explore the immunological background of this disease., Methods: The frequency, phenotype, cytokine secretion, and clinical relevance of MAIT cells were investigated. MAIT cells were collected from the peripheral blood of 14 adults with recent-onset OLP (7-120 days after disease onset) and 16 adults with long-term course OLP (>2 years after diagnosis) using flow cytometry and compared with 15 healthy blood donors. Statistical analyses were performed using the GraphPad Prism software., Results: MAIT cells from adults with recent-onset OLP exhibited an activated phenotype, as indicated by an increased frequency of CD69 + (p < 0.05) and CD38 + MAIT cells (p < 0.01) and elevated production of the proinflammatory cytokine IL-17 A (p < 0.01), compared with healthy adult donors. In adults with long-term OLP, MAIT cells exhibited an activated and exhausted phenotype, characterized by high expression of CD69 (p < 0.01) and PD-1 (p < 0.001) and increased production of granzyme B released (p < 0.01). Compared with recent-onset OLP patients, long-term OLP patients showed a decreased production of CD8 + , and CD4 - CD8 - cells, but an increase in PD-1 + production (p < 0.05)., Conclusions: Circulating MAIT cells exhibited activation in OLP patients across varying disease durations. Given that PD-1 expression is elevated in adults with long-term OLP, it is reasonable to infer that circulating MAIT cells in long-term OLP may exhibit a more exhausted state than those in recent-onset OLP., (© 2024. The Author(s).)

Background and Objectives: Oral lichen planus (OLP) is a T cell driven disorder that significantly impairs patients' quality of life. Previous reports suggest that both cellular and humoral activities against desmoglein (dsg) 1 and 3 may be involved in OLP pathogenesis. Here, we aim to analyze the frequency of occurrence and pathological significance of anti-dsg antibodies in a large cohort of OLP patients., Materials and Methods: OLP patients were screened for anti-dsg antibodies by enzyme-linked immunosorbent assay in three tertiary referral centers. OLP sera with anti-dsg antibodies were further analyzed by Western blot and dispase-based keratinocyte dissociation assay (DDA) to identify the targeted dsg ectodomains and to assess their pathogenicity., Results: Of 151-screened individuals with OLP, only four patients (2.6%) with erosive OLP showed serum IgG against dsg1/3. Western blot analysis with recombinant dsg3 ectodomains revealed preferential recognition of the extracellular domain 5. By DDA with spontaneously immortalized human keratinocytes, none of the sera from these four patients induced acantholysis., Conclusions: Activation of humoral immunity occurs prevalently in patients with erosive OLP, probably due to epitope spreading. OLP serum antibodies are unable to induce loss of intercellular adhesion in vitro, strongly suggesting that they are not disease causing but rather an epiphenomenon., (© 2024 The Author(s). Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

Objective: We intended to map the single-cell profile of OLP, explore the molecular characteristics of unconventional T cells in OLP tissues., Methods: Buccal mucosa samples from OLP patients and healthy individuals were used to prepare single-cell suspension. Single-cell RNA sequencing was used to analyze the proportion of all the cells, and the molecular characteristics of unconventional T cells. Immunohistochemical staining was used to detect the expression of unconventional T cells marker genes., Results: The cell clusters from buccal mucosa were categorized into immune cells, fibroblasts, endothelial cells, and epithelial cells. Unconventional T cells with phenotype of CD247 + TRDC + NCAM1 + were identified. Immunohistochemical staining revealed higher expression of unconventional T cell marker genes in OLP tissue, predominantly in the lamina propria. In OLP, unconventional T cells are in a unique stress response state, exhibited enhanced NF-κB signaling and apoptosis inhibition, enhanced heat shock protein genes expression, weakened cytotoxic function. A large number of ligand-receptor pairs were found between unconventional T cells and other cells, particularly with fibroblasts and endothelial cells., Conclusions: This study mapped the single-cell profile of OLP, delineated the molecular characteristics of unconventional T cells in OLP, and uncovered that these unconventional T cells are in a stress response state., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Oral lichen planus (OLP) is a common T cell-mediated oral mucosal immune inflammatory disease. Intraepithelial lymphocytes (IELs) are a unique subset of T cells that play an important role in regulating immune response. This study aims to investigate the phenotype and the differentiation mechanism of IELs in OLP., Methods: The expression of CD4, CD8α, CD8β, T-helper-inducing POZ/Krueppel-like factor (ThPOK), and RUNX family transcription factor 3 (Runx3) in the epithelium and peripheral blood mononuclear cells (PBMCs) of OLP was determined by immunofluorescence and immunohistochemistry. Then, the correlations among them were analyzed. Naïve CD4 + T cells were sorted from blood of OLP patients and stimulated with retinoic acid (RA) and transforming growth factor-β 1 (TGF-β 1 ). Then the expression of CD4, CD8α, CD8β, ThPOK, and Runx3 was investigated by immunocytochemistry., Results: CD8α expression and CD8αα + cells were upregulated in the epithelium of OLP, whereas they were downregulated in PBMCs of OLP. CD8β was not expressed in the epithelium of OLP. CD4, CD8α, and Runx3 expression and CD4 + CD8α + cells were increased, whereas ThPOK expression was decreased in the epithelium of OLP. CD8α expression was positively correlated with Runx3 expression, whereas ThPOK expression was negatively correlated with Runx3 expression. After RA and TGF-β 1 stimulation, CD8α and Runx3 expression was upregulated, and ThPOK expression was downregulated in naïve CD4 + T cells., Conclusion: CD4 + CD8αα + IELs may be the dominant phenotype of IELs in OLP, and the differentiation of CD4 + CD8αα + IELs in OLP is negatively regulated by ThPOK and positively regulated by Runx3., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Mucosal-associated invariant T (MAIT) cells assume pivotal roles in numerous autoimmune inflammatory maladies. However, scant knowledge exists regarding their involvement in the pathological progression of oral lichen planus (OLP). The focus of our study was to explore whether MAIT cells were altered across distinct clinical types of OLP., Methods: The frequency, phenotype, and partial functions of MAIT cells were performed by flow cytometry, using peripheral blood from 18 adults with non-erosive OLP and 22 adults with erosive OLP compared with 15 healthy adults. We also studied the changes in MAIT cells in 15 OLP patients receiving and 10 not receiving corticosteroids. Surface proteins including CD4, CD8, CD69, CD103, CD38, HLA-DR, Tim-3, Programmed Death Molecule-1 (PD-1), and related factors released by MAIT cells such as Granzyme B (GzB), interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-17A, and IL-22 were detected., Results: Within non-erosive OLP patients, MAIT cells manifested an activated phenotype, evident in an elevated frequency of CD69 + CD38 + MAIT cells (p < 0.01). Conversely, erosive OLP patients displayed an activation and depletion phenotype in MAIT cells, typified by elevated CD69 (p < 0.01), CD103 (p < 0.05), and PD-1 expression (p < 0.01). Additionally, MAIT cells exhibited heightened cytokine production, encompassing GzB, IFN-γ, and IL-17A in erosive OLP patients. Notably, the proportion of CD103 + MAIT cells (p < 0.05) and GzB secretion (p < 0.01) by MAIT cells diminished, while the proportion of CD8 + MAIT cells (p < 0.05) rose in OLP patients with corticosteroid therapy., Conclusions: MAIT cells exhibit increased pathogenicity and pro-inflammatory capabilities in OLP. Corticosteroid therapy influences the expression of certain phenotypes and functions of MAIT cells in the peripheral blood of OLP patients., (© 2024. The Author(s).)

