Lichenoid Lesions of the Oral Mucosa.

Lichenoid lesions involving the oral cavity present with an array of complex clinical manifestations and etiologies. The etiology ranges from local factors, systemic entities, and even autoimmune conditions. Several different types of lichenoid lesions may affect the oral cavity, and it is imperative that these are correctly diagnosed to ensure effective patient care. Lichenoid lesions such as chronic ulcerative stomatitis prove to be challenging as these are recalcitrant, present with overlapping features, require unique treatment and patients suffer a long time if not promptly diagnosed.

2-Deoxy-D-glucose impedes T cell-induced apoptosis of keratinocytes in oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated immunoinflammatory disease. Glycolysis plays an essential role in T-cell immune responses. Blocking glycolytic pathway in activated T cells represents a therapeutic strategy for restraint of immunologic process in autoimmune disorders. 2-Deoxy-D-glucose (2-DG) has been widely used to probe into glycolysis in immune cells. This study was aimed to explore the role of glycolysis inhibition by 2-DG on regulating immune responses of OLP-derived T cells. We observed that lactic dehydrogenase A (LDHA) expression was elevated in OLP lesions and local T cells. 2-DG inhibited the expression of LDHA, p-mTOR, Hif1α and PLD2 in T cells; meanwhile, it decreased proliferation and increased apoptosis of T cells. T cells treated by 2-DG showed lower LDHA expression and elevated apoptosis, resulting in a reduced apoptotic population of keratinocytes that were co-cultured with them, which was related to the decreased levels of IFN-γ in co-culture system. Rapamycin enhanced the effects of 2-DG on immune responses between T cells and keratinocytes. Thus, these findings indicated that OLP-derived T cells might be highly dependent upon high glycolysis for proliferation, and 2-DG treatment combined with rapamycin might be an option to alleviate T-cell responses, contributing to reducing apoptosis of keratinocytes.

Patch test of dental materials in Oral Lichen Planus with considering the role of saliva.

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.

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.

Recognition of oral potentially malignant disorders and transformation to oral cancer.

Oral potentially malignant disorders refer to oral mucosal disorders with increased risk for malignant transformation, primarily to oral squamous cell carcinoma (SCC). Leukoplakia and erythroplakia are the most common of these disorders, but others have been identified. Transformation rates to oral cancer vary based on multiple factors. Healthcare providers should be aware of risk factors and clinical manifestations of these disorders and should intervene early to monitor and/or treat them to reduce the potential for malignant transformation.

T cell-derived exosomes induced macrophage inflammatory protein-1α/ß drive the trafficking of CD8+ T cells in oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory disease with uncertain aetiology. Exosomes are nanosized particles with biological capacities. Here, we aimed to study the effects of T cell-derived exosomes (T-exos) on the pathogenesis of OLP and its mechanism. T-exos were incubated with Jurkat cells for 48 hours, and 26 cytokines in the supernatant were measured by luminex assay. The expression of macrophage inflammatory protein (MIP)-1α/ß was detected using immunohistochemistry and ELISA; that of CCR1/3/5 on peripheral T cells was determined by flow cytometry. Transwell assay was performed to investigate the chemotactic effect of MIP-1α/ß, and cells in the lower chambers were examinated by flow cytometry. As a result, OLP T-exos elevated the production of MIP-1α/ß, which were highly expressed in OLP tissues and plasma. CCR1/5 were markedly expressed on OLP peripheral T cells, and the majority of CCR1/5+ T cells were CD8+ T cells. Besides, MIP-1α/ß promoted the migration of OLP mononuclear cells, while inhibiting CCR1/5 significantly decreased the trafficking of mononuclear cells, especially that of CD8+ T cells. Conclusively, OLP T-exos-induced MIP-1α/ß may drive the trafficking of CD8+ T cells after binding with CCR1/5 in OLP, contributing to the development of OLP.

