Langerhans cells expressing HLA-DQ, HLA-DR and T6 antigens in normal oral mucosa and lichen planus

We compared Langerhans cells (LC) expressing HLA-DQ, HLA-DR and T6 antigens in biopsies from the same oral mucosal site in 12 patients with oral lichen planus and eight healthy volunteers. LC expressing each antigen were observed in all the specimens, but in lichen planus the cells were located in higher levels of the epithelium than in controls. Compared with controls, lichen planus contained significantly more HLA-DQ-positive LC (P = 0.04) and fewer HLA-DR-positive LC (P = 0.05), but there was no such difference in T6-positive LC. In lichen planus specimens, there were significantly more LC expressing HLA-DQ and T6 than HLA-DR (P = 0.0001 and 0.02 respectively); no such differences were found in normal mucosa. Epithelial cells in lichen planus expressed HLA-DR antigen, but not HLA-DQ or T6 antigens. We conclude that in lichen planus there is modulation of HLA-DR and HLA-DQ antigen expression by LC, or differences in the number of LC expressing those antigens.     

The activation of Langerhans cells in oral lichen planus

The numbers of CD1, HLADR, HLADP and HLADQ positive, intraepithelial, dendritic cells were compared in lesions of oral lichen planus and normal oral mucosa using an immunoalkaline phosphatase technique. In normal mucosa, there were equal numbers of CD1 and HLADR positive cells but significantly fewer cells were positive for HLADP (P less than 0.001) and HLADQ (P less than 0.05). In lichen planus, the cells appeared more dendritic and equal numbers of CD1, HLADR, HLADP and HLADQ positive cells were found, with significantly more HLADP (P less than 0.01) and HLADQ (P less than 0.05) positive cells than in normal mucosa. There was no change in the number of CD1 and HLADR positive cells. These results show that although there is no change in the total number of Langerhans cells (CD1 positive cells) in lichen planus, there is an increase in Class II major histocompatibility antigen expression. This suggests that in lichen planus, Langerhans cells are immunologically active and play a role in lesion development.     

Langerhans cell distribution and keratinocyte expression of HLADR in oral lichen planus

Keratinocyte expression of the Class II major histocompatibility complex antigen HLADR, is seen in several inflammatory disorders of skin and mucosa, including lichen planus. The purpose of this study is to determine whether the distribution of Langerhans cells and their expression of CD4 in oral lichen planus is related to keratinocyte HLADR. The numbers of CD1- and CD4-positive Langerhans cells were compared in areas of keratinocyte HLADR and areas showing no expression in oral lichen planus and with normal oral mucosa. Cells were identified using an immunoalkaline phosphatase technique and numbers were expressed per mm epithelial surface length. In lichen planus, an increase both in the number of Langerhans cells and the numbers expressing CD4 were found in areas of keratinocyte HLADR expression compared with HLADR negative areas and with normal oral mucosa. There was no difference in the numbers of Langerhans cells or their expression of CD4 between HLADR-negative areas in LP and normal oral mucosa. These results show that the distribution of Langerhans cells is related to keratinocyte expression of HLADR and suggest that Langerhans cell entry may be enhanced in these areas. Whilst it is possible this enhancement is mediated by CD4/HLADR interaction, other molecules are also likely to be important in controlling Langerhans cell entry into oral mucosa.     

Intra-epithelial subpopulations of T lymphocytes and Langerhans cells in oral lichen planus

This study has addressed the question of whether there is selective recruitment and distribution of intra-epithelial leucocytes in lesions of oral lichen planus (OLP). T-lymphocyte subsets were examined in the epithelium and peripheral blood of patients and controls using flow cytometry and double immunofluorescence, and the relationship between keratinocyte intercellular adhesion molecule-1 (ICAM-1) expression with T-lymphocyte and Langerhans cell (LC) distribution was examined. The circulating 'memory'subset (CD45RO⁺) of T-helper cells (CD4⁺) was increased from 49.1% in controls to 65.7% in patients ( P = 0.005), while the 'naive'subset (CD45RA⁺), which was absent from control epithelium, comprised 24% of helper cells in OLP ( P =0.037) and all T-cell and LC counts were significantly raised in ICAM-1-expressing areas of epithelium. These data demonstrate changes in intra-epithelial T-lymphocyte and LC populations compared with normal oral mucosa and suggest there is selective recruitment in OLP. In addition, Keratinocyte ICAM-1 expression does appear to be associated with accumulation of infiltrating T lymphocytes and LC.     