Objective: Oral lichen planus (OLP) is an immune-mediated condition featuring chronic inflammation. The World Health Organization classifies OLP as potentially malignant, but it is believed that the malignant transformation of OLP occurs in lesions with both lichenoid and dysplastic features (LD). This review discusses the issues surrounding OLP and LD, including their malignancy, classification, and categorization, and whether lichenoid inflammation causes dysplastic changes in LD or vice versa., Methods: English full-text literature on OLP, LD and/or dysplasia was retrieved from PubMed, CINAHL, and Google Scholar., Results: Thirty-six publications including original research articles, reviews, meta-analyses, books, reports, letters, and editorials were selected for review., Discussion: Research suggests that OLP has malignant potential, although small, and that LD should not be disregarded, as dysplasia presenting with or without lichenoid features may develop into cancer. There is also disagreement over the classification and categorization of LD. Different terms have been used to classify these lesions, including lichenoid dysplasia, OLP with dysplasia, and dysplasia with lichenoid features. Moreover, in LD, it is not clear if dysplasia or lichenoid infiltration appears first, and if inflammation is a response to dysplasia or if dysplasia is a response to the persistent inflammation. The main limitation in the literature is the inconsistency and subjective nature of histological diagnoses, which can lead to interobserver and intraobserver variation, ultimately resulting in the inaccurate diagnosis of OLP and LD., Conclusion: Although further research is required to understand OLP and LD, both lesions should be considered potentially malignant and should not be disregarded., Competing Interests: The authors have declared no conflicts of interest., (Copyright © 2024 CDHA | ACHD.)

Oral lichen planus (OLP) is a T cell-mediated immune mucosal disease of unknown pathogenesis. Whether mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), an intracellular signaling protein, is involved in the T-cell immune dysfunction of OLP remains elusive. MALT1 expression in local and peripheral T cells of OLP and controls was analyzed using immunohistochemistry, multiplex immunohistochemistry, and flow cytometry. The expression of MALT1 in activated Jurkat T cells incubated with either OLP plasma or interleukin (IL)-7/IL-15 was determined by flow cytometry. The effects of MALT1 and mechanistic target of rapamycin (mTOR) on T-cell immunity were investigated through western blot, CCK8 assay, and flow cytometry. The expression of MALT1 protein was elevated in local OLP T cells and mucosal-associated invariant T (MAIT) cells, while reduced in peripheral OLP T cells, MAIT cells, and follicular helper-like MAIT (MAITfh) cells. Stimulation with OLP plasma and IL-7/ IL-15 had no effect on MALT1 expression in activated Jurkat T cells. MALT1 protease-specific inhibitor (MI-2) induced mTOR phosphorylation, increased B-cell lymphoma 10 (BCL10) expression, inhibited T-cell proliferation, and promoted T-cell apoptosis. The combination of MI-2 and rapamycin increased MALT1 expression, further suppressed T-cell proliferation, and facilitated T-cell apoptosis. MALT1 expression is aberrant in both local lesions and peripheral blood of OLP. Inhibition of the mTOR pathway further enhances the suppression of T-cell proliferation and the promotion of apoptosis induced by the MALT1 inhibitor MI-2., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Evaluating the association of ABO blood group with different delayed hypersensitivity reactions, such as oral lichenoid reaction (OLR), can provide a new perspective for clinical practice. Therefore, this study designed to investigate ABO blood group antigens in OLR patients. In this case-control study, the ABO blood group of 112 OLR patients and 117 individuals without oral lesions were included. Gender, age, characteristics of the lesions, medications and restorative materials recorded. Chi-square test used to compare the frequency of ABO blood groups in OLR patients with controls. The O blood group was significantly higher in OLR patients and all its subtypes. Also, there were significant relation between O blood group, and severity of lesions. The frequency of dysplasia was non-statistically significant higher in OLR patients with O blood group than other blood group. Based on the results of the present study, O blood group was significantly more in patients with lichenoid reaction than control group, and AB blood group was the lowest. Also, O blood group showed a positive association with the more severe form of OLR lesions and frequency of dysplasia., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The molecular characteristics of oral lichen planus (OLP) are still unclear, and it is not possible to distinguish the clinical outcome of OLP patients in a short period of time for follow-up. Here, we investigate the molecular characteristics of lesions in patients with stable lichen planus (SOLP) and recalcitrant erosive oral lichen planus (REOLP)., Methods: Our clinical follow-up cohort was split into SOLP and REOLP groups based on the follow-up clinical data. The core modules associated with the clinical information were identified by weighted gene co-expression network analysis (WGCNA). The OLP cohort samples were divided into two groups by molecular typing, and a prediction model for OLP was created by training neural networks with the neuralnet package., Results: We screened 546 genes in five modules. After doing a molecular type of OLP, it was determined that B cells might have a significant impact on the clinical outcome of OLP. In addition, by means of machine learning, a prediction model was developed to predict the clinical regression of OLP with greater accuracy than the existing clinical diagnostic., Conclusions: Our study revealed humoral immune disorders may make an important contribution to the clinical outcome of OLP., (© 2023 Wiley Periodicals LLC.)

Discoid lupus erythematosus and oral lichen planus are chronic systemic immune system-mediated diseases with unclear etiology and pathogenesis. The oral mucosa is the common primary site of pathogenesis in both, whereby innate and adaptive immunity and inflammation play crucial roles. The clinical manifestations of discoid lupus erythematosus on the oral mucosa are very similar to those of oral lichen planus; therefore, its oral lesion is classified under oral lichenoid lesions. In practice, the differential diagnosis of discoid lupus erythematosus and oral lichen planus has always relied on the clinical manifestations, with histopathological examination as an auxiliary diagnostic tool. However, the close resemblance of the clinical manifestations and histopathology proves challenging for accurate differential diagnosis and further treatment. In most cases, dentists and pathologists fail to distinguish between the conditions during the early stages of the lesions. It should be noted that both are considered to be precancerous conditions, highlighting the significance of early diagnosis and treatment. In the context of unknown etiology and pathogenesis, we suggest a serological and genetic diagnostic method based on TNF-α and IL-10. These are the two most common cytokines produced by the innate and adaptive immune systems and they play a fundamental role in maintaining immune homeostasis and modulating inflammation. The prominent variability in their expression levels and gene polymorphism typing in different lesions compensates for the low specificity of current conventional diagnostic protocols. This new diagnostic scheme, starting from the immunity and inflammation of the oral mucosa, enables simultaneous comparison of discoid lupus erythematosus and oral lichen planus. With relevant supportive evidence, this information can enhance physicians' understanding of the two diseases, contribute to precision medicine, and aid in prevention of precancerous conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Zhang and Wang.)

