Aberrant expression of complement regulatory proteins, membrane cofactor protein and decay accelerating factor, in the involved epidermis of patients with vitiligo

BACKGROUND: Vitiligo is a pigmentary disorder of the skin characterized by the complete absence of melanocytes from the lesion. Complement-activating antimelanocyte antibodies have been implicated in vitiligo pathogenesis. As membrane regulators of complement activation, membrane cofactor protein, decay accelerating factor and CD59 protect cells from elimination by autologous complement, their absence or downregulation on melanocytes may be associated with autoantibody and complement-mediated melanocyte destruction in vitiligo. OBJECTIVES: We studied the expression of these regulatory proteins in non-lesional, perilesional and lesional vitiligo skin compared with those of control specimens. METHODS: We used immunohistochemistry to study the expression of the regulatory proteins, and flow cytometric analysis of cultured melanocytes to investigate possible constitutive changes in the expression levels of these molecules. We also investigated whether melanocytes can influence keratinocyte susceptibility to autologous complement by regulating keratinocytic decay accelerating factor and membrane cofactor protein expression levels. RESULTS: Immunohistochemical data showed that expression of membrane cofactor protein and decay accelerating factor in whole epidermis was lower in lesional and perilesional skin in comparison with non-lesional skin. The reduced in situ expression appeared to be specific to vitiligo. However, coculture experiments indicated that melanocytes do not influence keratinocyte susceptibility to autologous complement. Further, flow cytometric analysis of cultured melanocytes convincingly demonstrated that non-lesional vitiligo and control melanocytes have comparable decay accelerating factor, membrane cofactor protein and CD59 expression levels. CONCLUSIONS: It is therefore concluded that there is no constitutive melanocyte defect per se that could be related to the in vivo expression of these molecules in vitiligo. Nevertheless, the present data suggest that both keratinocytes and melanocytes in the involved vitiliginous whole epidermis express lower levels of decay accelerating factor and membrane cofactor protein compared with controls that could render them more vulnerable to autologous complement attack.     

The vascular lesions associated with skin necrosis in renal disease

Three renal allograft recipients and one uraemic patient presented with skin necrosis. In all cases, the subcutaneous arteries and arterioles were narrowed or occluded by mural calcification with or without intimal fibrosis. A review of the literature shows that uraemic patients or allograft recipients with skin necrosis involving the trunk or thighs have a poor prognosis while recovery is common in patients with more peripheral lesions. The aetiology of the arterial lesions is unknown. Their relationship to renal disorders and/or hyperparathyroidism is uncertain and therapy remains unsatisfactory.     

Stable and strong expression of basic fibroblast growth factor in naevus cell naevus contrasts with aberrant expression in melanoma

Summary It has been proposed that basic fibroblast growth factor (bFGF) is an autocrine growth factor of melanoma cells, in contrast with normal melanocytes where bFGF acts as a paracrine growth factor. As this notion is mostly based on the different requirements for bFGF in cultures of benign and malignant pigment cells in vitro, we performed an immunohistochemical study to examine bFGF expression in vivo using paraffin sections from naevus cell naevi (NCN) and malignant melanoma (MM). All the NCN (n=7) showed strong and homogeneous expression of bFGF protein, whereas the primary MMs (n=5) showed heterogeneous expression, with a population of negative cells. Metastatic MMs (n=5) also showed heterogeneous expression, and had a greater population of negative cells. These results suggest that bFGF has some, as yet unidentitied, role in the growth of benign NCN, and that overexpression of bFGF is neither a prerequisite for melanoma genesis nor for progression to metastatic MM.     