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.     

Induction and upregulation of adhesion receptors in oral and dermal lichen planus

The expression pattern of well-defined cell surface adhesion receptors called VLA-family, LFA-1 and ICAM-1 was determined semiquantitatively in biopsies of oral (n = 12) and dermal lichen planus (n = 5) and compared to normal uninvolved human oral mucosa (n = 12) and skin (n = 12) using an indirect immunoperoxidase technique. In both oral and dermal lichen planus, an induction of the beta 1-integrins VLA-1 and VLA-3 and an upregulation of VLA-6 was found in T cells infiltrating the basement membrane zone. These cell surface molecules function as receptors for collagen, fibronectin and laminin. A focal induction of ICAM-1 on basal keratinocytes could be detected at sites of intramucosal T cells. These results suggest that investigated adhesion receptors are crucially involved in the aggregation of T cells in both conditions. Further investigations have to be done to determine the functional role of these adhesion receptors in lichen planus.     

Th1 cytokines in oral lichen planus

BACKGROUND: Cell-mediated immune responses in oral lichen planus (OLP) may be regulated by cytokines and their receptors. METHODS: In situ cytokine expression and in vitro cytokine secretion in OLP were determined by immunohistochemistry and ELISA. RESULTS: The majority of subepithelial and intraepithelial mononuclear cells in OLP were CD8+. In some cases, intraepithelial CD8+ cells were adjacent to degenerating keratinocytes. CD4+ cells were observed mainly in the deep lamina propria with occasional CD4+ cells close to basal keratinocytes. Mononuclear cells expressed IFN-gamma in the superficial lamina propria and TNF-alpha adjacent to basal keratinocytes. Basal keratinocytes expressed TNF-alpha as a continuous band. TNF R1 was expressed by mononuclear cells and basal and suprabasal keratinocytes. There was variable expression of TGF-beta1 in the subepithelial infiltrate while all intraepithelial mononuclear cells were TGF-beta1-. Keratinocytes in OLP stained weakly for TGF-beta1. Unstimulated OLP lesional T cells secreted IFN-gamma in vitro. TNF-alpha stimulation down-regulated IFN-gamma secretion and up-regulated TNF-alpha secretion. IL-4, IL-10 and TGF-beta1 secretion were not detected. CONCLUSIONS: These data suggest the development of a T helper 1 immune response that may promote CD8+ cytotoxic T-cell activity in OLP.     

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

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

T lymphocytes, Langerhans cells and HLA-DR expression on keratinocytes in oral lesions associated with amalgam restorations

It has been shown recently that patients with mucosal lesions confined to areas opposing amalgam restorations (contact lesions) show a high rate of allergic reaction towards mercury. These lesions may, therefore, represent a contact hypersensitivity reaction. Contact lesions often have a lichenoid appearance. From a pathogenetic and differential diagnostic point of view we therefore evaluated the presence of lymphocyte subpopulations, Langerhans cells (LC) and the expression of HLA-DR antigens on mucosal keratinocytes in biopsies of contact lesions (Group 1) and in lichen planus lesions with (Group 2) and without (Group 3) partial contact with amalgam restorations. T lymphocytes dominated in all three groups and LC counts were similar. HLA-DR positive keratinocytes were found in 18-36% of lesions in all three groups. Thus, the immunologic parameters examined are not of value in discriminating between the types of lesions studied. Rather, it seems that the pattern observed is a common reaction of the oral mucosa to known (amalgam restorations) and unknown factors.     

口腔扁平苔藓基因表达谱中差异表达基因初步探讨

目的筛选口腔扁平苔藓组织中的差异表达基因,并对其进行功能分类。方法用4 000种人类基因多聚酶链反应产物制成BiostarH- 40s型表达谱芯片,分离纯化正常口腔黏膜组织和口腔扁平苔藓病变组织mRNA,制备表达谱探针,用ScanArray 4000 荧光扫描仪扫描芯片荧光信号图像,分析正常口腔黏膜组织和口腔扁平苔藓组织之间差异表达的基因。结果1）在4 000条基因中,有213条基因表达差异,其中122条基因表达上调,91条基因表达下调。2）在表达上调基因中,功能分类主要包括免疫相关基因、代谢相关基因、癌基因、细胞因子、细胞信号和传递蛋白。3）在表达下调基因中,功能分类主要包括DNA结合、转录和转录因子、细胞信号和传递蛋白、免疫相关基因、细胞因子、代谢相关基因。结论口腔扁平苔藓的发生、发展过程中存在着多条不同功能基因表达调控的改变。     