Adrenal glands are the major source of glucocorticoids, but recent studies indicate tissue-specific production of cortisol, including that in the oral mucosa. Both endogenous and exogenous glucocorticoids regulate the production of several proteins, including the glucocorticoid-induced leucine zipper (GILZ) and Annexin A1, which play important roles in the regulation of immune and inflammatory responses. Common inflammation-associated oral conditions include lichen planus and candidiasis, but the status of GILZ and Annexin A1 in these human conditions remains to be established. Accordingly, archived paraffin-embedded biopsy samples were subjected to immunohistochemistry to establish tissue localization and profile of GILZ and Annexin A1 coupled with the use of hematoxylin-eosin stain for histopathological assessment; for comparison, fibroma specimens served as controls. Histopathological examination confirmed the presence of spores and pseudohyphae for oral candidiasis (OC) specimens and marked inflammatory cell infiltrates for both OC and oral lichen planus (OLP) specimens compared to control specimens. All specimens displayed consistent and prominent nuclear staining for GILZ throughout the full thickness of the epithelium and, to varying extent, for inflammatory infiltrates and stromal cells. On the other hand, a heterogeneous pattern of nuclear, cytoplasmic, and cell membrane staining was observed for Annexin A1 for all specimens in the suprabasal layers of epithelium and, to varying extent, for inflammatory and stromal cells. Semi-quantitative analyses indicated generally similar fractional areas of staining for both GILZ and Annexin A1 among the groups, but normalized staining for GILZ, but not Annexin A1, was reduced for OC and OLP compared to the control specimens. Thus, while the cellular expression pattern of GILZ and Annexin A1 does not differentiate among these conditions, differential cellular profiles for GILZ vs. Annexin A1 are suggestive of their distinct physiological functions in the oral mucosa.

Background: Oral lichen planus (OLP) is a chronic autoimmune oral mucosal disease that seriously affects the life quality of the patients. But till now, the exact etiology and pathogenesis of OLP remain unclear. Our study is aimed at finding the key molecules and pathways involved in the pathogenesis mechanisms of OLP, providing more effective therapeutic strategies for OLP., Methods: Data from GSE52130 were downloaded from GEO datasets for analysis. Then, we carried out enrichment analysis of the differentially expressed genes (DEGs) using Gene Ontology (GO) and KEGG pathway analyses. Next, the CIBERSORT algorithm was used to assess immune cell infiltration in OLP patients. Furthermore, we also constructed a protein-protein interaction network using STRING and Cytoscape and simultaneously sought potential transcription factors plug-in including MCODE CytoHubba and iRegulon. In addition, ROC analysis was employed to assess the diagnostic performance of these hub genes. Lastly, we identified 6 promising novel drugs to treat OLP through Connectivity Map., Results: We illustrated that 255 DEGs were mainly enriched in the focal adhesion pathway and metabolism pathways. Besides, Cibersort analysis showed that M1 macrophages, T follicular helper cells, and T regulatory cells are more infiltrated in OLP samples. In addition, ROC analysis demonstrated that these hub genes owned higher diagnostic value in OLP, in which SPRR1B had the highest diagnostic value. And we also predicted that SOX7 was the most relevant transcription factor of those hub genes. Lastly, through the CMap database, we identified 6 small molecules as possible treatment drugs of OLP., Conclusion: Our research identified that SPRR1B could be used as potential biomarkers for the early diagnosis of OLP. In addition, as a chronic autoimmune oral mucosal disease, OLP has different infiltration types of immune cells. Furthermore, 6 small molecules were proposed as promising novel treatment drugs for OLP patients. Therefore, our research may provide new impetus for the development of effective OLP biological treatment options., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lou Geng et al.)

Oral lichen planus (OLP) is a localized autoimmune disease of the oral mucosa, with an incidence of up to 2%. Although corticosteroids are the first-line treatment, they cause several adverse effects. Quercetin, a naturally occurring compound, has fewer side-effects and provides long-term benefits. Besides, it has powerful anti‑inflammatory activities. Here, we combined network pharmacology with experimental verification to predict and verify the key targets of quercetin against OLP. First, 66 quercetin-OLP common targets were analyzed from various databases. The protein-protein interaction (PPI) network was constructed. Topology analysis and MCODE cluster analysis of common targets were conducted to identify 12 key targets including TP53, IL-6 and IFN-γ and their connections. Gene functions and key signaling pathways, including reactive oxygen species metabolism, IL-17 pathway and AGE-RAGE pathway, were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, in vitro experiments showed that quercetin interfered with Th1/Th2 balance by acting on IL-6 and IFN-γ to modulate the immune system in treating OLP. Quercetin considerably affected the apoptosis and migration of T lymphocytes in OLP patients. Our study reveals the potential therapeutic targets and signaling pathways of quercetin associated with OLP, and establishes the groundwork for future clinical applications., (© 2022. The Author(s).)

Background: Oral lichen planus (OLP) is a chronic inflammatory disease for which the pathogenesis is complex and not fully understood; autoimmunity has been suggested as a causative factor. World health organization (WHO) has classified OLP as a potentially malignant lesion. Cyclooxygenase-2 (COX-2) is an inducible key enzyme that generates prostanoids which play a critical role in inflammation, immunopathology; also considered as a malignant potential marker., Aims: The present study was conducted to analyze and compare epithelial COX-2 expression in OLP clinical subtypes and normal oral mucosa to evaluate its role in the pathophysiology of the disease process., Methods: This retrospective immunohistochemistry (IHC) study was performed on tissue sections of 30 OLP and 10 normal oral mucosae for COX-2 expression., Statistical Analysis Used: Descriptive and comparative statistical methods were done using 'one-way Analysis of Variance (ANOVA), 't' and Chi-square tests., Results: All the OLP showed epithelial COX-2 expression; strong expression was noted in 80% of the OLP while normal oral mucosa sections showed no expression. Cox-2 expression was significantly higher in erosive lichen planus compared to reticular lichen planus., Conclusions: Strong expression of COX-2 in OLP suggested its important role in pathogenesis. Although COX-2 has been connected to malignant development and autoimmunity, as the malignant development in OLP is quite rare, this study suggests that increased levels of COX-2 seen here may support an autoimmune cause of the disease process., Competing Interests: None

Oral lichen planus (OLP) is a chronic disease of uncertain etiology, although it is generally considered as an immune-mediated disease that affects the mucous membranes and even the skin and nails. Over the years, this disease was attributed to a variety of causes, including different types of microorganisms. This review analyzes the present state of the art of the disease, from a microbiological point of view, while considering whether or not the possibility of a microbial origin for the disease can be supported. From the evidence presented here, OLP should be considered an immunological disease, as it was initially proposed, as opposed to an illness of microbiological origin. The different microorganisms so far described as putative disease-causing agents do not fulfill Koch's postulates; they are, actually, not the cause, but a result of the disease that provides the right circumstances for microbial colonization. This means that, at this stage, and unless new data becomes available, no microorganism can be envisaged as the causative agent of lichen planus., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Oral lichen planus (OLP) is an inflammatory immune disease featured by dense T-cell infiltrate and basal keratinocytes degeneration. Immunity related GTPase M (IRGM) is vital for the induction of autophagy. Our previous studies have demonstrated aberrant autophagy in OLP, however, the involvement of IRGM-autophagy axis in OLP has not yet been revealed. The expression of IRGM and autophagy activity were evaluated in oral mucosal tissues and peripheral T cells of OLP patients and healthy controls, respectively. We found significant upregulation of IRGM and LC3B in lesions of patients with OLP as compared with healthy donors. IRGM, LC3B and NOD2 levels were also elevated in the peripheral T cells of OLP. Then, knockdown of IRGM after electrotransfection with siRNA resulted in attenuated autophagy, growth inhibition, and apoptosis of T cells. In addition, preincubation with IFN-γ promoted the expression of IRGM mRNA and induced autophagy in T cells. Furthermore, IFN-γ decreased the proliferation and apoptosis of T cells, whereas facilitated the viability of keratinocytes in a co-culture system of activated T cells and keratinocytes. Taken together, activated IRGM-autophagy axis under IFN-γ regulation in T cells might participate in the immunoregulatory mechanism of OLP., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This systematic review summarizes characteristics and treatment outcomes of dental amalgam-associated oral lichenoid lesions (OLLs) and oral lichen planus (OLP). Embase and MEDLINE were searched for original studies on OLLs or OLP associated with dental amalgam. Data extraction was completed from 44 studies representing 1855 patients. Removal of amalgam restorations led to complete resolution in 54.2% (n = 423/781), partial resolution in 34.8% (n = 272/781), and no resolution in 11.0% (n = 86/781) of the patients with OLLs, whereas complete resolution occurred in 37.1% (n = 72/194), partial resolution in 26.3% (n = 51/194), and no resolution in 36.6% (n = 71/194) of the patients with OLP. For patients with OLLs, 91.6% of the patients with positive patch tests and 82.9% with negative patch tests had improvement with removal of amalgam, whereas for patients with OLP, 89.2% of the patients with positive patch tests and 78.9% with negative patch tests had improvement with removal of amalgam. Our results suggest improvement occurs, regardless of patch testing status., Competing Interests: J.Y. has been a speaker, consultant, and investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, Leo, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, Valeant, and Xenon. The other authors have no funding or conflicts of interest to declare., (Copyright © 2020 American Contact Dermatitis Society. All Rights Reserved.)