Association of serum level of 25-hydroxy vitamin D with oral lichen planus: a case-control study / Asociación del nivel sérico de 25-hidroxi vitamina D con el liquen plano oral: un estudio de casos y controles

Introduction: Vitamin D deficiency is a global health problem that can be a risk factor for a broad range of diseases such as some autoimmune diseases. Due to the autoimmune base of lichen planus, it seems that a reduction of the serum level of vitamin D is related to lichen planus. In this study, we investigate the relation between serum level of vitamin D and oral lichen planus patients (OLP). Material and Methods: In this case-control study, 35 patients with OLP (including 15 men and 20 women) and 70 healthy volunteers (including 35 men and 35 women), aged between 30-60 years old, referred to Qazvin University of Medical Sciences were investigated. None of these volunteers had systemic diseases. Vitamin D levels were measured with ELFA (Enzyme Linked Fluorescent Assay) and the data was analyzed using the chi-squared test and t-test. Results: The mean serum level of vitamin D in the control group was 23.7±9ng/ml and in the case group was 18.12±8/7ng/ml. The results show that the serum level of vitamin D in patients with OLP is significantly less than in the control group (p<0.05). Conclusion: According to the results, the serum level of vitamin D in patients with OLP was significantly lower than that of healthy people.

Introducción: La deficiencia de vitamina D es un problema de salud global que puede ser un factor de riesgo para una amplia gama de enfermedades, como algunas enfermedades autoinmunes. Debido a la base autoinmune del liquen plano, parece que una reducción del nivel sérico de vitamina D está relacionada con el liquen plano. En este estudio, investigamos la relación entre el nivel sérico de vitamina D y los pacientes con liquen plano oral (LPO). Material y Métodos: En este estudio de casos y controles, 35 pacientes con LPO (incluidos 15 hombres y 20 mujeres) y 70 voluntarios sanos (incluidos 35 hombres y 35 mujeres), con edades comprendidas entre 30 y 60 años, remitieron a la Universidad de Medicina de Qazvin. Se investigaron las ciencias. Ninguno de estos voluntarios padecía enfermedades sistémicas. Los niveles de vitamina D se midieron con ELFA (ensayo fluorescente ligado a enzimas) y los datos se analizaron utilizando la prueba de chi-cuadrado y la prueba t. Resultados: El nivel sérico medio de vitamina D en el grupo de control fue de 23,7 ± 9 ng / ml y en el grupo de casos fue de 18,12 ± 8/7 ng / ml. Los resultados muestran que el nivel sérico de vitamina D en pacientes con OLP es significativamente menor que en el grupo de control (p<0.05). Conclusión: De acuerdo con los resultados, el nivel sérico de vitamina D en pacientes con LPO fue significativamente menor que en personas sanas.

The mTOR-glycolytic pathway promotes T-cell immunobiology in oral lichen planus.

Oral lichen planus (OLP) is a T-cell-mediated inflammatory mucosal disease. T cells require rapid metabolic reprogramming for their effector functions after activation by immunologic stimuli. The mammalian target of rapamycin (mTOR) is a central player in the metabolic reprogramming and immune responses of T cells. The present study investigated the role of mTOR in the immunometabolism of OLP. mTOR and its direct target eukaryotic initiation factor 4E binding protein 1 (4E-BP1) were highly phosphorylated in peripheral T cells of OLP patients. Rapamycin-mediated blockage of mTOR activation restrained both T-cell proliferation and DNA synthesis, promoted apoptosis, and decreased Th1/Th2 and Th17/Treg ratios. Dual blockage of mTOR and phosphatidylinositol 3-kinase (PI3K) exerted stronger inhibition on T-cell immunobiology than selective repression of PI3K alone. Rapamycin also blocked the glycolytic pathway in T cells. Moreover, glucose-induced activation of mTOR-glycolytic pathway increased T-cell proliferation, DNA synthesis, and the Th17/Treg ratio, and decreased T-cell apoptosis. In contrast, inhibition of glycolysis by 2-Deoxy-d-glucose (2-DG) yielded the opposite effects on T-cell immunobiology by blocking the mTOR pathway. In conclusion, enhanced activation of the mTOR-glycolytic pathway promoted T-cell immunobiology, suggesting that dysregulation of immunometabolism might be associated with T-cell dysfunction in OLP.

Dental Implants in Patients with Oral Lichen Planus: A Systematic Review.

