Cadherins in Cutaneous Biology

The role of cadherins in cutaneous biology has focused mainly on the classical cadherins, E- and P-cadherin. In this review, roles for cadherins in skin morphogenesis, keratinocyte differentiation, and cancer metastasis are discussed. E-cadherin is expressed on the surfaces of whole epidermal layer cells, and P-cadherin is expressed only on the surfaces of basal cells. Ultrastructural studies have shown that E-cadherin is distributed on the cytoplasmic membranes of keratinocytes with a condensation in the intercellular space of the desmosomes. During human skin development, P-cadherin expression is spatiotemporally controlled and closely related to the segregation of basal layers as well as to the arrangement of epidermal cells into eccrine ducts. In human skin diseases, E-cadherin expression is markedly reduced on the acantholytic cells of tissues in pemphigus and also in Darier's disease. Keratinocytes cultured in high calcium produce a much more intense immunofluorescence of intercellular E- and P-cadherin than do cells grown in low calcium. Ultrastructural studies show that E-cadherin on the cytoplasmic membrane of the keratinocytes is shifted to desmosomes under physiological conditions and therein expresses an adhesion function is association with other desmosomal cadherins. Cell adhesion molecules are now considered to play significant roles in the cellular connections of cancers and metastatic cells. Reduced expression of E-cadherin on invasive neoplastic cells has been demonstrated for cancers of the stomach, liver, breast, and several other organs. This reduced expression of E-cadherin is observed in squamous cell carcinoma and Paget's disease. Soluble E-cadherins in sera are elevated in various skin diseases, including bullous pemphigoid, pemphigus vulgaris and psoriasis, but not in patients with burns. Markedly high levels in soluble E-cadherin are demonstrated in patients with metastatic cancers.     

Immunopathological study of proliferation-associated antigens in proliferative skin diseases

59 specimens consisting of 10 psoriasis vulgaris, 1 squamous cell carcinoma, 1 Paget disease, 3 keratoacanthomas, 1 pemphigus vulgaris, 18 cutaneous T cell lymphomas, 2 ATLs, and other skin diseases were studied by immunoperoxidase technique. We used four antibodies to demonstrate a cell proliferation-associated antigen (PC, DNA polymerase-alpha and transferrin receptor) and epidermal growth factor receptor. Our observations suggested that the expression of PC and DNA polymerase-alpha may correlate well with cell proliferation, which were demonstrated in the epidermis of psoriasis vulgaris. Primary and metastatic squamous cell carcinoma and some of psoriasis vulgaris had a positive staining for EGF-R, while normal epidermis and almost all other skin diseases were negative.     

Cutaneous squamous cell carcinoma developing in lupus vulgaris exfoliativus persistent for 40 years

Background  A 65-year-old man is described with a 40-year history of lupus vulgaris exfoliativus, a form of cutaneous tuberculosis that resembles psoriasis. He had been misdiagnosed as having psoriasis vulgaris for many years. A cutaneous squamous cell carcinoma developed within a plaque of lupus vulgaris exfoliativus.
Methods  A skin biopsy provided the correct diagnoses.
Results  The patient was successfully treated with medication for tuberculosis and had his skin cancer cured by surgical excision.
Conclusions  With an increasing worldwide incidence of tuberculosis, one needs to be aware of its cutaneous forms and variants, as well as its complications, in particular skin cancer. Lupus vulgaris exfoliativus may resemble psoriasis vulgaris.     