Lichen planus is the most common skin disease that affects the oral mucosa. Oral Lichen Planus is a T-cell-mediated autoimmune disorder. In the current study, for the first time, an oral cavity condition in skin patch tests with adding saliva is simulated. In addition, the patch results are compared with healthy subjects. Forty-one OLP patients and 63 healthy subjects were enrolled in the study. All participants were provided with patch tests, including allergens, in combination with saliva in chambers. Allergens from the European baseline (standard) series selected according to the most prevalent positive results in the previous study were applied. Positive results of Mercury and Cobalt tests were significantly higher in the case group. In this study, the differentiation of patients with lichen planus and lichenoid was identified according to the Van der Meij & Van der Waal criteria. The patch test was conducted for healthy individuals as well. The most important of all was the use of patients' saliva in the patch test, done for the first time in this field. In the case of OLP, a patch test can help identify positive reactions to dental materials; thus, the replacement of dental restorations may be needed.

Oral lichen planus (OLP) is a T cell-mediated common chronic inflammatory mucosal disease, with limited therapies available for long-term use. Previous study showed that ratio of genus Streptococcus decreased significantly in OLP patients when compared with controls. Buccal cotton swab samples of 43 OLP patients and 48 healthy individuals were collected for real-time quantitative polymerase chain reaction (RT-PCR) to investigate relative abundance alteration of Streptococcus salivarius in OLP lesions. Bacterial supernatants of S. salivarius ATCC® BAA-2593™ were collected by centrifugation and added to HSC-3 cells, and quantitative analysis of expression of IL-1β, IL-6, IL-8, and TNF-α in the HSC-3 cells was determined by RT-PCR. Then, a randomized, non-blinded, controlled study was conducted. Forty patients with symptomatic OLP were randomly allocated into two groups and received topical treatment of 0.1% triamcinolone acetonide dental paste (group A) and S. salivarius K12 lozenge (group B), respectively, for 4 weeks. Sign scores, visual analogue scale (VAS), and adverse reactions were recorded. Relative abundance of S. salivarius in the OLP group was lower than that of control group (P < 0.05). After treated with 0.1% supernatants of S. salivarius ATCC® BAA-2593™, the expression level of IL-6 in the HSC-3 cells significantly reduced (P < 0.001), while IL-1β, IL-8, and TNF- α showed a decreasing tendency (P > 0.05). There was significant reduction in sign scores and VAS scores in both groups after the 4-week treatment, with no significant difference between two groups. No adverse reaction was observed. S. salivarius might maintain local immune balance by inhibiting the NF-κB pathway. Topical application of Streptococcus salivarius K12 seemed to be effective in treatment of symptomatic OLP, especially with promising potential in long-term use. More detailed clinical studies with long follow-up period and standardized usage/dosage are expected to acquire definite conclusions.

Background: Oral lichen planus (OLP) is a T-cell-mediated inflammatory disease with a risk of malignant transformation. Although the etiology of OLP is still uncertain, growing evidence suggests that oral microbiota, antigen-specific, and non-specific mechanisms are involved in the pathogenesis of OLP. Antigen-specific mechanisms include antigen presentation, T-cell activation, nuclear factor-kappa B signaling pathway, and cytokine secretion, while non-specific mechanisms consist of matrix metalloproteinases (MMP)-9 upregulation, psychological pressure, oxidative damage, aberrant expression of microRNAs (miRNAs), and autophagy. Till now, there is no cure for OLP, and the main purpose of OLP therapy is symptomatic control., Finding: Seafood and its derivative omega-3 polyunsaturated fatty acids (n-3 PUFAs) can suppress antigen presentation, T-cell activation, and nuclear factor-kappa B signaling pathway, modulate the overexpressed inflammatory cytokines, inhibit the expression of MMP-9, as well as regulate the expression of miRNAs and autophagy. And they are possible agents for ameliorating psychological disorder and oxidative damage. Moreover, n-3 PUFAs supplementation has a beneficial effect on preventing tumorigenesis., Conclusion: n-3 PUFAs consumption may provide a non-toxic, inexpensive administration for OLP.

Aim: To determine whether there is an immunogenic connection and antigen difference between the HLA antigens in the erosive (EOLP) and reticular (ROLP) oral lichen planus., Materials and Method: 73 patients with ROLP and EOLP have been tested. Typing of the HLA antigens has been made for locus A and B. The typing of the HLA was conducted with the use of microlymphocyto toxic test by Terasaki. The reading of the findings has been conducted with an inverse microscope. When a reaction has 4 points it is considered to be positive., Results: The most frequently typified antigens in ROLP from locus A are HLA А2 (57.57%) and А3 (33.33)%, and for locus B 21.21%. In EOLP it is А9 (8888%). In locus B a connection has been found with HLA B8 (77.77%). The statistical analysis with the ×2 test has shown that the carriers of HLA A9 display a relative risk (RR) of 3.65 and ×2=20.72. Consequently, there is high static importance for locus A p<0,001. For locus B, In EOLP for HLA B8, RR=6. 7 ×2=37.64 and p<0,001. ROLP has shown association with HLA A3, where RR=2. 31 and ×2 =9.14 and p<0.05., Conclusions: In ROLP A3 antigen and in EOLP A9 and A8 may be considered as carriers with proneness to OLP.