Background and Objectives: To integrate the available published data on patients with oral lichen planus (OLP) rehabilitated with dental implants, as well as to review the recommendations for OLP patients receiving implants. Materials and Methods: An electronic search was undertaken in February 2019 using five databases. Publications reporting cases of patients with OLP and rehabilitated with implant-supported oral prosthesis were included. Results: Twenty-two publications were included (230 patients, 615 implants). The overall implant failure rate was 13.9% (85/610). In patients with oral squamous cell carcinoma (OSCC) the failure rate was 90.6% (29/32), but none of these implants lost osseointegration; instead, the implants were removed together with the tumor. One study presented a very high implant failure rate, 76.4% (42/55), in patients with "active lichen planus", with all implants failing between 7-16 weeks after implant placement, and its conflicting and incongruent results are discussed in detail. There was a statistically significant difference between the failure rates in implants installed in different jaws (maxilla/mandible) and when implants of different surfaces were used (turned/moderately rough), but not between patients with reticular or erosive OLP types, or between male and female patients. If OSCC patients and the cases of the latter study are not considered, then the failure rate becomes very low (2.7%, 14/523). The time between implant placement and failure was 25.4 ± 32.6 months (range 1-112). The mean ± SD follow-up was 58.9 ± 26.7 months (1-180). Conclusions: When the results of the one study with a very high failure rate and of the cases that developed OSCC are not considered, the dental implant failure rate in OLP patients was 2.7% after a follow-up of approximately five years. Recommendations are given when treating OLP patients with dental implants.

Lichenoid sialadenitis in chronic graft versus host disease.

Chronic graft versus host disease (cGVHD) remains the principal long-term life-threatening complication in hematopoietic stem cell transplant recipients. We present a case of lichenoid sialadenitis in a 23-year-old-man with systemic cGVHD. The histological examination showed a lymphocytic inflammatory infiltrate adjacent to the salivary gland duct, similar to the histological aspects described in the typical manifestations of oral lichen planus and lichen planopilaris. This consists of a band-like inflammatory infiltrate not only targeting the cutaneous epithelium but also adnexal structures, such as hair follicles and salivary gland ducts. It is well described that the oral lesions in cGVHD share most of morphological and clinical manifestations with those described in oral lichen planus. The mechanisms of lichenoid salivary gland ducts destruction might be similar, although xerostomy appears to be specific to cGVHD, which may represent a clinical sign of massive salivary gland impairment related to ductal lichenoid destruction in patients with cGVHD.

Análise da imunoexpressão de 8-Hidroxi-2'-Deoxiguanosina em liquen plano oral / Analysis of the immunoexpression of 8-Hydroxy-2'-Deoxyguanosine in oral lichen planus

O Líquen Plano Oral (LPO) é uma doença mucocutânea crônica imunomediadae relativamente comum na mucosa oral. Diversas pesquisas têm sido desenvolvidas com intuito de elucidar a patogênese dessa lesão, destacando-se aquelas que utilizam biomarcadores de estresse oxidativo. O objetivo deste estudo foi avaliar o dano oxidativo ao DNA no LPO por meio da expressão imuno-histoquímica da 8-OHdG, para verificar o possível envolvimento deste biomarcador na patogênese desta lesão. A imunoexpressão da proteína 8-OHdG foi avaliada semiquantitativamente no epitélio de 46 casos de LPO e 17 amostras de mucosa oral clinicamente normal e os dados submetidos à análise estatística por meio dos testes nãoparamétricos de Kruskall-Wallis e Mann Whitney. O nível de significância foi estabelecido em 5% (p> 0,05). Ao analisar a imunoexpressão do 8-OHdG nas formas erosivas e reticulares do LPO e na mucosa oral normal, foi observada tendência à maior imunoexpressão nuclear da 8-OHdG nos LPOs erosivos, em comparação aos LPOs reticulares e à mucosa oral normal. Contudo, o teste não-paramétrico de Kruskall-Wallis não evidenciou diferenças estatisticamente significativas entre os grupos (p=0,088). Também foi observada tendência à maior intensidade de marcação para a 8-OHdG em casos de LPO reticular e erosivo, se comparados à mucosa oral normal, embora também não tenha sido encontrada significância estatística (p=0,085). Em relação à sintomatologia, foi observada maior imunomarcação tanto citoplasmática quanto nuclear (p=0,004 e p=0,016, respectivamente) da 8-ÓHdG nos casos sintomáticos, em comparação com os casos assintomáticos. Os resultados deste estudo indicam uma elevada expressão imuno-histoquímica da 8-OHdG em LPO, sugerindo o papel do estresse oxidativo em sua patogênese, podendo constituir um alvo terapêutico adicional para essa doença (AU).

