Gene polymorphism in oral lichen planus

口腔扁平苔藓（OLP）是一种常见的口腔黏膜慢性炎症性疾病,成年人患病率为0.5%~2%。OLP的病因和发病机制尚不明确,研究显示其发病可能与某些基因的遗传多态性相关,目前研究较多的有肿瘤坏死因子、干扰素、白细胞介素、酶类、受体等基因家族。本文就基因多态性与口腔扁平苔藓的相关性进行综述。     

口腔白斑与扁平苔藓单核苷酸基因多态性研究进展

单核苷酸多态性（single nucleotide polymorphism，SNP）是人类基因组中最丰富的一种DNA序列变化，发生在基因内或其邻近序列的SNP控制个体之间表型的差异，包括疾病的易感性和对药物的反应等。口腔白斑（oral leukoplakia，OLK）和口腔扁平苔藓（oral lichen planus，OLP）是一组常见的口腔黏膜病，关于这两种疾病的多态性研究近年来正悄然兴起，现简要综述这两种疾病的SNP研究进展。     

Macrophages in oral lichen planus

The presence and distribution of macrophages within 15 non-ulcerated lesions of oral lichen planus was investigated using an immunoperoxidase technique for the detection of the macrophage markers lysozyme and α₁ antitrypsin. All specimens contained mononuclear lysozyme and α₁ antitrypsin positive cells which were concentrated in a band immediately beneath the epithelium and often associated with areas of damaged basal cells. Cell counts revealed that 11% of the positive cells were in the epithelium and 89% in the lamina propria. Approximately 61% of all positive cells were found within a 125 μm wide zone centred on the basement membrane. These results suggest that in oral lichen planus macrophages are in close proximity to the epithelial basal cells, where cell damage occurs, and play a role in the pathogenesis of his condition.     

Apoptosis in oral lichen planus

Apoptotic cell death may be a contributory cause of basal cell destruction in oral lichen planus (OLP). Therefore. the purpose of this study was to investigate the rate of apoptosis in OLP and the expression of two proteins (FasR and FasL) regulating this process. Biopsies from 18 patients with histologically diagnosed OLP were investigated, with comparison to normal oral mucosa of healthy persons. For visualisation of DNA fragmentation, the TUNEL method was used. In order to characterise the infiltrating cell population (CD3. CD4, CD8) and expression of FasR and FasL, we used an immunohistochemical technique. The results showed that T cells dominated in the subepithelial cell infiltrate. Within the epithelium the apoptotic cells were confined to the basal cell layer, and more apoptotic cells were seen in areas with basal cell degeneration and atrophic epithelium. There was a prominent expression of FasR/FasL in OLP. with a rather uniform distribution throughout the inflammatory cell infiltrate. In the epithelium, the FasR/FasL expression was more abundant in the basal cell area compared to the suprabasal cell layer. In conclusion, apoptosis within the epithelium is significantly increased in situ in OLP compared to normal oral mucosa, and seems to be related to the epithelial thickness.     

Macrophages in oral lichen planus

The presence and distribution of macrophages within 15 non-ulcerated lesions of oral lichen planus was investigated using an immunoperoxidase technique for the detection of the macrophage markers lysozyme and alpha 1 antitrypsin. All specimens contained mononuclear lysozyme and alpha 1 antitrypsin positive cells which were concentrated in a band immediately beneath the epithelium and often associated with areas of damaged basal cells. Cell counts revealed that 11% of the positive cells were in the epithelium and 89% in the lamina propria. Approximately 61% of all positive cells were found within a 125 micron wide zone centred on the basement membrane. These results suggest that in oral lichen planus macrophages are in close proximity to the epithelial basal cells, where cell damage occurs, and play a role in the pathogenesis of this condition.     