Lichen planus (LP) is a chronic inflammatory mucocutaneous disease involving the oral mucosa and skin. Both oral LP (OLP) and cutaneous LP (CLP) are histopathologically characterized by dense subepithelial lymphocyte infiltrates; however, the mechanisms underlying lymphocyte recruitment to sites of LP lesions are not fully understood. Here, we assessed the induction of peripheral lymph node addressin (PNAd)-expressing high endothelial venule (HEV)-like vessels in 19 OLP and 17 CLP cases. To do so, we performed immunohistochemical staining for PNAd and CD34, followed by quantitative analysis. We also conducted triple immunohistochemistry for PNAd and either CD3 and CD20 or CD4 and CD8 to identify the lymphocyte subset preferentially recruited via HEV-like vessels. PNAd-expressing HEV-like vessels were induced in and around lymphocyte aggregates in all cases of OLP and in 10 of 17 CLP cases, and these vessels were more frequently observed in OLP relative to CLP. Although the number of T-cells attached per HEV-like vessel exceeded the number of B-cells in both OLP and CLP, the number of CD4 + T-cells attached was greater than the number of CD8 + T-cells only in OLP. These findings combined suggest that PNAd-expressing HEV-like vessels play a more important role in the pathogenesis of OLP compared with CLP.

Background: 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., Methods: 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., Results: 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., Conclusion: Our findings indicate that the CCL17-CCR4 axis might be responsible for the inflammatory infiltration of T cells in OLP., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Backgrounds: To explore the expression and functions of the tripartite motif-containing protein 21 (TRIM21) in oral lichen planus(OLP) lesions., Methods: 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., Results: 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 72 hours., Conclusion: Overexpressed TRIM21 in OLP may be a primary proinflammatory molecule rather than a secondary and inducible regulatory factor in immunopathogenesis of OLP., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oral Potentially Malignant Disorders (OPMDs) including Oral Lichen Planus (OLP) are associated with risk of transformation to oral squamous cell carcinoma (OSCC). Available data show that innate immune cells involving polymorphonuclear neutrophils (PMNs) with their ability to neutrophil extracellular traps (NETs) formation are likely to be directly involved in development of cancer. Examination of NETs generation by TGF-β - induced neutrophils of OLP patients showed increased amounts of traps with MPO, H3Cit and cfDNA, known to be released with NETs. The presence of excessive amounts of NETs components may lead to numerous adverse consequences associated with potential transformation to OSCC. Bacterial-related infection may enhance the NETs formation and lead to consequences resulting from the excessive number of individual elements of these networks. It is likely that regulating NETs release by the flavonoids presented herein may be beneficial not only for inhibiting OLP development, but also in reducing risk of transformation to OSCC., (Copyright © 2019. Published by Elsevier GmbH.)

Objective: To investigate the effects of exogenous interleukin (IL)-35 on the balance of helper T cell 17 (Th17) and regulatory T cell (Treg) in peripheral blood of patients with oral lichen planus (OLP). Methods: Totally 12 peripheral blood samples of OLP patients (OLP group, one male and 11 female, 26-68 years old; four cases of reticular OLP and eight cases of erosive OLP) were collected from patients of Department of Oral Mucosal Specialist of the Affiliated Hospital of Guizhou Medical University from October to December 2016. During the same period, thirteen normal peripheral blood samples were collected from the Physical Examination Center of the Affiliated Hospital of Guizhou Medical University (normal control group, one male and 12 female, 20-68 years old). The peripheral blood mononuclear cells (PBMC) were extracted in sterile condition and CD4+ T cells were sorted by flow cytometry (FCM). Quantitative real-time PCR (qPCR) technique was used to detect the mRNA expression levels of retinoid-related orphan nuclear γt (RORγt) and forkhead box3 (Foxp3). The CD4+ T cells were divided into experimental group and control group. The CD4+ T cells of experimental group were cultured in vitro by adding rhIL-35, and the CD4+ T cells of control group were cultured with the same volume of phosphate buffered saline (PBS). After the completion of the culture, the cells were collected. The expression levels of the same factors were detected by qPCR. Results: The expression [ M ( Q (25), Q (75))] of Foxp3 [0.15 (0.09, 0.30)] and RORγt mRNA [1.04 (0.45, 2.15)] in the CD4+ T cells of OLP were significantly higher than those in normal control group [0.04 (0.02, 0.06), 0.10 (0.05, 0.11)] ( Z= -4.134, P <0.01; Z=- 3.699, P <0.01). The ratio of ROR γt/Foxp3 mRNA in OLP group [6.22(3.67, 15.34)] was higher than that in normal control group [2.50 (1.24, 5.23)] ( Z= -2.665, P= 0.007). In the CD4+ T cells of OLP patients, the expression of Foxp3 mRNA in the experiment group [0.40 (0.21, 1.22)] was higher than that in the control group [0.15 (0.11, 0.26)]( Z= -2.510, P= 0.012), and the expression of ROR γt mRNA between two groups showed no significant difference ( P >0.05). The ROR γt/Foxp3 mRNA ratio [3.44 (1.55, 8.16)] of the experiment group was lower than that in the control group [6.22 (4.43, 12.21)] ( Z= -2.746, P= 0.006). Conclusions: There was a Th17/Treg imbalance with predominated by Th17 cells in the peripheral blood of patients with OLP. Exogenous rhIL-35 had an immunomodulatory effect on the balance of Th17/Treg.

Oral lichen planus (OLP) is a chronic inflammatory oral mucosal disorder mediated by T cells, with a multifactorial etiology. Hashimoto's thyroiditis (HT) is a common autoimmune disease characterized by hypothyroidism. Although many clinical studies conducted over the past several decades have reported the cooccurrence of OLP and HT, the underlying mechanism remains unclear. This review summarizes potential mechanisms that might be involved in the cooccurrence of OLP and HT. We find that OLP and HT share a common or overlapping pathogenesis in terms of immune, heredity, environmental, and hormonal factors, which might cause cooccurrence. Furthermore, considering the latency of HT, a routine screen for thyroid diseases, particularly HT, is suggested for confirmed OLP patients., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Peiyao Wu et al.)

Oral lichen planus (OLP) is a kind of oral epithelial disorder featured with keratinocyte apoptosis and inflammatory reaction. The pathogenesis of OLP remains an enigma. Herein, we showed that the levels of miR-26a/b were robustly down-regulated in oral mucosal biopsies, serum and saliva in OLP patients compared with healthy control. Moreover, we found the binding sites of vitamin D receptor (VDR) in the promoter regions of miR-26a/b genes and proved that the induction of miR-26a/b was VDR dependent. The reduction of miR-26a/b expression was also detected in the oral epithelium of vitamin D deficient or VDR knockout mice. miR-26a/b inhibitors enhanced apoptosis and Type 1T helper (Th1) cells-related cytokines production in oral keratinocytes, whereas miR-26a/b mimics were protective. Mechanistically, we analyzed miRNA target genes and confirmed that miR-26a/b blocked apoptosis by directly targeting Protein Kinase C δ (PKCδ) which promotes cellular apoptotic processes. Meanwhile, miR-26a/b suppressed Th1-related cytokines secretion through targeting cluster of the differentiation 38 (CD38). In accordant with miR-26a/b decreases, PKCδ and CD38 levels were highly elevated in OLP patients' samples. Taken together, our present investigations suggest that vitamin D/VDR-induced miR-26a/b take protective functions in OLP via both inhibiting apoptosis and impeding inflammatory response in oral keratinocytes.