Reciprocal altered expression of T-cadherin and P-cadherin in psoriasis vulgaris

BACKGROUND: The most characteristic change in psoriasis vulgaris is markedly increased, persistent keratinocyte proliferation. The underlying mechanism of excessive epidermal growth is controversial. We previously found and reported that T-cadherin was expressed in keratinocytes and confined to the basal layer of mouse and human skin. Invasive cutaneous squamous cell carcinoma showed a loss of T-cadherin expression. Another study showed that T-cadherin was a negative growth regulator of epidermal growth factor in T-cadherin transfectant neuroblastoma cells. OBJECTIVES: To obtain insight into the role of T-cadherin in keratinocyte proliferation and to investigate further the pathogenesis of psoriasis vulgaris, we examined the expression of T-cadherin, as well as E- and P-cadherin, in psoriasis vulgaris. METHODS: Four untreated active psoriatic skin samples from psoriasis vulgaris patients and four normal human skin samples from plastic surgery were collected, cryosectioned and immunohistochemically stained by antihuman T-, P- and E-cadherin antibodies. Further, the immunofluorescence intensities of T- and P-cadherin on the basal layer of the epidermis were quantitatively measured by the histogram function of LSM 510 software installed in a Zeiss laser scanning confocal microscope. The data were statistically analysed by Student's t-test. RESULTS: It was observed that T-cadherin was weakly and discontinuously expressed on the basal layer of psoriatic skin, while it was intensively expressed on all basal keratinocytes in normal human skin. In contrast, P-cadherin was strongly expressed throughout the entire epidermal layer in psoriatic skin samples, although its expression is restricted to the basal cell layer in normal human skin. There were no obvious differences in E-cadherin expression between normal human skin and psoriatic skin. Statistical analyses showed that the immunofluorescence intensity of T-cadherin in the basal cell layer of psoriatic skin (35 +/- 9.08) was significantly decreased compared with that in normal human skin (131.75 +/- 3.49, P = 2.46 x 10(-6)). There was a significant increase (P = 0.00139) in the immunofluorescence intensity of P-cadherin in the basal layer of psoriatic skin (68.25 +/- 12.13) compared with normal human skin (26 +/- 4.90). CONCLUSIONS: The present study demonstrates that there is downregulation of T-cadherin expression and upregulation of P-cadherin expression in psoriatic skin, which are considered to be involved in the hyperproliferation of keratinocytes in psoriasis vulgaris.     

E-钙黏素,P-钙黏素在进行期银屑病皮损中的检测

目的研究E-钙黏素(E-cadherin),P-钙黏素(P-cadherin)在寻常性银屑病中的表达。方法用免疫组化方法检测正常皮肤组织及进行期银屑病皮损中E-cadherin,P-cadherin蛋白的表达。结果E-cadherin蛋白在正常人皮肤组织表皮全层表达,在进行期银屑病皮损表达在颗粒层和棘层上部及基底层表达明显下降或缺失;在正常人皮肤组织中,P-cadherin主要表达于基底层,而在银屑病皮损中则强烈表达于表皮全层。结论E-cadherin表达的下调和P-cadherin表达的上调,可能与银屑病角质形成细胞高度增殖有关。     

Loss-of-function variants of the filaggrin gene are not major susceptibility factors for psoriasis vulgaris or psoriatic arthritis in German patients

Psoriasis vulgaris and atopic dermatitis share a number of features such as chronic cutaneous inflammation and disturbed epidermal barrier function. Genome-wide scans have revealed a conspicuous overlap of susceptibility loci for both diseases involving chromosomal regions 1q21, 3q21, 17q25, and 20p12. Recently, two loss-of-function variants in the gene encoding filaggrin at 1q21 were shown to be strongly associated with atopic dermatitis. In view of a possible genetic overlap of the two skin diseases, we investigated 375 patients suffering from psoriasis vulgaris, 375 patients with psoriatic arthritis, and 376 control probands. Moreover we directly studied expression of filaggrin in 10 patients suffering from psoriasis vulgaris. Our immunohistochemical analysis revealed a checkered pattern with alternating positive broadened or almost absent filaggrin expression. However, no association was found for the two variants of filaggrin (FLG). We conclude that despite a markedly altered filaggrin expression in psoriatic skin, loss-of-function variants of the FLG gene are neither associated with psoriasis vulgaris nor with psoriatic arthritis. The abnormal staining might reflect the altered epidermal differentiation. Our findings imply that the genetic background underlying the epidermal barrier defect in psoriasis is distinct from that found in atopic dermatitis.     

