MONOCYTE ADHESION TO FIBRONECTIN IN PSORIASIS

Background. After vascular extravasation, mononuclear cells (MNC) undergo chemotaxis and adhesion to extracellular matrix proteins, resulting in their differentiation into macrophages. Although endothelial adhesion and chemotaxis are altered in psoriasis, MNC adhesion to extracellular matrix proteins has not been previously studied in the disease. Since MNC adhesion to endothelial cells is abnormally regulated in psoriasis by TGF-beta, we tested they hypothesis that in psoriasis substance P also regulates the adhesion of monocytes to the extracellular matrix protein fibronectin. Methods. Monocytes from 16 normal controls and 11 psoriatic individuals were isolated and purified using a two-step gradient centrifugation procedure. Adhesion to fibronectin was studied by plating monocyte suspensions onto fibronectin-precoated microtiter plates. The number of adherent cells was quantified by measuring their hex-osaminidase activity. Results. Although statistically significant differences in the basal (unstimulated) adhesion or in the substance P-stimulated adhesion between normal control monocytes and those obtained from psoriatic individuals were not observed, a subpopulation of psoriatics was identified who responded to substance P. Furthermore, this in vitro response to substance P was correlated with the clinical status of the subpopulation which was characterized by unstable psoriasis triggered by stressful life events. Conclusions. The results of this study indicate that priming of monocytes by the extracellular matrix protein fibronectin or by elevated levels of substance P are not critical steps in the pathogenesis of stable, chronic psoriasis. Substance P may contribute to the appearance of new lesions in some individuals with unstable psoriasis.     

某些粘附分子在皮肤血管炎中表达的研究

目的 研究某些细胞粘附分子（ＩＣＡＭ－１，ＶＣＡＭ－１，ＥＬＡＭ－１）在皮肤血管炎中的表达及其意义。方法 采用免疫组织化学方法研究皮肤血管炎皮损部和非皮损部细胞粘附分子的表达。结果 皮肤血管炎皮损部粘附分子表达均高于非皮损部及正常皮肤，ＶＣＡＭ－１与ＥＬＡＭ－１表达呈正相关。结论 患者皮损粘附分子（ＩＣＡＭ－１，ＶＣＡＭ－１，ＥＬＡＭ－１０表达上调，提示其参与皮肤血管炎的发病机制。     

The effect of methotrexate on the expression of cell adhesion molecules and activation molecule CD69 in psoriasis

BACKGROUND: The mechanism of the action of methotrexate (MTX) in the treatment of psoriasis has not been completely elucidated. OBJECTIVE: To assess the effect of MTX on the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, activation molecule CD69 and T-cell phenotype in skin specimens from patients with psoriasis. METHODS: We performed an immunohistochemical analysis of the expression of T-cell phenotype and cell adhesion/activation molecules in skin biopsies from patients with psoriasis treated with a fixed dose of MTX (12.5 mg/week). To determine data on the epidermal/dermal T-cell infiltration we carried out a manual quantification. RESULTS: Skin samples prior to therapy showed a moderate to severe inflammatory infiltrate, mainly due to T lymphocytes with a helper/inducer (CD4) phenotype. Most of these cells also expressed ICAM-1 and VCAM-1. Blood vessels showed expression of E-selectin and VCAM-1, and keratinocytes were positive for ICAM-1 staining. The cell infiltrate was reduced after therapy, as well as the expression of cell adhesion molecules. However, we also noted the persistence of the T lymphocyte phenotype CD8(+), expressing the CD69 activation molecule, after the MTX treatment. CONCLUSIONS: MTX downregulates the expression of some adhesion molecules, a phenomenon that may contribute to its anti-inflammatory therapeutic effect in psoriasis. The infiltrating T cells post-treatment have an activated cytotoxic phenotype, which may suggest a pathogenic role in the continuation and/or recurrence of psoriasis.     

PUVA suppresses the expression of cell adhesion molecules of lymphocytes

Abstract To determine the therapeutic mechanism of PUVA in psoriasis vulgaris, the effects of PUVA on activated T lymphocytes were investigated in vitro. Peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers were activated with Con A stimulation (Con A blasts). Both untreated PBMC and Con A blasts were irradiated with UVA light in the presence of 8-methoxypsoralen (8-MOP). The expressions of CD4, CDS, VLA-4 and LFA-1 of PBMC and Con A blasts were stained with each monoclonal antibody and the intensity of fluorescence was analyzed by FACScan. PUVA-treated PBMC showed decreased response to both Con A and PHA stimulation. PUVA treatment also suppressed the IL-2 production of Con A blasts and IL-2 response of PBMC with increasing UVA fluence. The expressions of LFA-I, VLA-4, CD4, CDS and CD25 (IL-2R) molecules were decreased in PUVA-treated Con A blasts. Con A blasts were more sensitive than untreated PBMC to PUVA treatment. These results suggest that the therapeutic effects of PUVA on psoriasis vulgaris can be induced by suppression of the expression of cell surface molecules of activated T lymphocytes.     