The present study was aimed to investigate the effects of the long non-coding RNA DQ786243 in the regulation of Treg cells in oral lichen planus (OLP), as well as to evaluate its potential molecular mechanisms. Here we found that the expression of DQ786243 and Foxp3 were both overexpressed in the CD4 + cells from the peripheral blood of OLP patients, and their expression was positively correlated. Meanwhile, compared with the normal CD4 + cells, the frequency of Foxp3 + Treg cells in the OLP CD4 + cells was significantly higher. DQ786243 overexpression in normal CD4 + cells resulted in the upregulation of Foxp3 and the higher frequency of Foxp3 + Treg cells. Furthermore, we found that the induction of Foxp3 + Treg cells by DQ786243 significantly increased its suppressive function, and suppressed the function of other CD4 + T cells such as Th1 and Th17 by decreasing the levels of IFN-γ and IL-17. Moreover, we found that DQ786243 overexpression markedly elevated the expression of miR-146a via regulating Foxp3, and thus inhibiting the NF-κB signaling. In conclusion, these findings indicate that DQ786243 may regulate the induction and function of CD4 + Treg cells through Foxp3-miR-146a-NF-κB axis, implicating a novel insight into understanding the progression of OLP., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Oral lichen planus (OLP) is an autoimmune mucocutaneous disease characterized by T cell infiltrating in microenvironment. T cell-mediated immune dysfunctions are of importance in the pathogenesis of OLP. Insulin-like growth factor 1 (IGF1) has profound effects on maintenance of immune functions; however, its specific mechanism in OLP remains unknown. This study aims to explore how IGF1 regulates T-cell immune functions in OLP., Methods: IGF1 in OLP lesions was stained by immunohistochemistry and immunofluorescence. Additionally, proliferation, apoptosis and autophagy of T cells were examined after stimulation with IGF1 for 24 h, respectively. Z-VAD-FMK, a pan-caspase inhibitor, was used to explore IGF1-mediated crosstalk between apoptosis and autophagy. The modulation of IGF1 on ERK and PI3K/mTOR pathway was also analyzed., Results: IGF1 was increased in OLP lesions and was remarkably co-located with T cells. IGF1 significantly enhanced T-cell proliferation, suppressed apoptosis and induced autophagic flux. Moreover, autophagy was induced by apoptosis inhibitor, Z-VAD-FMK, thereby reducing death of T cells. IGF1 could facilitate Z-VAD-FMK-induced autophagy and then decrease proportion of apoptotic T cells. IGF1-treated T cells also showed elevated phosphorylation of ERK, PI3K and mTOR., Conclusions: IGF1 inhibited apoptosis and promoted autophagy in T cells, potentially contributing to the pathogenesis of OLP., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Immunological methods, which have been widely used in autoimmune blistering diseases (AIBDs) of the oral mucosa, can also be adopted as auxiliary diagnostic tools in oral lichen planus (OLP) and discoid lupus erythematosus (DLE). AIBDs, characterized by autoantibodies against structural proteins of keratinocytes or the basement membrane zone, clinically present as blisters and erosions of the oral mucosa. When atypical lesions occur, OLP or DLE may be confused with AIBDs. The improvement of diagnostic accuracy is necessary due to the significant differences in treatment and prognosis among these diseases. A variety of immunological methods are used for qualitative and quantitative detection of target antigens and autoantibodies. These methods can evaluate efficacy of treatment, monitor diseases and guide treatment decisions. In this review, we discuss the application of immunofluorescence, biochemical tests, and protein microarrays for AIBDs, OLP and DLE, as well as the differential diagnostic methods using immunological tests., (© 2019 British Association of Dermatologists.)

The etiology of oral lichen planus (OLP) is still not clear. The purpose of this study was to explore the role of CXC chemokine receptor 3(CXCR3) and its ligand CXC motif chemokine 10(CXCL10) in the pathogenesis of OLP. We examined the expression of CXCR3 and CXCL10 in OLP patients and healthy controls by quantitative real-time PCR, Western blotting, ELISAs, and immunohistochemistry, respectively. Moreover, we detected the effects of CXCL10/CXCR3 axis on T lymphocyte migration, proliferation and apoptosis by Transwell assays, CCK8 assays, and flow cytometry. We found that the expression of CXCR3 and CXCL10 was significantly increased in OLP patients. In addition, T lymphocyte migration rate of CXCL10 stimulation group was significantly higher than that of control and CXCR3 antagonist groups. After antagonizing CXCR3, the migration ability of T lymphocytes was significantly decreased, and regardless of whether CXCL10 was added in the upper chamber culture medium, the number of migrating cells was similar. The addition of CXCL10 stimulant could stimulate the proliferation of T lymphocytes, but there was no significant difference compared with control group. After antagonizing CXCR3, the proliferation rate of T lymphocytes was significantly reduced. However, there were no significant differences in the apoptosis rates of T lymphocytes between CXCL10 stimulation group, antagonist CXCR3 group, and control group. Due to the change of expression in CXCR3 and CXCL10, and its interaction in mediating the directional migration of peripheral blood T lymphocytes, affecting the proliferation of T lymphocytes, it suggests that CXCL10/CXCR3 axis may be related to the immune mechanism of OLP.

Objectives: Oral lichen planus (OLP) is a T cell-mediated immune-related chronic disease, featured by accumulation of T cells and apoptosis of keratinocytes. Insulin-like growth factors 1 (IGF1) signaling, in combination with its downstream PI3K/AKT/MTOR cascade, plays pivotal roles in the regulation of inflammation and immune response. Meanwhile, TRB3 acts as a connective protein in the pathway. This study investigated the possible function of IGF1-PI3K/AKT/MTOR pathway in the local immunity of OLP., Methods: The expression of phosphorylated IGF1R (p-IGF1R) and TRB3 in lesional tissues of OLP was measured. The effects of T cells pretreated with PI3K inhibitor LY294002, MTOR antagonist rapamycin and exogenous IGF1 on the cell proliferation and apoptosis, as well as supernatant inflammatory cytokine levels were detected in co-culture system of activated T cells and oral keratinocytes, respectively., Results: The expression of p-IGF1R and TRB3 in OLP lesions was significantly increased when compared with controls (P < 0.001). Rapamycin-treated T cells displayed enhanced apoptosis rate and promoted proliferation of their keratinocytes in the co-culture system. Notably, abnormal expression of IFN-γ and IL-4 were detected in supernatant of T cell alone and co-culture system in response to pharmacological modulators of IGF1-PI3K/MTOR pathway., Conclusions: The aberrant IGF1-PI3K/AKT/MTOR signaling may participate in the immunoregulatory mechanism of OLP, via regulation on the crosstalk between T cells and keratinocytes, as well as imbalanced cytokine networks., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: Oral lichen planus (OLP) is a common T-cell-mediated oral mucosal disease, whose pathogenesis mainly includes antigen-specific and non-specific mechanisms. As a refractory chronic inflammatory disease, there is still no curable management for OLP till now., Findings: Artemisinins are a family of compounds that are widely used as frontline treatment for malaria worldwide. In addition to its well-established antimalarial properties, emerging evidence hints that artemisinin family drugs also possess preferential immunoregulatory and anti-inflammation properties, such as modifying T lymphocytes' activation and cytokines release, modulating Th1/Th2 balance, activating regulatory T cells (Tregs), modulating inflammatory signaling pathways, as well as acting on non-specific mechanisms of OLP. However, there is still no report focused on the influence of artemisinins on OLP., Conclusion: This review outlined the data-based immunomodulatory effects of artemisinins on different immune cells in conjunction with their therapeutic prospective with regard to the pathogenesis of OLP, suggesting that artemisinin and its derivatives might be possible candidates for treatment of OLP.