CO2 laser evaporation of oral lichen planus

Oral lichen planus is a relatively common disease of the oral mucosa. The buccal mucosa and lateral border of the tongue are mostly involved, although the condition can occur anywhere in the oral cavity. The erosive type in particular can cause spontaneous pain during eating. In the period from 1975 to 2003, a group of 21 patients with 39 lesions of oral lichen planus which caused pain, even after conservative therapy, were treated with CO2 laser evaporation. During a follow-up period of 1-18 years (mean 8 years) 21 patients were pain free (85%) and 6 patients (15%) experienced painful recurrence after treatment. After retreatment with CO2 laser evaporation there were no complaints of pain. Among the many treatments available, high-potency topical corticosteroids remain the most consistent and effective. In patients whose condition is unresponsive to topical corticosteroids, CO2 laser evaporation can cause long-term remission of symptoms, and may even be the treatment of first choice in patients suffering from painful oral lichen planus.     

Malignant transformation in oral lichen planus

A carcinoma arose in the buccal mucosa of a 71-year-old woman suffering from several systemic diseases, and on extensive medication. The buccal mucosa had been affected by oral lichen planus for more than 9 years. The possibility of malignant transformation of oral lichen planus is discussed.     

Osteopontin expression in oral lichen planus

To explore circulation levels of osteopontin (OPN), tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 from patients with oral lichen planus (OLP) for clinical application. A group of 26 subjects with OLP were compared with 26 sex- and age-matched control (NC) subjects. Local lesion tissue was examined for OPN by immunohistochemical analysis. And, serum OPN, proinflammatory TNF-α and TGF-β1 levels were measured by enzyme-linked immunoabsorbent assay. The serum concentrations of OPN and TNF-α were significantly higher in OLP patients than the NC group ( P  < 0.05). Although serum concentrations of TGF-β1 increased slightly, they were not statistically significant. Erosive-form OLP exhibited significantly elevated TGF-β1 serum levels, compared with reticular-form OLP. The above results suggest that the production of OPN is associated with the inflammatory process of OLP development, and may serve as a potential disease marker of OLP.     

Apoptosis-associated markers in oral lichen planus

Hypothesizing that loss of basal cells in oral lichen planus is due to apoptosis. we evaluated LP specimens for apoptosis-regulating proteins [positive regulators Bcl-x_s, Bax, Fas/Fas-ligand, p53. and negative regulators (anti-apoptotic) Bcl-2, Bcl-x_L] and compared results with reactions in normal mucosa and chronically inflamed gingiva. Also, sections were evaluated with an in situ TUNEL assay that identifies apoptotic DNA fragments. Basal keratinocytes in normal buccal mucosa, nonspecific gingivitis, and LP were negative for Bcl-2 protein, but meta-nocytes and iymphoid cells were positive. Keratinocyte staining for Bcl-x was negative to weak in normal buccal mucosa and gingivitis, and moderate in LP. Keratinocytes (especially upper prickle cells) in all tissues stained similarly for Bax at weak to moderate levels. Also, no differences in Fas and Fas-ligand staining were evident. Prominent p53-positive staining was seen in all LP biopsies (10–100% of basal keratinocytes) but not in normal buccal mucosa and gingivitis. Few basal keratinocytes in 5/10 LP cases exhibited a positive in situ signal for DNA fragment-associated apoptosis. That the Bcl-2 family of proteins and Fas/Fasligand were detected in normal and diseased tissues, and were occasionally expressed differently in oral LP, supports the notion that apoptosis is a potential mechanism of keratinocyte loss, especially in LP. The pattern of p53 staining in oral LP suggests over-expression of wild-type protein; a phenomenon that would arrest the cell cycle to allow repair of damaged DNA. or trigger apoptosis. While immunohistochemical evidence for apoptosis-associated basal keratinocyte death in LP was slight, it appeared that it may be p53 protein, and possibly Bcl-x. associated.     