血小板和血管内皮细胞在系统性红斑狼疮出血倾向中的意义

本文从血小板和血管内皮细胞方面对系统性红斑狼疮(SLE)出血倾向进行探讨,结果发现活动期SLE除存在外周血小板破坏过多,骨髓巨核细胞代偿增生外,同时有血浆TXB_2含量减低、血小板聚集功能异常;还存在内皮细胞产生的活性物质(6-Keto-PGF_1α,vWf:Ag和Fn)显著升高(P均<0.01)。并探讨了其发生可能的机理和临床意义。     

寻常性银屑病患者T细胞增殖功能的测定

本文采用植物血凝素(PHA)和刀豆蛋白A(ConA)诱导的T淋巴细胞转化试验测定了寻常性银屑病患者和正常人的T细胞增殖功能。结果表明:银屑病患者对PHA的增殖功能与正常人相比差异无显著性意义(P>0.05),而对ConA的增殖功能明显降低(P<0.01),且与疾病的活动性无关。该结果提示本病存在T细胞功能的缺陷。     

PHARMACOLOGIC MODULATION BY CETIRIZINE OF SOME ADHESION MOLECULES EXPRESSION IN PSORIATIC SKIN LESIONS

Background. Adhesion molecules play a major role in the pathogenesis of inflammatory skin diseases by regulating lymphocyte trafficking and homing in an inflamed area. Methods. The expression of the lymphocyte function-associated antigen-1 (LFA-1) and of its ligand, the intercellular adhesion molecule-1 (ICAM-I) has been studied in psoriatic skin lesions of 10 patients with guttate, nummular, and palmoplantar psoriasis. In addition, the peculiar immunophenotype of infiltrating cells (CD3, CD4, CD8, CD25) and their correlation with HLA-DR expression before and after treatment with oral cetirizine, a highly selective, third generation H_1-receptor antagonist has been examined using the labeled avidin biotin (LAB) system. Results. Cetirizine treatment modulated in vivo the expression of adhesion molecules LFA-I/ICAM-1 as shown in all cases by decreased levels of their expression on keratinocytes and on dermal endothelial cells (P < 0.001). The expression of HLA-DR on keratinocytes and endothelial cells was also inhibited after treatment. The numbers of infiltrating CD3–, CD4–, CD8–positive cells were reduced, whereas there was no significant modification of CD25–positive cells within the epidermis and the dermis. Conclusion. This open clinical trial suggests that cetirizine could be effective in treating psoriasis: (1) for its symptomatic control on itching; (2) for its immunopharmacologic modulation of leukocyte integrins and on the immunophenotype pattern of infiltrating and resident cells, and (3) for contributing to the clearing of the lesions clinically.     

DEOXYRTBONUCLEIC ACID (DNA) LOSS, CELL LOSS AND CELL TURNOVER IN EXFOLTATIVE PSORIASIS

SUMMARY. DNA was measured in the naturally exfoliated skin scales from 2 patients with generalized exfoliative psoriasis. The mean DNA values indicated that the rate of loss of cells from the skin in these 2 patients was approximately 4 million/min. No DNA was found in skin scales from 3 patients with ichthyosis vulgaris. The difference in DNA content of scales in these disorders appeared to reflect the fact that psoriatic scales were nucleated, whereas the ichthyotic ones were not. It is suggested that the DNA content of psoriatic scales is a reflection of the high turnover of epithelial cells in this condition.     