寻常型银屑病皮损HIF-1α和血清IGF-Ⅱ水平的检测

目的：探讨缺氧诱导因子-1α（HIF-1α）和胰岛素样生长因子-II（IGF-II）在寻常型进行期银屑病发病中的意义.方法：对42例寻常型进行期银屑病患者中的20例取其皮损进行免疫组化法,检测其HIF-1α的表达和分布,同时取20例健康皮肤组织作对照;对另外22例患者的血清标本采用ELISA法,检测其IGF-II浓度,并取健康血清20例作对照.结果：皮损组HIF-1α表达阳性细胞数（25.21±24.45）明显高于对照组（3.80±7.27）（P〈0.05）,两组间阳性率差异有统计学意义;患者血清IGF-II水平（308.39±432.74）明显高于正常对照组（106.73±23.23）（P〈0.05）,两组间具有统计学差异.结论：患者皮损中HIF-1α的表达和血清IGF-II的水平均较正常水平明显增高,二者可能参与银屑病的发病过程.     

银屑病患者粒-单核巨噬细胞集落刺激因子表达的研究

目的 探讨脓疱性银屑病和寻常性银屑病患者皮损组织及外周血粒-单核巨噬细胞集落刺激因子（GM-CSF）表达的变化。方法 免疫组化法和双抗体夹心酶联免疫吸附法（ELISA）分别检测脓疱性银屑病和寻常性银屑病患者皮损组织和外周血中GM-CSF表达水平,并与正常人进行比较。结果 与正常人对照组相比,脓疱性银屑病组和寻常性银屑病组皮损组织中GM-CSF表达均增高（P < 0.01）,且脓疱性银屑病组皮损组织中GM-CSF表达高于寻常性银屑病组（P < 0.01）。与正常人对照组相比,脓疱性银屑病组和寻常性银屑病组外周血中GM-CSF含量均升高（P < 0.01）,且脓疱性银屑病组外周血中GM-CSF水平高于寻常性银屑病组（P < 0.01）。结论 GM-CSF可能参与银屑病的发病。     

Increased serum C‐reactive protein level in Japanese patients of psoriasis with cardio‐ and cerebrovascular disease

Psoriasis is a chronic inflammatory skin disease, which may be associated with metabolic syndrome accompanied by cardio‐ and cerebrovascular diseases. We investigated the relation between serum C‐reactive protein (CRP) and cardio‐ and cerebrovascular diseases in Japanese psoriasis vulgaris patients. Ninety‐seven psoriasis vulgaris patients and 79 healthy controls were assessed for serum CRP levels by immunoturbidimetry. The data were analyzed in terms of Psoriasis Area and Severity Index (PASI) scores, and comorbidity of cardio‐ and cerebrovascular disease and metabolic syndrome. Serum CRP levels in psoriasis vulgaris patients were significantly higher than those of healthy controls. There was no significant difference between male and female CRP levels in either psoriasis or healthy controls. No correlation was detected between PASI scores and serum CRP levels, either. Psoriasis with cardio‐ and cerebrovascular disease showed significantly higher CRP levels compared with those without the diseases. Furthermore, psoriasis with metabolic syndrome showed significantly higher serum CRP levels than those without the metabolic syndrome. In conclusion, serum CRP level is increased in psoriasis, and may be a useful marker for the prediction of the future risk of cardio‐ and cerebrovascular disease.     

Soluble E-selectin in sera of patients with atopic dermatitis and psoriasis—correlation with disease activity

Summary E-selectin endothelial leucocyte adhesion molecule-1 is expressed on endothelial cells in distinct inflammatory skin diseases. E-selectin mediates the adhesion between activated endothelium and different inflammatory cells. To evaluate soluble E-selectin as a marker of disease activity in patients with atopic dermatitis and psoriasis, the concentration of soluble E-selectin, determined by ELISA, was studied in sera of patients before and after treatment and compared with normal non-atopic controls. The disease severity was established using clinical scoring systems. Levels of soluble E-selectin were significantly elevated in sera of patients with atopic dermatitis and psoriasis (as compared with controls). Clinical improvement, after treatment, in patients with atopic dermatitis, but not in psoriasis, was associated with a significant decrease in serum levels of soluble E-selectin. There was a significant correlation of soluble E-selectin and disease activity in patients with atopic dermatitis. These data indicate that soluble E-selectin is another parameter to evaluate the inflammatory response in atopic dermatitis and psoriasis. Determination of soluble E-selectin may be a useful measure of disease activity in atopic dermatitis.     

