Increased sensory neuropeptides in nodular prurigo: a quantitative immunohistochemical analysis

Seven patients with nodular prurigo, five patients with lichenified eczema and seven control volunteers were studied immunohistochemically using antisera to the pan-neuronal marker protein gene product 9.5 (PGP), and the neuropeptides calcitonin gene-related peptide (CGRP), substance P (SP), tyrosine hydroxylase (TH), vasoactive intestinal polypeptide (VIP) and the C-flanking region of neuropeptide Y (C-PON). PGP-, CGRP- and SP-immunoreactivities were also evaluated using image analysis quantification, and the data compared by statistical analysis. No significant changes were noted in the lichenified skin of patients with chronic eczema, compared with the control groups. In contrast, a significant increase in PGP immunoreactive nerve fibers was seen in lesional skin of all nodular prurigo cases studied, when compared with non-lesional skin from the same patient or from control subjects (P < 0.001). In one case massive neural hyperplasia was also identified. Staining for CGRP and SP showed a large increase of immunoreactive nerves in lesional skin of nodular prurigo patients, which closely paralleled that of PGP. Staining with VIP, C-PON and TH was similar in both lesional and non-lesional skin. These results indicate that neural changes in nodular prurigo are associated with an increase of sensory neuropeptides, which could be related to the intense pruritus which accompanies nodular prurigo. The absence of significant changes in lichenified skin suggests that the increase in CGRP- and SP-immunoreactive nerve fibres is a characteristic feature of nodular prurigo and may be important in its pathogenesis.     

Neuropeptide and neuronal marker studies in vitiligo

Neuropeptide and neuronal marker immunoreactivity was studied in skin biopsies from lesional and marginal areas in 12 patients with vitiligo, and in seven normal controls. The vitiligo was active in seven, static in two, and of unknown activity in three. Antibodies against general neuronal marker PGP 9.5 (PGP 9.5), substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY), were used. The epidermis, dermo-epidermal junction, papillary and reticular dermis, and appendages, were assessed semiquantitatively for reactivity with each antibody. Staining with PGP 9.5 in the upper dermis was assessed quantitatively by image analysis. An increase in reactivity against NPY antibody was seen in five of 10 cases (three with active vitiligo) in the marginal areas, and in three of 12 subjects (all with active vitiligo) in the lesional vitiligo areas. VIP antibody reactivity showed a minimal increase in the marginal and lesional vitiligo areas (in two cases each, both of whom had active vitiligo), SP and CGRP reactivities did not differ from normal. PGP 9.5 staining was minimally increased at the dermo-epidermal junction and lower Malpighian layer in biopsies from marginal areas in three of 10 subjects (all with active vitiligo). Quantitative analysis of PGP 9.5 reactivity in the upper dermis showed no difference between vitiligo and normal biopsies. These findings support the concept of neuronal or neuropeptide involvement in vitiligo, and in particular suggest that NPY may have a role in the pathogenesis of the disease.     

Immunohistochemical analysis of sensory nerves and neuropeptides,and their contacts with mast cells in developing and mature psoriatic lesions

The distribution of the neuropeptides substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene related peptide (CGRP) was studied immunohistochemically in psoriatic skin during the Koebner response (6 h, 2 days, 7 days, 14 days, 21 days), and in mature psoriatic plaques, of 37 psoriatic patients. The morphological association of sensory nerves, SP and VIP with papillary mast cells was also monitored. The nerves containing SP, VIP or CGRP were very scanty in control skin, and in non-lesional and Koebner-negative psoriatic skin. The first psoriatic lesions were seen 7 days after tape stripping the symptomless psoriatic skin. SP- and VIP-containing nerves were slightly increased in Koebner-positive specimens, but the increase was very prominent in dermal papillae of mature psoriatic plaques. In the plaques, nerve-mast cell contacts were significantly increased (p<0.001) compared with non-lesional psoriatic skin. Only SP-positive fibres were detected in the epidermis and in contact with papillary mast cells. VIP was mainly located around capillaries where SP was also found. No change was noted in CGRP-positive fibres between lesional and non-lesional specimens. The appearance of SP and VIP in the capillary walls is morphological evidence for their function as vasodilators in psoriatic lesion. A slight increase in SP- and VIP-positive fibres in Koebner-positive specimens suggests that these neuropeptides may participate in the inflammatory reaction at an early stage. Their prominence in mature psoriatic plaques in turn indicates a role for them in the maintenance of psoriatic lesions. Morphological contacts between mast cells and SP-containing nerves give further evidence to the view that SP is capable of amplifying the inflammatory reaction also through the axon-reflex mechanism.Part of this work was presented at the meeting of the European Society for Dermatological Research, London, UK, 4–7 April 1992     