E‐cadherin and p120ctn protein expression are lost in hidradenitis suppurativa lesions

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease affecting the pilosebaceous units in the axilla, groin and buttocks. While the pathogenesis of HS is not clear, mechanical stress exacerbates HS. In this study, we aimed to determine whether intracellular adhesive junctions may be aberrant in HS patient skin. Strikingly, we observed loss of E‐cadherin and p120ctn protein expression, two key adherens junction proteins, in ~85% of HS severe skin lesions. Moreover, loss of protein expression was apparent in non‐lesional skin from HS patients and the degree of loss positively correlated with HS Hurley Stage of disease. E‐cadherin expression was unaltered in other inflammatory skin conditions including chronic wound epithelium, atopic dermatitis, and acne vulgaris compared with healthy skin suggesting that its loss may be uniquely relevant to HS pathogenesis. A complete loss of α‐catenin, β‐catenin and ZO‐1 was not observed; however, some cytoplasmic staining of the catenins was noted in HS epithelium. We also demonstrated diminished desmosome size in HS lesional skin. Overall, our data suggested that loss of adherens junction proteins and diminished desmosome size in HS skin contributes to the skin's inability to withstand mechanical stress and provides rationale as to why mechanical stress exacerbates HS symptoms.     

Basement membrane and connective tissue proteins in early lesions of Kaposi's sarcoma associated with AIDS

Nearly one-third of all young homosexual men diagnosed as having acquired immune-deficiency syndrome (AIDS) develop a disseminated form of dermal Kaposi's sarcoma (KS). Although the histogenesis of KS cells is unclear, certain evidence suggests that the aberrant cells are of endothelial derivation. We have examined the presence and distribution of connective tissue-specific and basement membrane-specific macromolecules by indirect immunofluorescence and immunoperoxidase staining of frozen sections in early cutaneous lesions of KS from individuals with AIDS. The KS cells typically line the spaces between collagen bundles of the reticular dermis. When stained for the connective tissue-specific glycoprotein fibronectin, all Kaposi's sarcoma lesions showed an intense staining pattern, revealing a complex array of linear deposits of antigen that outlined the exterior surface of the collagen bundles. Antibodies to laminin and type IV collagen, both basement membrane-specific macromolecules, produced an intense staining pattern similar to that found with the anti-fibronectin antiserum, indicating that all 3 antigens are closely codistributed. In contrast, antibodies to type I collagen, the major collagen of the dermis, uniformly stained the collagen bundles in the KS lesions and in the normal control skin. Antiserum to factor VIII-associated antigen, an antigen specific to blood vascular endothelium, frequently stained the KS lesions but the staining pattern was diffuse and of variable intensity. The results suggest that KS cells are derived from the endothelium of the blood microvasculature and maintain their secretory phenotype of secreting basement membrane-specific macromolecules.     

Ultraviolet B-induced skin angiogenesis is associated with a switch in the balance of vascular endothelial growth factor and thrombospondin-1 expression

We have previously shown that targeted overexpression of the endogenous angiogenesis inhibitor thrombospondin-1 (TSP-1) in the epidermis prevented chronic ultraviolet B (UVB)-induced angiogenesis and cutaneous photodamage in mice, suggesting that angiogenesis plays a critical role in the mediation of UVB effects on the skin. Nevertheless, the molecular regulation of angiogenesis factors and inhibitors by acute UVB irradiation still remains to be elucidated. We performed quantitative analyses of cutaneous vascularity and of vascular endothelial growth factor (VEGF) and TSP-1 expression after acute UVB irradiation of mouse skin. Skin vascularity in the upper dermis was greatly increased until day 8 after a single dose of UVB irradiation (200 mJ per cm2) and associated with upregulation of VEGF mRNA expression, with downregulation of TSP-1 mRNA, and with protein expression in the hyperplastic epidermis. After 13 days, skin vascularity was normalized with downregulation of VEGF mRNA expression and upregulation of TSP-1 mRNA expression to the levels observed in non-UVB-irradiated skin. In contrast, the angiogenic UVB response was prolonged in TSP-1-deficient mice. We found a pronounced induction of the TSP-1 receptor CD36 in CD31-positive vessels on day 8 after UVB irradiation, associated with vascular endothelial cell apoptosis. These results demonstrate that acute UVB irradiation leads to a shift toward a proangiogenic environment and they suggest that the balance between VEGF and TSP-1 plays a critical role in the control of angiogenesis and vascular regression induced by acute UVB irradiation.     