Jagged1蛋白在银屑病、基底细胞癌及皮肤鳞状细胞癌中的表达

目的探讨Jagged1蛋白在银屑病、基底细胞癌及皮肤鳞状细胞癌中的表达及意义。方法采用免疫组化Envision法检测Jagged1蛋白在银屑病、基底细胞癌及皮肤鳞状细胞癌皮损中的表达。结果 Jagged1蛋白在寻常性银屑病患者皮损中呈阴性表达,在基底细胞癌及皮肤鳞状细胞癌中的表达较正常人皮肤增强,差异有统计学意义(P<0.01);Jagged1蛋白在基底细胞癌及皮肤鳞状细胞癌中的表达较银屑病增强,差异有统计学意义(P<0.05)。结论 Jagged1蛋白在银屑病发病机制中与角质形成细胞异常增生及真皮乳头血管增生等组织病理变化可能不相关,提示此蛋白可能与皮肤恶性肿瘤的异常增生有关。     

Evaluation of Sialyl Lewisx Antigen in the Skin and the Sera of Patients with Psoriasis Vulgaris

The roles of sialyl-Lewis^x antigen were evaluated in the pathogenesis of psoriasis. Sialyl-Lewis^xexpression was investigated immunohistochemically in the epidermis of normal human skin and erythematous lesional skin of psoriasis vulgaris by avidin-biotin-peroxidase complex procedures. A few sialyl-Lewis^x positive dendritic cells were detected in the epidermis of normal human skin. In 7 out of 9 cases of psoriasis vulgaris, the number of sialyl-Lewis^x-positive epidermal dendritic cells increased in the erythematous lesion over the adjacent normal skin; there were no marked changes in the numbers of CD1a-positive cells in the epidermis between the two skin types. In the double immunofluorescence studies, more than half of the sialyl-Lewis^x-positive epidermal cells in psoriatic erythema were stained with a monoclonal Lag antibody that specifically reacts with Birbeck granules and related structures of human Langerhans cells. Furthermore, we determined the changes in serum levels of sialyl-Lewis^x antigens in patients with psoriasis. Although levels in the sera were not significantly elevated over those of controls, the increases correlated with the degree of disease activity. These findings suggest that sialyl-Lewis^x antigen is possibly involved in the development of psoriasis.     

Therapeutic effects of antibacterial treatment for intractable skin diseases in Helicobacter pylori-positive Japanese patients

In order to understand the pathogenic relationship between Helicobacter pylori (H. pylori) and skin diseases, we examined the serum levels of IgG antibody against H. pylori and then performed gastroscopic examinations in Japanese patients with chronic skin diseases. These H. prylori-positive patients were treated with antibacterial eradication therapy, and therapeutic efficacy was evaluated. A total of 198 patients who were resistant to conventional therapies were randomly selected. They included 50 cases with chronic urticaria, 32 with pruritus cutaneous, 74 with atopic dermatitis, 15 with nummular dermatitis, 17 with prurigo chronica multiformis, 6 with psoriasis vulgaris, and 4 with erythroderma. Positive anti-H. pylori antibody was detected in 102 out of these 198 patients; more than half of the ones with chronic urticaria, pruritus cutaneous, nummular dermatitis, and prurigo chronica multiformis had positive antibodies. Gastroscopy was then performed in 48 cases with positive antibodies. Eradication therapy was effective in 60% of the patients with chronic urticaria, in 58% with pruritus cutaneous, in 54% with nummular dermatitis, and in 50% with prurigo chronica multiformis. In chronic skin diseases, persistent infection with H. pylori may be an eruption trigger and may cause deterioration of the disease into an in tractable and chronic form.     