Expression of CD1 and HLA-DR by Langerhans cells (LC) in oral lichenoid drug eruptions (IDE) and idiopathic oral lichen planus (LP)

Numbers of Langerhans ceils (LC) expressing the common thymocyte antigen (T6/CD1) are similar in oral lichen planus (LP) and in normal oral epithelium: however, expression of class II major histocompatibility antigens (HLA-DR/Ia) by Langerhans cells is greater in lichen planus than in normal epithelium, a phenomenon believed to be associated with activation and antigen presentation. This study quantified the numbers of T6+ve and HLA-DR + ve Langerhans cells in oral lichen planus and lichenoid drug eruptions (LDE) to investigate whether differences may reflect differing routes of antigen presentation. Six patients with oral lichenoid drug eruptions and six control idiopathic oral lichen planus patients had lesional biopsies. An immunoperoxidase technique was used to demonstrate binding of T6 and HLA-DR antibodies to identify dendritic intra-epithelia! cells as Langerhans cells and activated Langerhans cells, respectively. In lichenoid drug eruptions, the number of HLA-DR+ve LC was significantly lower than the number of T6+ve LC ( P < 0.05), whereas in idiopathic lichen planus the numbers of T6+ve and HLA-DR+ve LC did not differ significantly ( P = 0.20). The results provide evidence for differences in the routes of antigen presentation in lichenoid drug eruptions and idiopathic lichen planus.     

Ets-1在口腔扁平苔藓中的表达研究

目的 :分析Ets 1(E2 6transformation specific)在口腔扁平苔藓 (OLP)的表达及意义。 方法 :采用免疫组化ABC法检测Ets 1蛋白在 2 0例口腔扁平苔藓和 8例正常口腔黏膜组织中的表达。结果 :70 % (14 /2 0 )的口腔扁平苔藓病例中Ets 1呈阳性表达 ,明显高于正常黏膜组织 ,两者比较有显著性差异 (P <0 .0 5 )。阳性表达率在溃疡型OLP与斑块型OLP间亦有显著性差异 (P <0 .0 5 ) ,并与病程相关 (P <0 .0 5 )。结论 :Ets 1在口腔扁平苔藓中过表达并与其发病有关。     

Cytological and cytochemical investigations on granular cells in oral lichen planus

Two biopsy specimens showed unusual histology characterized by features consistent with resolving oral lichen planus and voluminous, finely granular cells in the lamina dopria. resembling the cells of granular cell tumour. Immunocytochemistry and lipid-pigment histochemistry indicated that the granular cells are macrophages of low proliferative activity laden with early ceroid. It is likely that damaged basal keratinocytes provide debris for the formation of the latter.'Oral ceroid granuloma' would be an appropriate term for collections of such reactive macrophages occurring in the oral tissues.     

Cytological and cytochemical investigations on granular cells in oral lichen planus

Two biopsy specimens showed unusual histology characterized by features consistent with resolving oral lichen planus and voluminous, finely granular cells in the lamina propria. resembling the cells of granular cell tumour. Immunocytochemistry and lipid-pigment histochemistry indicated that the granular cells are macrophages of low proliferative activity laden with early ceroid. It is likely that damaged basal keratinocytes provide debris for the formation of the latter. 'Oral ceroid granuloma' would be an appropriate term for collections of such reactive macrophages occurring in the oral tissues.     

Oral lichen planus: immunohistology of mucosal lesions.