Objective: Cytokines have regulatory and leading roles in the immunopathogenesis of oral lichen planus (OLP). Here, we present the findings of a meta-analysis that evaluated serum and salivary interferon-γ (IFN-γ) levels in patients with OLP compared with those in controls and the correlation of this cytokine with the progression of OLP., Study Design: Four databases-PubMed, Web of Science, Scopus, and Cochrane Library-were searched, from their start dates to November 2017, for reports in all languages on the effect of OLP on salivary and serum IFN-γ., Results: Eleven studies were included and analyzed in this meta-analysis. The pooled mean difference (MD) values were estimated to be 3.60 pg/mL (P = .23) and -0.02 pg/mL (P = 1.00) for serum and salivary levels of IFN-γ, respectively, in the patients with OLP compared with controls. The pooled MD values were -2.52 pg/mL (P = .03) and -2.01 pg/mL (P = .20) for serum and salivary IFN-γ levels in the erosive type, respectively, compared with the nonerosive type., Conclusions: According to the results of meta-analysis, there was no statistically significant differences in IFN-γ levels between the OLP group and the control group both in serum and salivary levels and also between erosive and nonerosive types of OLP at the salivary level; so this cytokine is not considered to have an important role in the pathogenesis or severity of OLP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Exosomes are newly recognized natural nanocarrier and intercellular messenger that emerge as important mediators of signal transmission. Exosomes have been reported to modulate the inflammatory response of a number of diseases. This study investigated the effects of circulating exosomes from oral lichen planus (OLP) on T cells., Methods: Plasma-derived exosomes were purified from both OLP patients and control groups. T cells were observed under a confocal laser scanning microscope after co-cultivation with PKH67 labeled exosomes for 12, 24, and 48 hours. The effects of exosomes exposure on T cells were analyzed with several functional assays, investigating proliferation, apoptosis, and migration. Production of interleukin (IL)-2, -4, -10, and interferon (IFN)-γ was measured via enzyme-linked immunosorbent assay., Results: PKH67-labeled exosomes were taken up by T cells in a time- and dose-dependent manner. Several biological functions of T cells were promoted. In particular, the circulating erosive OLP exosomes significantly enhanced T-cell proliferation and attenuated the apoptosis. The migration capacity of T cells increased remarkably in response to erosive OLP exosome treatment. In addition, the ratio of IFN-γ/IL-4 was significantly elevated in OLP patients., Conclusions: Our findings indicate that the circulating OLP exosomes are involved in the biological functions of T cells, potentially promoting the OLP progression by regulating the T-cell-mediated inflammatory response., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Backgrounds: To investigate alterations in histone modification and histone deacetylases (HDACs) in patients with oral lichen planus (OLP), and to evaluate correlations with inflammatory cytokine production., Methods: Global histone H3/H4 acetylation and HDAC activity in CD4+ T cells from 23 patients with OLP and 10 healthy control subjects were examined using spectrophotometry. The mRNA levels of eight members of four classes of HDAC genes were measured by real-time quantitative polymerase chain reaction. Forty cytokines involved in inflammation were examined with a cytokine array. The correlation between histone modification and cytokine production was analyzed., Results: Global histone H3 hypo-acetylation was observed in OLP patients. Patients with OLP had significantly higher HDACs activity,and higher HDAC6 and HDAC7 mRNA level compared with the controls. Of the 40 cytokines in the cytokine array, eight were significantly increased in OLP patients: interleukin (IL)-4, IL-8, IL-1ra, tumor necrosis factor receptor II (TNFR II), macrophage inflammatory protein 1b (MIP-1b), fibrosis-associated tissue inhibitors of metalloproteinase 1 (TIMP)-1, monocyte chemotactic protein 1 (MCP-1), and eotaxin-2. In the OLP group, the acetylation level of histone H3 was negatively correlated with IL-4 and MCP-1 production, and the expression of HDAC6 mRNA was positively correlated with MCP-1 production. In the non-erosive subgroup, acetylation of histone H3 was negatively correlated with IL-4, IL-16, and TIMP-2 production. In the erosive OLP subgroup, the expression of HDAC7 mRNA was positively correlated with MIP-1a production., Conclusion: Aberrant histone modification of CD4+ T cells in peripheral blood could occur in OLP patients, and possibly affects inflammatory cytokine production., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Oral lichen planus (OLP) is a common T lymphocyte-mediated autoimmune disease of unknown etiology. The mammalian target of rapamycin (mTOR) can regulate proliferation, apoptosis, and autophagy of T lymphocytes, therefore impacting the T lymphocyte-mediated immunity. The present study was aimed to investigate the possible association between Akt/mTOR/4E-BP1 (eIF4E-binding protein 1) signaling, phospholipase D (PLD) and hypoxia-inducible factor 1 alpha (Hif-1α) in peripheral T lymphocytes of OLP and the correlation of their expression with the disease severity., Design: RAE (reticular, atrophic and erosive lesion) scores were used to assess the disease severity of OLP. Akt, mTOR, 4E-BP1, PLD1, PLD2 and Hif-1α expression in peripheral T lymphocytes were measured by using quantitative real-time polymerase chain reaction. Associations of Akt/mTOR/4E-BP1 expression with PLD1, PLD2 and Hif-1α expression were also assessed, respectively. Moreover, correlations of their expression with RAE scores were analyzed., Results: Expressions of mTOR, 4E-BP1, PLD2 and Hif-1α mRNA were significantly reduced in peripheral T lymphocytes of OLP patients, especially in erosive form. mTOR expression was positively correlated with PLD2 and Hif-1α expression in OLP. Moreover, mTOR, PLD2 and Hif-1α expression were negatively correlated with RAE scores, respectively., Conclusions: Deregulated PLD2/mTOR/Hif-1α may contribute to the development of OLP and reflect the severity of the disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Immunoglobulins (IgA, IgG, and IgM) are significant anti-inflammatory factors. The meta-analysis aimed to assess the serum and salivary levels of Igs as more important immunoglobulins in patients affected by oral lichen planus (OLP) compared to the healthy controls. Four databases, including PubMed/Medline, Scopus, Web of Science, and Cochrane Library as well as Iranian databases were checked up to January 2018 without language restriction. The quality of each involved study was done using the Newcastle⁻Ottawa Quality Assessment Scale (NOS) questionnaire. A random-effects model analysis was done by RevMan 5.3 software applying the mean difference (MD) plus 95% confidence intervals (CIs). The CMA 2.0 software was applied to calculate the publication bias among the studies. Out of 70 studies found in the databases, 8 studies were involved and analyzed in the meta-analysis. The meta-analysis included 282 OLP patients and 221 healthy controls. The pooled MDs of serum levels of IgA, IgG, and IgM were -0.13 g/L [95% CI: -0.24, -0.02; P = 0.02], 1.01 g/L [95% CI: -0.91, 2.93; P = 0.30], and -0.06 g/L [95% CI: -0.25, 0.14; P = 0.56], respectively; whereas, the salivary IgA and IgG levels were 71.54 mg/L [95% CI: 12.01, 131.07; P = 0.02] and 0.59 mg/L [95% CI: -0.20, 1.38; P = 0.14], respectively. Considering the few studies performed on saliva, the results suggested that the salivary levels, especially IgA level had higher values than the serum levels. Therefore, the salivary immunoglobulins can play a significant function in the OLP pathogenesis.