Neuropeptides in the skin of patients with atopic dermatitis

There is increasing evidence that neuropeptides may be involved in the pathogenesis of atopic dermatitis (AD). This study examines whether neuropeptide distribution in the skin of patients with AD differs from normal controls. The distribution and density of several neuro-peptides were examined in lesional and non-lesional skin of AD patients (n= 5) and in normal controls (n= 4) using indirect immunofluorescence and image analysis. Cholinergic innervation was studied using cholinesterase histochemistry. Staining with the general neuronal marker protein gene product 9·5 showed a subepidermal network of nerves with fibres penetrating the epidermis, and nerves around blood vessels, sweat glands and hair follicles. Image analysis of nerves around sweat glands showed a significantly higher nerve density in non-lesional compared with both normal controls and lesional skin (P < 0·05); lesional compared with control skin showed no significant difference. In the epidermis the density of nerves was not significantly greater in non-lesional compared with lesional skin and controls. Calcitonin gene-related peptide immunoreactivity was similar in all subjects except in three of the AD patients, where more nerves appeared to penetrate the epidermis. Substance P immunoreactivity in the papillary dermis was seen in all AD patients hut no controls. Vasoactive intestinal polypeptide and neuropeptide Y staining were similar in all groups. Acetyleholinesterase-positive nerves were found around sweat glands in all subjects, the staining being greatest in non-lesional and least in lesional skin. Occasional nerves were seen in the papillary dermis in lesional skin of two out of the four patients. We have demonstrated quantitative differences in nerve growth in clinically normal skin of AD patients, and altered cutaneous neuropeptide expression in these patients which may contribute to the pathogenesis of AD.     

PGP 9.5 distribution patterns in biopsies from early lesions of atopic dermatitis

Peripheral nerve fibres are often increased in lesional skin of atopic dermatitis (AD) patients. We attempted to study nerve fibre profiles, using PGP 9.5 as neuronal marker, in early AD lesions in 10 patients, as compared to non-lesional skin in the same patients and skin from healthy controls. The number of PGP 9.5-positive nerve fibre profiles was not different in the biopsies taken from normal-looking AD skin and healthy controls. The total number of PGP 9.5-positive nerve fibre profiles in the whole skin sections was higher in both the epidermis and the dermis in the group of skin biopsies taken from early lesions of AD patients. Further, the number of epidermal PGP 9.5-positive dendritic cells was increased in AD skin. It seems reasonable that PGP 9.5-positive nerve fibres and PGP 9.5-positive dendritic cells have pathological roles in AD. The findings might serve as a basis for further studies in evaluating novel diagnostic and therapeutic approaches.     

Interleukin-8 immunoreactivity in the skin of healthy subjects and patients with palmoplantar pustulosis and psoriasis.

Previous studies have shown that neutrophil-activating peptide 1/interleukin-8 (IL-8) is present in psoriatic scales and to a lesser extent in normal human epidermis. A panel of monoclonal antibodies and polyclonal antisera raised against IL-8 was used to localize IL-8 with immunoperoxidase techniques in non-lesional and lesional skin of patients with psoriasis and palmo-plantar pustulosis (PPP), and in corresponding sites from healthy subjects. Intracellular IL-8 immunoreactivity was found in all epidermal cell layers in biopsies of healthy subjects and in non-lesional and lesional skin in both PPP and psoriasis. The most intense immunolabeling was regularly found in the basal cell layer. Intercellular epidermal IL-8 immunolabeling was regularly detected in lesional biopsies in PPP and psoriasis, but not in healthy subjects or non-lesional skin in PPP and psoriasis. No intercellular immunolabeling was detected after successful treatment of lesional skin. The majority of cells along the eccrine sweat glands, dermal mononuclear cell infiltrates, and endothelial cells were IL-8 immunoreactive in all biopsies studied. The present study suggests that IL-8, its precursor form, or, alternatively, a degradation product is present in normal human epidermis.     