Acantholysis and spongiosis are associated with loss of syndecan-1 expression

BACKGROUND: Syndecan-1, a heparan sulfate proteoglycan present on the membrane of keratinocytes, functions in intercellular adhesion. Acantholysis and spongiosis are both characterized by diminished intercellular adhesion that may lead to blister formation. In spongiotic conditions, desmosomal stretching occurs prior to cell separation while in acantholytic conditions, cell separation occurs without stretching. While many of the structural relationships have been described, the molecular interactions regulating keratinocyte to keratinocyte adhesion are not yet fully understood. METHODS: Sections from ten cases of Grover's disease, two pemphigus vulgaris, one pemphigus foliaceus, one bullous pemphigoid, two herpes simplex, and ten spongiotic dermatitis were stained with BB-4, a monoclonal anti-syndecan-1 antibody. RESULTS: Nine of ten Grover's, all three pemphigus, and both herpes cases showed absent or markedly decreased syndecan-1 expression by acantholytic keratinocytes, with a sharp delineation from adjacent unaffected skin. The remaining Grover's case showed moderate loss of syndecan-1 expression. The pemphigus foliaceus case showed retention of staining along the basal cell layer, but expression was lost in the mid stratum spinosum. All ten spongiotic cases showed a diffuse mild decrease in staining, with loss of syndecan-1 expression surrounding microvesicles. Bullous pemphigoid, as expected, did not show loss of syndecan expression. CONCLUSIONS: The loss of syndecan-1 expression evident in acantholytic conditions and, to a lesser extent in spongiotic conditions, may contribute to the decreased intercellular adhesion characteristic of these lesions.     

Scarring skin lesions of discoid lupus erythematosus are characterized by high numbers of skin-homing cytotoxic lymphocytes associated with strong expression of the type I interferon-induced protein MxA

BACKGROUND: Infiltrating T lymphocytes are considered to play a major pathological role in skin lesions of cutaneous lupus erythematosus (CLE), a cutaneous autoimmune disease of unknown aetiology. Earlier histological studies revealed that the inflammatory infiltrate in CLE skin lesions is predominantly composed of T lymphocytes, with a slight predominance of CD4+ over CD8+ T cells, but failed to explain the development of scarring skin lesions, characteristic for chronic discoid lupus erythematosus (CDLE). Because recent investigations have highlighted the relevance of cytotoxic lymphocytes in autoimmune tissue destruction, we hypothesized that the scarring CDLE lesions might be caused by cytotoxic T lymphocytes. OBJECTIVES: To analyse skin biopsies of 15 patients with CLE [10 female, five male; localized CDLE (lCDLE), n = 5; disseminated CDLE (dCDLE), n = 5, subacute CLE (SCLE), n = 5] and five control biopsies taken from healthy controls and to characterize the inflammatory infiltrate. Methods We used immunohistochemistry, including staining for the cytotoxic molecule granzyme B, the skin-homing molecule cutaneous lymphocyte antigen (CLA) and the protein MxA, which is specifically induced by type I interferons (IFNs). RESULTS: We found a strong coexpression of granzyme B and CLA on lesional lymphocytes of patients with scarring lCDLE and dCDLE, which was significantly enhanced when compared with nonscarring SCLE and healthy controls. The increased expression of granzyme B was closely associated with the lesional expression of the type I IFN-induced protein MxA. CONCLUSIONS: Our results provide evidence that type I IFNs and potentially autoreactive cytotoxic lymphocytes targeting adnexal structures are highly associated with scarring lupus erythematosus lesions and might be responsible for their scarring character.     

Psoriasis lesions are associated with specific types of emotions. Emotional profile in psoriasis

Background

At present there is still controversy about the relationship between emotional stress and psoriasis lesions. Most of the published literature does not include the broad spectrum of emotional response.

Objective

The aim of this study was to evaluate the association between skin lesions and emotional state in a large sample of patients with psoriasis.