Vascular adhesion protein-1 (VAP-1) is overexpressed in psoriatic patients

BACKGROUND: Vascular adhesion protein (VAP)-1 is an adhesion molecule with an enzymatic activity that partakes in the migration process of lymphocytes. OBJECTIVES: The aim of this study was to investigate the expression of VAP-1 in the skin and serum of psoriatic patients. MATERIAL AND METHODS: Seventy-one patients suffering from psoriasis aged between 23 and 89 years were included in the study. The mean psoriasis severity assessed according to the psoriasis area and severity index was 14.2+/-9.6 points. The soluble VAP-1 serum concentration was evaluated by ELISA and VAP-1 expression in the skin (nine patients) immunohistochemically. RESULTS: The serum concentration of soluble VAP-1 was significantly higher in psoriatic patients than in healthy controls (403.4+/-130.8 ng/mL vs. 246.4+/-68.0 ng/mL; P<0.0001). No significant relationships were found between sVAP-1 concentration and studied clinical parameters, except the presence of pruritus. Mean number of VAP-1 positive vessels in psoriatic skin, both lesional (19.8+/-1.4) and non-lesional (9.4+/-1.4), was significantly higher than in healthy skin (5.4+/-1.5; P<0.005). Lesional psoriatic skin demonstrated significantly more VAP-1 positive vessels than non-lesional skin (P<0.01). CONCLUSIONS: Significant overexpression of VAP-1 in both lesional and non-lesional psoriatic skin and higher serum level of soluble VAP-1 in psoriatic patients may indicate the role of VAP-1 in chronic inflammation occurring in psoriasis. However, because of lack of correlation between soluble VAP-1 serum levels and psoriasis severity this hypothesis needs further investigation.     

Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin

A positive correlation between disease severity and the frequency of cutaneous lymphocyte-associated antigen (CLA)-positive T cells in the blood of untreated patients with psoriasis has been previously observed. A dose-dependent inverse relationship between disease severity and the frequency of circulating CLA(+) T cells in psoriasis patients on methotrexate (MTX) treatment is reported. Circulating T cells from a patient with psoriasis were monitored for CLA expression on a daily basis for 5 weeks. A decrease in the intensity and frequency of CLA(+) mononuclear leucocytes was consistently observed in the blood during the first 3-4 days after each MTX intake, but the CLA expression increased thereafter until the next weekly dose was taken. The MTX treatment of this patient was then discontinued for 16 days, and a marked subjective exacerbation was reported within 9 days, which was confirmed objectively (laser Doppler perfusion imaging) after 11 and 16 days. Biopsies taken 4 days after the last MTX intake showed only a few mononuclear leucocytes in lesional skin, but the exacerbation coincided with a marked increase in CLA expression by mononuclear blood leucocytes, followed by an increase in endothelial E-selectin and a striking influx of CLA(+) mononuclear cells into lesional skin. Conversely, a clinical improvement after the patient resumed the MTX treatment was associated with reduction in CLA expression by mononuclear cells in the blood, downregulation of endothelial E-selectin and an approximate threefold decrease in mononuclear leucocyte infiltration of lesional skin. No MTX-associated changes were detected in the expression of very late antigen-4, vascular cell-adhesion molecule-1 nor the late activation marker CD25. It is concluded that MTX decreases the expression of CLA and E-selectin and that this may be a major mechanism for the therapeutic effect of MTX on psoriatic skin lesions.     

蘘荷氯仿提取物对人真皮微血管内皮细胞表面黏附分子的表达及淋巴细胞黏附作用的影响

【摘要】 目的 探讨蘘荷对人真皮微血管内皮细胞（HDMEC）表面黏附分子的表达及淋巴细胞黏附作用的影响。方法 用蘘荷氯仿提取物（CFMG）与肿瘤坏死因子（TNF）-α/白介素（IL）-1α分别诱导或按不同顺序联合诱导HDMEC不同时间,用酶联免疫吸附试验（ELISA）检测细胞间黏附分子-1（ICAM-1）、血管细胞间黏附分子-1（VCAM-1）和E选择素表达水平。使用γ计数器测定HDMEC对T淋巴细胞和Ramos细胞的黏附能力。用Sigma Plot 12软件包对数据进行配对t检验。 结果 与0.2%二甲基亚砜相比,CFMG轻度下调HDMEC表面ICAM-1、VCAM-1和E选择素表达水平（均P > 0.05）;与细胞培养液相比,TNF-α显著上调ICAM-1、VCAM-1、E选择素的表达水平（均P < 0.01）,IL-1α上调ICAM-1和E选择素的表达水平（均P < 0.01）,对VCAM-1轻度上调（P > 0.05）。CFMG预处理可显著抑制TNF-α和IL-1α对黏附分子表达水平的上调作用（均P < 0.01）,但是CFMG后处理对经TNF-α和IL-1α刺激后升高的黏附分子表达水平影响不大（均P > 0.05）。与0.2% DMSO相比,CFMG轻度降低HDMEC对T淋巴细胞和Ramos细胞黏附率（均P > 0.05）,而与细胞培养液相比,TNF-α和IL-1α显著提高其黏附率（均P < 0.01）。 结论 蘘荷脂溶性粗提物可能通过阻遏前炎症细胞因子TNF-α和IL-1α对HDMEC表面黏附分子的上调作用,抑制组织中炎细胞浸润从而起到抗炎作用。 【关键词】 蘘荷; 内皮细胞; 细胞黏附分子; 细胞因子     