Aim: The current study will attempt to throw light on the role of desmoglein 1 and desmoglein 3 in the pathogenesis of erosive lichen planus and their response to topical application of tacrolimus., Materials and Methods: Twenty patients with erosive oral lichen planus received tacrolimus ointment three times daily for eight weeks. Assessments using the clinical score and a visual analog scale were recorded at each visit. Serum concentrations of circulating autoantibodies to desmoglein 1 and desmoglein 3 will be determined by enzyme-linked immunosorbent assay (ELISA) at baseline, four weeks and eight weeks after treatment. Statistical software SPSS v.17.0 was used for statistical analysis., Results: All patients showed significant improvement in all outcomes within the follow-up periods when compared with the baseline (p < 0.05). The mean value of the visual analog scale were 8.30 ± 1.49, 4.15 ± 1.14, 2.10 ± 0.91, 0.90 ± 0.79, and 0.0 ± 0.0 starting from baseline to the end of follow up period. The mean value of the clinical score were 4.7 ± 0.48, 2.9 ± 1.29, 1.8 ± 1.32, 1.31 ± 0.69, and 0.69 ± 0.09 starting from baseline to the end of follow-up period. There was a significant decrease in the levels of anti-Dsg1 and anti-Dsg3, during the follow-up period (p < 0.05)., Conclusion: The concluded data suggest that antibodies against desmoglein 1 and desmoglein 3 seem to play a key role in the pathogenesis of oral lichen planus. Also, there is a significant decrease in the level of anti-Dsgl and anti-Dsg3 autoantibodies with topical tacrolimus 0.1% ointment., Clinical Significance: Monitoring the serum level of antibodies against keratinocyte cadherins Dsg 1 and Dsg 3 can be used to evaluate the effect of topical application of tacrolimus on Erosive Oral lichen planus.

Objective: To determine the levels of antithyroid antibodies and thyroid hormones in the sera of patients with oral lichen planus (OLP), and to quantify the expression of thyroid proteins in OLP lesions., Subjects and Methods: Venous blood samples were drawn from 110 patients with OLP who had no history of thyroid disease or levothyroxine supplementation (OLP+/LT 4 -). A random population sample of 657 healthy subjects was used as the control group. Two additional groups were used as comparators. Immunohistochemical and qPCR analyses were performed on tissue specimens collected from the patients with OLP and thyroid disease and healthy subjects., Results: No association was found between the presence of antithyroid antibodies and OLP. More patients in the OLP+/LT 4 - group showed high levels of thyroid-stimulating hormone and low levels of free thyroxine than were seen in the control group. Thyroid-stimulating hormone receptor was more highly expressed in the OLP lesions of patients with thyroid disease than in the healthy oral mucosa., Conclusions: A significant number of patients with OLP who are not previously diagnosed with thyroid disease have thyroid parameters that are compatible with hypothyroidism. The expression of thyroid-stimulating hormone receptor in OLP lesions suggests that mechanisms related to autoimmune thyroid disease are involved in the aetiology of OLP., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Mesenchymal stem cells (MSCs) have been used clinically and experimentally to relieve severe immune-related diseases due to their immunomodulatory properties, but these are impaired by inflammation. Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory mucosal disease. In the present study, we found MSCs from OLP with higher expression of interleukin (IL)-6, tumour necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β) and IL-10 compared with control. Total glucosides of paeony (TGP) significantly improves the immunomodulatory function of MSCs by inhibiting IL-6 and TNF-α expression and increasing TGF-β and IL-10 expression. Moreover, TGP can downregulate p-STAT3 expression through upregulation of miR-124. The changes of IL-6, TGF-β and p-STAT3 were further confirmed by overexpression and knockdown of miR-124 in MSCs. Taken together, the immune-regulating function of MSCs can be improved by TGP via the miR-124/STAT3 pathway., (Copyright © 2018. Published by Elsevier Masson SAS.)

Objective: This study aimed to investigate the ratio of T helper cell 17 (Th17) and regulatory T cells (Treg) in peripheral blood of oral lichen planus (OLP) and explore the pathogenesis of its possible role and significance., Methods: The peripheral blood samples were obtained from 33 patients with OLP (15 cases of reticular OLP and 18 cases of erosive OLP) and 17 healthy controls. The percentages of Th17 and Treg cells were detected by flow cytometry (FCM). Real-time fluorescence quantitative polymerase chain reaction (qPCR) technique was used to detect the expression levels of retinoid-related orphan nuclear receptor γt (RORγt) and forkhead box 3 (Foxp3)., Results: The proportions of Th17, Treg cells, and their transcription factors (RORγt and Foxp3) in OLP were higher than those in the control groups (P<0.05). By contrast, in Treg cells and Foxp3, no significance was observed between erosive OLP and reticular OLP. Th17/Treg ratio increased in OLP. This ratio was significantly increased in erosive OLP compared with those in the control groups and reticular OLP (P<0.01). Nevertheless, no significance was noted between reticular OLP and control groups. Statistical analysis demonstrated positive correlations among Th17 cells, Th17/Treg, and clinical characteristics (r=0.66, P=0.00; r=0.66, P=0.00; r=0.52, P=0.00; r=0.50, P=0.00). Positive correlations also existed between Th17 and Treg cells (r=0.39, P=0.03)., Conclusions: Th17 cells, Treg cells, and their ratios all increased in the peripheral blood of OLP. Moreover, the imbalance inTh17/Treg may play a role in the pathogenesis of erosive OLP.

Oral lichen planus (OLP) is a complex immunological disorder, mediated in part by the release of cytokines by activated T-cells. Recently, the role of novel cytokines including IL33 and IL35 has been described in various chronic inflammatory diseases. IL33, a member of the IL-1 superfamily of cytokines, functions as an 'alarmin' released after cell necrosis to alert the immune system to tissue damage or stress. IL35, a member of IL12 cytokine family, is produced by regulatory T-cells and suppresses the immune response. The expression of IL33 and IL35 is yet to be investigated in OLP. The aim of this study was to determine the presence and topographical distribution of IL33 and IL35 in OLP using immunohistochemistry and quantitative real-time reverse transcriptase polymerase chain reaction (qPCR). For IHC, formalin-fixed paraffin-embedded archival specimens of OLP (n = 10) and a non-specific inflammatory (NSI) control group (n = 9) were used. A double-labelling immunofluorescence technique was used to determine the expression of IL33 and IL35 on CD3 + T-cells. In addition, 12 fresh tissue samples (OLP n = 6 and NSI controls n = 6) were used to determine the gene expression of IL33 and EBI3 (one chain of the dimeric IL35). Quantitative and qualitative analysis was performed with statistical significance set at p < 0.05. IHC showed positive immunostaining with IL33 and IL35 in both OLP and NSI. Comparison of the numbers of IL33 + and IL35 + cells in OLP and NSI did not show any significant difference. In OLP, there were significantly more IL33 + cells in the deeper connective tissue region than at the epithelial-connective tissue interface. Interestingly, all IL35 + cells observed in both OLP and NSI tissues showed ovoid/plasmacytoid morphology. Double-labelling immunofluorescence showed that IL33 and IL35 expression was not localized within CD3 + T-cells. The gene expression experiments showed significantly higher expression of EBI3 (fold regulation 14.02) in OLP when compared to the inflammatory controls. IL33 gene expression was not different between the groups. However, within the OLP tissues, there was a significantly higher expression of IL33 than EBI3. Our data demonstrate the expression of IL33 and IL35 in OLP lesions. Further studies are needed to understand the functional role of these cytokines in OLP pathogenesis.