Methods

823 psoriasis patients were recruited (mean age 45.9 years, 55.7% female) and answered two online questionnaires: lesion severity and current extension were evaluated using a self-administered psoriasis severity index (SAPASI); emotional state was assessed using the positive and negative affect schedule (PANAS). Second order factors were calculated and correlated with the SAPASI.

Results

We found positive associations between the extent and severity of skin lesions and the negative and submissive emotions, a negative correlation with dominance emotions and no association with positive emotions.

Conclusions

Our data supports the relationship between emotions and skin lesions. It also allows for discrimination of the associations between psoriasis lesions and the specific type of emotions.

     

VCAM-1 expression on endothelium in lesions from cutaneous lupus erythematosus is increased compared with systemic and localized scleroderma

Summary The cutaneous lesions in systemic sclerosis (SSc) and lupus erythematosus (LE) are pathologically distinct and may display separate cell adhesion receptors. We have scored lesional skin for the presence of cell adhesion molecules that may influence inflammatory and fibrotic processes in five patients with LE, six patients with diffuse scleroderma and four patients with morphoea. The immunohistological distribution, and the number and intensity of cells staining, were recorded for VCAM-1, ICAM-1, E-selectin, α2 to α6 and β2 integrins and HLA-DR, VCAM-1 staining intensity was increased on endothelium from lesions in LE compared with SSc (P=0.05). Low-level VCAM-1 and E-selectin expression was present on endothelium from uninvolved skin including that from patients with morphoea. HLA-DR expression was increased on infiltrating mononuclear cells (P < 0.05) and keratinocytes in LE (P < 0.05) and the number of fibroblasts staining for ICAM-1 was increased in lesions from patients with SSc, although this did not reach statistical significance. Overall, with respect to endothelial adhesion events, our findings support an important role for VCAM-1 in sustaining chronic inflammation in cutaneous LE.     

结节性红斑患者皮损中一氧化氮合酶、血管内皮生长因子的表达

目的 :　探讨一氧化氮合酶 (NOS)和血管内皮生长因子 (VEGF)在结节性红斑中的表达。方法 :用ABC免疫组化方法检测了 4 2例结节性红斑患者皮损和 15例正常人皮肤组织中NOS和VEGF。结果 :结节性红斑皮损中NOS和VEGF的检出率分别为 80 .95 %及 6 6 .6 7% ,阳性信号的表达与分布基本一致(χ2 =2 .2 2 <3.84 ,P >0 .5 ,u =0 .36 6 <0 .6 78,P >0 .5 ) ,主要位于表皮角质层和部分棘细胞、真皮及皮下脂肪层小血管内皮细胞和腺上皮细胞内 ,正常人皮肤组织中NOS和VEGF的表达微弱 ,分布于表皮角质层和部分棘细胞 ,真皮及皮下脂肪层未见。结论 :　结节性红斑皮损中有NOS和VEGF的强阳性表达 ,可能与病毒等微生物引起的免疫反应有关。     

Proliferation and hyperplasia of vascular endothelium in human skin

In a number of diseases of the skin, proliferation of endothelial cells is altered. Replication of endothelial cells has been evaluated by incorporating tritiated thymidine, and compared in inflammatory and neoplastic disorders. An attempt at pathogenic classification is proposed.     

Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis

Neovascularization appears to play an early and important part in the evolution of psoriatic plaques. We studied the distribution and production of two known angiogenesis factors, endothelial cell stimulating angiogenesis factor (ESAF) and vascular endothelial growth factor (VEGF), in the skin of patients with chronic plaque psoriasis and normal control subjects. Our results showed that tissue levels of ESAF and VEGF were significantly elevated in involved as compared with normal control skin (P = 0.006 and P < 0. 0001, respectively). Tissue levels of ESAF and VEGF were also raised in involved skin as compared with uninvolved skin in patients with psoriasis (P = 0.001 and P < 0.0001, respectively). Tissue levels of ESAF and VEGF in plaques of psoriasis correlated closely with the clinical severity of psoriasis (r = 0.6 and r = 0.9, respectively). Serum levels of ESAF and VEGF were significantly raised in patients with psoriasis as compared with control subjects (P = 0.001 and P = 0.02, respectively). In vitro culture studies revealed that ESAF is produced by both keratinocytes and fibroblasts in approximately equal quantities in normal skin, whereas VEGF is secreted predominately by keratinocytes. A similar pattern is seen in both involved and uninvolved skin of patients with psoriasis. However, there is increased secretion of both factors in keratinocytes and fibroblasts from involved and uninvolved skin as compared with normal control skin (P < 0.001). The increased levels and secretion in plaques of psoriasis of two molecules, ESAF and VEGF, known to promote new blood vessel formation, suggest a pathogenetic role for them in this disease.     

Erythema multiforme lesions are associated with expression of a herpes simplex virus (HSV) gene and qualitative alterations in the HSV-specific T-cell response

A common form of erythema multiforme, herpes-associated erythema multiforme (HAEM), occurs following infection with herpes simplex virus (HSV). Here we report that HSV gene expression and the qualitative nature of the virus-specific T-cell responses are related to HAEM lesion development. Skin from HAEM lesions and 1–3 months healed HAEM lesional skin were positive for the viral DNA polymerase gene (Pol) by polymerase chain reaction. However, gene expression as determined by immunohistochemistry with Pol-specific antibody was seen only in HAEM lesions, suggesting that lesion development is associated with Pol gene expression. Similar HSV-specific T-cell lymphoproliferative responses were seen in peripheral blood mononuclear cells (PBMCs) from patients with acute or healed HAEM lesions or HSV lesions and from HSV-seropositive patients with unrelated inflammatory diseases. However, the T-cell receptor variable (Vβ ) chain repertoire of HSV-stimulated PBMCs obtained from HAEM lesions was altered; the prevalence of some families of variable chain (namely Vβ16 and Vβ19) was reduced, whereas the prevalence of others was increased (namely Vβ2 and Vβ7). Vβ2 cells were found in HAEM lesional skin positive for Pol antigen, suggesting that these cells home to viral antigen-positive skin.     

血管内皮生长因子和血管生成素在斑秃皮损中的表达

目的:探讨血管内皮生长因子(VEGF)和血管生成素在斑秃患者皮损处的表达情况.方法:取新鲜斑秃患者皮损和正常人头皮行冰冻切片,采用免疫组化的方法检测VEGF和血管生成素蛋白的分布和表达.结果:人毛囊的毛乳头、真皮鞘,皮脂腺等处均表达VEGF和血管生成素蛋白.斑秃患者此两种因子表达明显低于正常对照(P<0.05),且表达强度与斑秃严重程度呈负相关.结论:VEGF和血管生成素表达下调可能与斑秃的发病有关.     

血管内皮生长因子在扁平苔藓及银屑病皮损中的表达

目的探讨扁平苔藓及银屑病患者皮损表皮血管内皮生长因子(VEGF)表达情况。方法用抗VEGF及CD34抗体行免疫组化染色,对扁平苔藓及银屑病皮损标本进行观察,计数表皮下方真皮的毛细血管密度。结果正常人表皮VEGF基本阴性,扁平苔藓及银屑病患者非病变部VEGF阴性,移行部表皮上层VEGF染色逐渐由弱到强,由间断到连续;病变部表皮VEGF阳性,以表皮上层细胞质的细颗粒状染色为主。CD34染色各部分真皮上层毛细血管密度为;扁平苔藓的非病变部(45.61±15.70)个/mm²、移行部(68.63±15.36)个/mm²、病变部(92.07±16.84)个/mm²;银屑病的非病变部(43.73±14.55)个/mm²、移行部(72.12±18.81)个/mm²、病变部(100.29±21.93)个/mm²,各病种三个部位之间比较差异均有统计学意义。结论扁平苔藓及银屑病皮损表皮分泌VEGF,并与真皮毛细血管增生扩张密切相关。