寻常型银屑病与单纯疱疹病毒1型相关性的研究

目的 探讨寻常型银屑病与单纯疱疹病毒1型(HSV-1)的可能相关性。方法 应用PCR法检测患者皮损、外周血单一核细胞(PBMCs)和咽拭子中HSV-1DNA,ELISA法检测患者血清中抗HSV-1的IgM、IgG抗体,并与正常人对照做比较。结果 患者皮损、PBMCs和咽拭子中HSV-1DNA检出率分别为37.5%、18.6%和18.8%,血清中抗HSV-1的IgM、IgG抗体检出率分别为37.2%和53.5%.经χ²检验,患者皮损、PBMCs中HSV-1DNA和血清中IgM抗体检出率显着高于正常人对照,点滴状患者的皮损、PBMCs和咽拭子中HSV-1DNA以及血清中抗HSV-1IgM抗体检出率显着高于斑块状患者。结论 寻常型银屑病尤其是皮损呈点滴状者与HSV-1显着相关,患者可能存在HSV-1的近期感染。     

Serum β2-microglobulin levels in psoriatic patients

β₂-Microglobulin (β₂-M) is a low molecular weight protein forming the light chain of the class I major histocompatibility complex. It is found on the cell surface of all nucleated cells. Its serum concentration is found to be increased in kidney diseases, neoplasia, AIDS, chronic inflammation and autoimmune diseases. Inflammation plays an important role in the pathogenesis of psoriasis, especially psoriatic arthritis and immunological upset is one of the most implicated factors in the etiology of the disease. In this study, the sera β₂-M levels were evaluated in cases diagnosed as psoriasis vulgaris and psoriatic arthritis, and a statistically significant increase was found in cases of psoriatic arthritis compared to those of psoriasis vulgaris and the control group.     

CCL27及其受体在银屑病血清和皮损中的表达

目的:检测趋化因子CCL27及其受体CCR10在银屑病患者血清和皮损中的表达.方法:采用ELISA方法检测40例银屑病患者血清CCL27水平,并采用免疫组化SP法检测其中25例患者皮损和15例正常人皮肤中CCL27和CCR10的表达情况.结果:(1)银屑病患者血清CCL27水平(799.94±214.54)pg/mL,高于健康人对照组(373.10±92.84)pg/mL,P<0.001.(2)在寻常型银屑病患者皮损,CCL27强烈表达于皮肤基底层至颗粒层,CCR10表达于真皮浅层淋巴细胞,表达阳性率明显高于正常人皮肤(P<0.001).结论:CCL27与受体CCR10相互作用,参与了银屑病的发病.     

Heat shock proteins 60 and 70 expression of cutaneous lichen planus: comparison with normal skin and psoriasis vulgaris

BACKGROUND: Heat shock proteins (HSPs) are expressed by most living cells and play fundamental roles in many biological processes. Their synthesis increases by a variety of stresses in order to enable cellular survival. Although it is known that they play an important role in immune and inflammatory responses of the skin, the role of HSPs in the pathogenesis of skin diseases has been studied in only limited skin diseases. Lichen planus (LP) is a relatively common papulosquamous dermatosis, and cell-mediated immunity plays an important role in its pathogenesis. Although an altered expression of certain HSPs was reported in oral LP lesions, the expression of HSPs in cutaneous lesions of LP has not been investigated. In this immunohistochemical study, we aimed at investigating the role of HSPs in the pathogenesis of LP by studying whether there is any difference in HSP expression in cutaneous lesions of LP when compared to normal skin and psoriasis vulgaris (PV). METHODS: Formalin-fixed paraffin-embedded skin biopsy specimen blocks from LP patients (n = 39), patients with psoriasis (n = 20), and normal skin controls (n = 20) were used in the study. Antibodies to HSPs 60 and 70 were applied immunohistochemically by using streptavidin-biotin-horseradish peroxidase complex. An immunoreactivity intensity distribution index (IRIDI) was calculated to express the proportion of the immunoreactive cells as well as the staining intensity in different layers of the epidermis. RESULTS: The mean IRIDI scores for HSP60 expression in the basal, suprabasal, and superficial epidermal layers of cutaneous LP were moderately higher than those of normal skin, but not different from those of PV skin. These scores for HSP70 in lesions of LP were moderately lower than those for normal skin in the basal layer, but not significantly different from normal in the other two layers. Scores for HSP70 in PV lesions were markedly lower in all three layers. In the cells of the inflammatory infiltrates (mostly lymphocytes), HSP60 scores for LP were moderately higher, compared to those for PV, whereas scores for HSP70 were much lower for LP and very much lower for PV. CONCLUSIONS: Significantly altered levels of HSP proteins were found in cutaneous LP lesions in comparison with normal skin and psoriasis, suggesting the role of HSPs in the pathogenesis of LP.     