The Oral Lichen Planus (OLP) is a chronic immune mediated mucocutaneous disease and relatively common in the oral mucosa. Several researches have been carried out with the intention of identifying pathogens of this lesion, standing out as research that uses oxidative stress biomarkers. Among these biomarkers, there is an 8-hydroxy-2'-deoxyguanosine (8- OHdG), which is generated after oxidative damage in DNA. The aim of this study was to evaluate the oxidative damage to DNA in the OLP through the immunohistochemical expression of 8-OHdG, to verify the possible involvement of this biomarker in the pathogenesis of this lesion. An immunoexpression of 8-OHdG protein was evaluated in a semi-quantitative way in the epithelium of 46 cases of OLP and 17 samples of clinically normal oral mucosa and with statistical analysis data using Kruskall-Wallis and Mann Whitney non-parametric tests. The level of significance was established at 5% (p> 0.05). When analyzing an immunoexpression of 8-OHdG in the erosive and reticular forms of OLP and normal oral mucosa, there was a trend of greater nuclear immunoexpression of 8-OHdG was observed in erosive OLP, compared to reticular OLP and normal oral mucosa. However, the Kruskall-Wallis non-parametric test did not show statistically significant differences between groups (p = 0.088). There was also a trend of greater intensity of marking for 8- OHdG in cases of reticular and erosive OLP, when compared to the normal oral mucosa, although no statistical significance was found (p = 0.085). In relation to symptomatology, greater immunomarking was observed, both cytoplasmic and nuclear (p = 0.004 and p = 0.016, respectively) of 8ÓHdG in symptomatic cases, in comparison with asymptomatic cases. The results of this study indicate a high immunohistochemical expression of 8-OHdG in OLP, suggesting an oxidative stress role in its pathogenesis, which may constitute an additional therapeutic target for this disease (AU).

Thymoma-associated multiorgan autoimmunity.

Thymoma-associated multiorgan autoimmunity is a relatively new term to describe the rare paraneoplastic syndrome that complicates thymoma, which can involve the thyroid, liver and intestine in addition to the skin. The pathology often indicates a graft-versus-host-like pattern commonly observed in recipients of an allogeneic haematopoietic cell transplant. We report a case of type B2 and B3 thymoma with invasion to the lung and pleura in a patient who presented with oral lichen planus and graft-versus-host-like erythroderma. The cutaneous lesions improved after complete resection of the thymoma in combination with systemic glucocorticoids, which was subsequently complicated by cytomegalovirus pneumonitis.

Lichen planus and diabetes mellitus: Systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to perform a systematic review and meta-analysis answering the following questions: (a) "What is the prevalence and risk of oral lichen planus among patients with diabetes mellitus?" and (b) "What is the prevalence and risk of diabetes mellitus among patients with oral lichen planus?". MATERIAL AND METHODS: A bibliographic search was conducted in PubMed/Medline and Scopus database from 1966 to March 2018, using the following terms: "Lichen planus" AND "Diabetes mellitus" AND "Prevalence" AND "Oral mucosal lesions". RESULTS: Twenty-two studies were included in this review. Twelve studies assessed the prevalence of diabetes mellitus among patients with lichen planus. The prevalence reported ranges from 1.6% to 37.7% with a relative risk of 2.432. Ten studies assessed the prevalence of lichen planus among patients with diabetes mellitus which showed a prevalence of lichen planus ranging from 0.5% to 6.1% with a relative risk of 1.4. CONCLUSIONS: Contradictory results were found when analyzing the relationship between lichen planus and diabetes mellitus. Diverse factors should be considered when studying this association for a correct interpretation of results. Diabetes mellitus has high prevalence and morbidity, which is why new case-control studies are needed to further investigate this association.