皮肤白细胞碎裂性与淋巴细胞性血管炎某些粘附分子表达的比较研究

目的：比较细胞粘附分子ＩＣＡＭ－１、ＶＣＡＭ－１和ＥＬＡＭ－１在皮肤白细胞碎裂性和淋巴细胞性血管炎的表达及其意义。方法：采用免疫组化方法研究两型血管料的粘附分子表达情况。结果：角质形成细胞ＩＣＡＭ－１在淋巴细胞性血管炎（８５．７１％）表达明显高于白细胞碎裂性血管炎（１１．１１％（Ｐ〈０．０００１）,ＩＣＡＭ－１、ＶＣＡＭ－１、ＥＬＡＭ－１在两型血管炎血管内皮中表达无区别（Ｐ值分别为１,０．０６８,０．４６）。结论：无论在白细胞碎裂性还是淋巴细胞性血管炎、粘附分子表达均上调。两种血管炎粘附分子表达率的不同反应了局部细胞因子释放的不同,这对揭示血管炎发病机理将具有重要意义。     

Research in practice: the systemic aspects of psoriasis

Psoriasis is a common, chronic inflammatory and frequently severe skin disease. Recent epidemiologic studies have documented an increased cardio‐vascular mortality in psoriasis patients. Our own work focuses on endothelial cells as mediators for the development of inflammatory infiltrates and more recently as a victim of injury caused by infiltrating cells. In this context, we have measured systemic effects of this seemingly cutaneous inflammation, which results in a metabolic state much like that in patients developing diabetes mellitus and insulin resistance. The latter is an important pathomechanism causing endothelial cell dysfunction and subsequently cardiovascular diseases such as myocardial infarction or stroke. Co‐morbidities observed in psoriatic patients therefore represent complications of the accompanying systemic inflammation and are likely to be mediated through the mechanism of insulin resistance. As psoriasis is a risk factor for cardiovascular diseases, its adequate management must include the treatment of other known risk factors. Dermatologists should discuss the elevated cardiovascular risk with their psoriasis patients and encourage them not to smoke and to normalize their body weight.     

SQUAMOUS CELL CARCINOMA IN POROKERATOSIS IN TWO PATIENTS

Malignancy arising in porokeratoses is a well recognised but infrequently reported complication. Histological studies suggest that malignancy arises from the abnormal clone of keratinocytes which produce the cornoid lamella. We report two cases of squamous cell carcinoma arising in porokeratoses and postulate genetic, environmental and host factors as important in the evolution of their malignancy.     

FORMULATION OF 1-ALPHA,25-DIHYDROXYCHOLECALCIFEROL TOPICAL OINTMENT FOR PSORIASIS TREATMENT

A means of accurate and rapid formulation of 1-Alpha,25-dihydroxycholecalciferol topical ointment is described. The accuracy of the formulation technique is within 95% of the theoretical ointment concentration (lug/gram of petrolatum base). Moreover, the stability of the formulated ointment is examined at room temperature (21 degrees C) and refrigerated (2 degrees C) over 40 days storage. When protected from light the loss of potency is 6% at 21 degrees C and negligible at 2 degrees C.     

CURRENT CONCEPTS IN THE PATHOGENESIS OF PSORIASIS

Psoriasis is a multi-factorial skin disease with a complex pathogenesis. Various factors which have been suggested to play a key role in the pathogenesis are T cells, antigen presenting cells (APC''s), keratinocytes, Langerhans'' cells, macrophages, natural killer cells, an array of Th1 type cytokines, certain growth factors like vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), and others. It has been hypothesized that the disease starts with the activation of T cell by an unknown antigen, which leads to secretion of an array of cytokines by activated T cells, inflammatory cells, and keratinocytes. The characteristic lesion of psoriasis is due to the hyper-proliferation of the keratinocyte. Activated Langerhans'' cells migrate from skin to lymph nodes presenting the antigen to nodal naïve T cells (cells that have not been activated by antigen previously). The T cells activated by non-antigen-dependent mechanism may, however, become antigen-specific memory cells that react with a cross-reactive auto-antigen such as keratin (molecular mimicry). The genetic background of the disease may be suggested from the fact that concordance rate is 63–73% in monozygotic twins, as compared to 17–20% in dizygotic twins. Several disease susceptibility loci have been suggested as predisposing factors, PSORS1-PSORS9.