Immune mechanisms in oral lichen planus

Oral lichen planus (OLP) is a T cell-mediated inflammatory disease of the oral mucosa that has been extensively researched over many years but as yet the mechanisms of pathogenesis are still not fully understood. Whilst the specific aetiological factors driving OLP remain ambiguous, evidence points to the development of a chronic, dysregulated immune response to OLP-mediating antigens presented by innate immune cells and oral keratinocytes leading to increased cytokine, chemokine and adhesion molecule expression. These molecules recruit T cells and mast cells to the diseased site and orchestrate a complex interplay between cells that culminates in keratinocyte cell death, mucosal basement membrane destruction and long-term chronicity of the disease. The main lymphocytes involved are thought to be CD8+ cytotoxic and CD4+ Th1 polarised T cells although recent evidence indicates the involvement of other Th subsets such as Th9, Th17 and Tregs, suggesting that a more complex immune cell relationship exists during the disease process. This review provides an overview of the immune mechanisms at play in OLP pathogenesis with particular emphasis on the role of the different Th subsets and how these recent discoveries may guide research towards identifying potential therapeutic targets.     

Immunopathogenesis of oral lichen planus

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

Telomerase activity in oral lichen planus

The purpose of this study was to determine the expression of telomerase in refractory oral lichen planus. Using a polymerase chain reaction-based telomerase activity assay, we investigated telomerase activity in 20 oral lichen planus specimens (erosive 9, atrophic 11). Telomerase activity was detected in 14 cases (erosive 7, atrophic 7). Furthermore, 13 cases of lichen planus with mild dysplasia proved telomerase-positive in eight specimens and six of seven cases devoid of dysplasia were also positive in the telomerase assay. The data indicate that, in general, telomerase activity might be frequently detectable in OLP. The data also suggest that telomerase activity might not be particularly associated with the premalignant phenotype in OLP.     

Mast cells in oral lichen planus

Biopsies from lichen planus affected oral mucosa were compared with biopsies from healthy oral mucosa, in terms of the number of mast cells, their location and their morphological alteration at the light microscopic and electron microscopic level. In comparison with the normal oral mucosa an increased number of mast cells was found below the subepithelial infiltrate. This difference was statistically highly significant (p less than 0.001). In the deeper part of the infiltrate mast cells were found to contain granules which presented an altered morphology upon electron microscopic examination. These cells had many of the ultrastructural changes that have been reported for mast cells undergoing degranulation. The present morphological observations suggest that mast cells participate in the recruitment of lymphocytes to the subepithelial infiltrate.     

Candidal infection in oral lichen planus

The prevalence of candidal infection in lichen planus (LP) and its possible association with ulceration were independently examined in two archived series of 108 and 77 cases derived from two separate populations. To ensure that similar material was being compared, each case was histopathologically reassessed and confirmed as LP or reclassified as nonspecific lichenoid stomatitis (NSLS), lichenoid dysplasia (LD), or other (O). Three further sections, cut at 25 microns intervals, were stained with periodic acid-Schiff reagent for the identification of intraepithelial candidal pseudohyphae. As control specimens, 61 normal and 59 hyperkeratotic mucosal samples were similarly processed and examined. Candidal infection was found in 17.4% and 16.4% of ulcerated and nonulcerated LP cases, respectively, and in 40.0% and 16.7% of ulcerated and nonulcerated NSLS cases, respectively. One case of LD was infected. Each control series contained one infected case. The results indicate that candidal infection occurs more readily in LP and NSLS, with no apparent association with ulceration in LP. The comparatively marked increase in the infection prevalence of ulcerated NSLS cannot be statistically confirmed, and its significance remains uncertain.     

Granular cells in oral lichen planus

OBJECTIVE AND DESIGN: Three cases of granular cells associated with oral lichen planus (OLP) have been reported to date, which prompted us to look for the presence of granular cells in a consecutive series of 250 cases of OLP in the period 1996-1998. RESULTS: Only one case with granular cell changes was encountered in that series. H&E stained slides as well as direct immunofluorescence examination showed characteristics compatible with OLP. Part of the subepithelial connective tissue was replaced by a granular cell proliferation; S-100 protein was diffusely expressed in all granular cells, whereas no expression of smooth muscle actin was observed. CONCLUSION: Based on these findings it seems unlikely that the granular cells in the present case represent a so-called 'oral ceroid granuloma'. The presence of granular cells might rather have been a reactive phenomenon triggered by the inflammatory infiltrate or a granular cell tumour (GCT). Whether the simultaneous presence of a GCT and OLP in this particular case was based on a causal relationship or on coincidence still remains unknown.