The skin microbiome and the gut-skin axis

The microbiome plays a significant role in human health, homeostasis, immune system, and disease pathogenesis. Disrupted communication between the microbiome and host has been extensively studied in gastrointestinal diseases. To a lesser extent, there is emerging research on the skin microbiome and its connection with the gut, referred to as the gut-skin axis and its effects on dermatologic conditions. A basic overview will be provided of the gut and skin microbiome with a focus on the impact of this connection on cutaneous diseases, such as psoriasis, atopic dermatitis, rosacea, acne vulgaris, photoaging, and cutaneous wounds. In addition, we shall discuss nutrition-based approaches mediated through the gut-skin axis and topical treatments that could serve as potential adjunctive management by manipulation of the microbiome. In particular, there is a growing body of research on oral probiotics, prebiotics, and dietary modifications that may help improve symptoms for a variety of dermatologic conditions in select demographic groups.     

银屑病患者血清和皮损中血管内皮细胞粘附分子的对比研究

目的 探讨银屑病患者血清和皮损中4种血管内皮粘附分子表达与银屑病疾病活动性之间的关系。方法 采用ELISA法检测36例银屑病患者治疗前后和36例健康人的血清中可溶性粘附分子（sICAM-1、sICAM-3、sVCAM-1、sELAM）的浓度。同时用ABC免疫组化染色技术检测了36例银屑病患者皮损和临床治愈处皮肤粘附分子（ICAM－1、ICAM－3、VCAM－1、ELAM）的表达情况。结果 与正常人相比，银屑病患者皮损部位4种粘附分子的原位表达呈明显上调（P＜0.005），同时患者血清中4种可溶性粘附分子浓度也明显升高（P＜0.001）。经治疗后银屑病患者皮损部位4种粘附分子的原位表达明显下调（P＜0.05），同时血清中4种可溶性粘附分子浓度比前也下降（P＜0.05）；血清中4种可溶性粘附分子的浓度与银屑病疾病活动严重指数（PASI）均呈正相关，但治疗前后sVCAM-1的水平上升和下降的幅度最大，且与PASI的相关性最好。结论 血管内皮细胞粘附分子参与银屑病的发病机制；患者血清中可溶性粘附分子浓度的升高可能与皮损部位血管内皮细胞上相应的粘附分子高表达有关；血清VCAM－1的水平可以作为反映银屑病疾病活动的一个新的敏感指标。     

Phospholipase A2 activating factor in sera of patients with psoriasis vulgaris

Phospholipase A2 (PL-A2) has been known to be activated in either affected or un-affected skin of patients with psoriasis vulgaris. The present study was designated to investigate whether or not there is a factor activating PL-A2 in their sera, using cultured murine epidermal cells (NCTC-2544). The cultured cells prelabeled with 3H-arachidonic acid (3H-AA). After adding a serum, the release of 3H-AA into medium from the cells was measured. The sera from 20 patients with psoriasis vulgaris showed significantly increased releases of 3H-AA as compared with those by sera from 10 healthy individuals, indicating that there may be a PL-A2 activating factor in the sera of psoriasis vulgaris. The PL-A2 activating factor in the patient sera was not inactivated with added 2 different PL-A2 inhibitors. The sera were not able to produce 3H-AA from 3H-AA labeled phospholipids. Therefore, PL-A2 activating factor does not seem to be PL-A2 itself existing in the sera. Through heat stability, dialysis, and fractionation studies, the PL-A2 activating factor in sera was found to be a protein, which had a molecular weight of more than 50 kd and was stable at 56 degrees C.