BACKGROUND: Current evidence suggests that immunological mechanisms are involved in oral lichen planus (OLP) pathogenesis. The events implicate activated epithelia that comprise antigen-presenting Langerhans cells, immunocompetent keratinocytes and subepithelial inflammatory infiltrate. Also, the presence of a high density of leucocyte cells may occur for the expression of a variety of adhesion molecules. The aim of this study was to analyse the immunoexpression of some adhesion molecules as well as lymphocytic markers in order to determine the disease pathogenesis in a Venezuelan population. METHODS: The 18 OLP and 10 normal oral mucosa biopsies were immunostained for CD4, CD8, CD1a, LFA-1, VCAM-1 and ICAM-1. RESULTS: The results showed an increased number of CD4+, CD8+, CD1a+ cells in OLP. Serial sections showed CD4+ and CD8+ cells also expressed LFA-1. The expression of ICAM-1 and VCAM-1 were significantly higher in OLP. CONCLUSIONS: The immunological reaction begins with Langerhans cells activation, which presents an antigen to CD4+ lymphocytes. Those cells through ICAM-1 and LFA-1 promote epithelial destruction. Afterwards, cytokine production, ICAM-1 and VCAM-1 expression can activate CD8+ lymphocytes leading to the chronic form of the disease.     

Occurrence of oral leukoplakia and lichen planus in diabetes mellitus

The occurrence of oral leukoplakia and lichen planus in 1600 patients with diabetes mellitus (815 type 1: insulin-dependent, 761 type 2: non-insulin-dependent)-under care at the International Medicine Department-was studied. Precancerous lesions and conditions were diagnosed and grouped according to internationally accepted criteria. The prevalence of oral leukoplakia in diabetic patients was 6.2%, as compared to 2.2% in the healthy controls, that of oral lichen was 1.0% in the test-, and 0.0% in the control group. Leukoplakia and lichen both showed the highest occurrence in the second year of established diabetes, and their prevalence was higher among insulin-treated diabetics. Smokers were more often affected, by both kind of lesions, oral lichen showed a more frequent association with candidiasis. The prevalence of oral leukoplakia and lichen in diabetes mellitus patients was higher, than average ratios in population samples from the same country.     

Psychological profile in oral lichen planus

AIM: Oral lichen planus (OLP) is an oral lesion with an enigmatic etiology. To explore the possibility of psycho-somatization, we evaluated the psychological personality profiles of OLP patients. METHODS: Twenty patients with reticular; 20 with erosive form of OLP, and 25 controls were tested with the psychological Minnesota Multiphasic Personality Inventory (MMPI)-202 test. Eight clinical scales (hypochondriasis, depression, hysteria, psychopathic deviate, paranoia, psychasthenia, schizophrenia, and hypomania) as well as cortisol level, CD3, CD4, CD8, and CD16 markers by group were compared. Psychosomatization was evaluated by the use of internalization ratio (IR) Index. RESULTS: A characteristic MMPI profile was noted in the OLP groups with high IR index value. Significant differences among the groups were detected for cortisol, CD4, CD8, and CD16 counts. Mean values for hypochondriasis, depression, and hysteria were all significantly different with significantly higher mean scores for both reticular and erosive OLP subjects compared with controls. CONCLUSIONS: Prolonged emotive stress in many OLP patients may lead to psychosomatization and may contribute to the initiation and clinical expression of this oral disorder. Clinical significance: If additional research involving a larger and more diverse sample of patients confirms these findings, clinical trials will be needed to determine whether adjunctive psychological intervention provides a benefit in treating patients with OLP.     

Associations between mast cells and laminin in oral lichen planus

Mast cell numbers are increased significantly in oral lichen planus (OLP). In other inflammatory conditions, mast cells frequently adhere to extracellular matrix proteins such as laminin. The aim of this study, therefore, was to determine whether the distribution of mast cells in OLP is related topographically to laminin in vascular and epithelial basement membranes. Monoclonal antibodies for tryptase, laminin and the α6β1 CD49f laminin-binding integrin were used to identify mast cells, basement membranes (blood vessels and basal epithelium) and the "classical" laminin adhesion receptor, respectively. A double-labelling immunoperoxidase technique was employed to examine and compare mast cell-laminin relationships in OLP (n=19) and normal buccal mucosa (NBM, n=13). In both OLP and NBM, the majority of mast cells were located close to vascular basement membranes. Quantitative studies revealed that the number of mast cells associated with the laminin of vascular basement membranes (distance <1 μm) was two-fold and three-fold higher, respectively, in the superficial and deep layers in OLP compared with NBM (P<0.001). The frequency distribution of mast cells associated with basal epithelium was not statistically different in both groups (P>0.05). The association of mast cells with laminin may be an important determinant of mast cell density in OLP. During OLP lesion formation and progression, the preferential distribution of mast cells in the immediate perivascular region provides an ideal situation for mast cell-derived mediators to influence the vascular endothelium.     

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.     

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.