Circulating exosomes regulate T-cell-mediated inflammatory response in oral lichen planus.

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.

Psychological disorders and oral lichen planus: A systematic review.

The aim of the present study was to identify and analyze scientific evidence available in the literature to answer the following question: Are psychological disorders associated with the development of oral lichen planus (OLP)? Using scientific databases (PubMed, LILACS, and Science Direct), a literature search was conducted between December 2016 and January 2017, using previously selected keywords. Two independent reviewers critically assessed the results in three stages, strictly obeying the inclusion and exclusion criteria defined in the study protocol. We assessed paper quality based on STROBE (Strengthening The Reporting of Observational studies in Epidemiology). After analysis, we selected 14 papers, of which 10 showed evidence of association between psychological disorders (in particular, stress, anxiety, and depression) and the development of OLP. The paper-quality assessment by means of STROBE showed that 13 papers presented intermediate quality and one paper presented high quality. In the present systematic review, we found an association between psychological disorders and the development of OLP.

[Expression and significance of interleukin-35 in lesion tissue of oral lichen planus patients].

Objective: To investigate the expression of Epstein-Barr virus-induced gene 3 (EBi3) and interleukin-12p35 (IL-12p35) in two subunits of interleukin-35 (IL-35) in oral lichen planus (OLP) lesions, and to explore the role of IL-35 played in the formation and development of OLP lesions. Methods: Totally 41 samples of OLP lesions and 15 samples of normal tissues were collected from patients of the Department of Periodontology and Oral Medicine, Affiliated Stomatological Hospital of Guizhou Medical University from October 2010 to December 2016. The expression levels of EBi3 mRNA and IL-12p35 mRNA in the samples were detected by quantitative real-time PCR (qPCR) and the distribution and expression of protein EBi3 and IL-12p35 were detected by immunohistochemistry. The potential relationship between IL-35 and clinicopathological features of OLP was analyzed. Results: The expression [M(Q(25), Q(75))] of EBi3 [3.38 (1.63, 11.25)] and IL-12p35 mRNA [6.39 (2.55, 14.30)] in OLP lesion tissues were significantly higher than those in normal control group [1.41 (0.33, 3.16), 2.47 (1.10, 5.14)] (Z=-2.806, P=0.005; Z=-2.276, P=0.023), respectively. The positive expression rates of EBi3 and IL-12p35 were 66% (27/41) and 39% (16/41), respectively, were significantly higher in OLP lesion tissues comparing with that in normal oral mucosa tissues [0%(0/15)] (P<0.05). The relative expressions of EBi3 and IL-12p35 were positively correlated (r=0.404, P=0.009). A significant correlation was found between EBi3 protein over expression and the degeneration of base cells in OLP lesions (χ(2)=9.172, P=0.010). The positive expression rate of IL-12p35 protein in erosive type lesions was higher than that in non-erosive type lesions (χ(2)=7.220, P=0.007). The positive expression rate of IL-35 protein in OLP lesions [34% (14/41)] was higher than that in normal control group (χ(2)=6.829, P=0.009). The expression rate of IL-35 in erosive type lesions (10/20) was significantly higher than that in eruption type lesions (4/21) (χ(2)=4.364, P=0.037). Conclusions: The expression of IL-35 in OLP localized lesions was up-regulated, suggesting that IL-35 might play an important role in OLP lesion formation.

Oral Lichen Planus: an Overview of Potential Risk Factors, Biomarkers and Treatments

Oral lichen planus (OLP) is an immune-related disorder with unknown exact etiology but established prevalence in females. There are six clinical forms of OLP, ranging from asymptomatic white keratotic lesions to painful erosions and ulcerations. The aim of the present report is to overview pathologic and therapeutic aspects. Peroxidation products, antioxidants, cortisol, and immunoglobulins are potential biomarkers to predict OLP occurrence. The risk of OLP development in patients with hepatitis B and C infection is 2-fold greater than in healthy individuals, while there is no significant relation with diabetes mellitus. Corticosteroids are common drugs to treat OLP and their combination with other agents can be most effective. Folic acid and variants of vitamin B are also potential treatments since they target hematological abnormalities.