Expression of nerve growth factor receptors in cutaneous inflammation

Evidence indicates that the neurotrophin nerve growth factor (NGF) is a mediator of cutaneous inflammatory responses. Cellular responses to NGF are facilitated by two receptors called trk A and p75 neurotrophin receptor (p75^NTR). In the current study we have investigated the expression of these receptors in lesional and non-lesional skin from patients with plaque psoriasis and in normal skin exposed to three times the minimal erythema dose of ultraviolet (UV) B radiation. Trk A immunostaining was confined to the basal keratinocytes in normal skin. There was a significant reduction in trk A immunostaining in both non-lesional and lesional psoriatic skin compared with control skin. In UVB-irradiated normal skin, there was a significant reduction in trk A immunostaining at 4 h after irradiation, which was still evident at 48 h. In normal skin, p75^NTR immunopositive fine nerve fibres were present throughout the dermis and occasionally seen in the epidermis. Thick nerve fibres were evident in the deep dermis and in the middle region of the dermis. p75^NTR immunopositive basal keratinocytes were occasionally seen. There was a statistically significant loss of p75^NTR immunopositive fine nerve fibres in the epidermis of lesional psoriatic skin and a statistically significant loss of p75^NTR immunopositive fine nerve fibres in the dermis in both non-lesional and lesional psoriatic skin. p75^NTR immunopositive thick nerve fibres were reduced in lesional psoriatic skin compared with normal skin. UVB irradiation of normal skin led to a statistically significant decrease in the p75^NTR immunopositive fine nerve fibres in the epidermis at 48 h after irradiation. There was no significant reduction in the dermal p75^NTR immunoreactivity. These results demonstrated that expression of both NGF receptors is decreased following an acute inflammatory stimulus and also in association with a chronic inflammatory dermatosis.     

Neuropeptides in skin disease: increased VIP in eczema and psoriasis but not axillary hyperhidrosis

The neuropeptides vasoactive intestinal polypeptide (VIP), substance P and somatostatin were studied in skin biopsies from patients with eczema, psoriasis and axillary hyperhidrosis. VIP concentrations were elevated in skin affected by eczema and psoriasis, whereas substance P and somatostatin levels did not differ from controls. There was a higher concentration of VIP, but not of substance P or somatostatin, in normal axillary skin when compared to adjacent trunk skin, with abundant VIP-containing fibres surrounding eccrine sweat glands. The VIP concentration was unchanged in skin affected by axillary hyperhidrosis. VIP may increase local blood flow in eczema and psoriasis, but does not appear to play a role in axillary hyperhidrosis.     

Substance P is diminished and vasoactive intestinal peptide is augmented in psoriatic lesions and these peptides exert disparate effects on the proliferation of cultured human keratinocytes.

An involvement of neurogenic components in the pathogenesis of psoriatic lesions has been suggested and neuropeptides are thought to play a modulatory role in cutaneous inflammation. In this study, we evaluated the immunoreactivity of the neuropeptides vasoactive intestinal polypeptide (VIP) and substance P (SP) in the skin of patients with chronic plaque psoriasis, by immunohistochemistry and radioimmunoassay. No differences were observed, by immunohistochemistry, in the expression and localization of VIP and SP between psoriatic and normal skin. Using the radioimmunologic technique on whole skin homogenates, VIP levels were significantly increased in psoriatic lesions as compared to normal skin. By contrast, SP levels were significantly lower in lesional and non-lesional psoriatic skin than in normal skin. In addition, we examined the effect of VIP and SP on the proliferation of cultured normal human keratinocytes. VIP (1-28) (1 nM-1 microM) as well as VIP fragments (10-28) (1 nM-1 microM) and (22-28) (1 nM-1 microM) stimulated the proliferation of keratinocytes in a dose-dependent manner, whereas the VIP fragment (1-12) (1 nM-1 microM) was ineffective. The VIP antagonist (N-Ac-Tyr1, D-Phe2)-GRF (1-29)-NH2 (0.1 microM) significantly inhibited the VIP effect on keratinocytes. On the other hand, SP (0.1 microM) not only failed to stimulate keratinocyte growth, but also blocked the VIP-induced stimulation of these cells. The imbalance of cutaneous VIP and SP and their disparate effects on the proliferation of normal human keratinocytes in culture would suggest that these peptides are involved in the pathogenesis of psoriasis and may exert different modulatory activities in the mechanisms underlying the psoriatic lesion.     

Altered cutaneous innervation in psoriatic skin as revealed by PGP 9.5 immunohistochemistry

Summary There is conflicting evidence in the literature as to whether cutaneous nerves are altered in psoriasis or not. In this study, antibodies to protein gene product (PGP) 9.5 were used to visualize cutaneous nerves in biopsies from involved and uninvolved skin of nine patients with psoriasis and from normal skin of eight healthy controls. A profound reduction in the epidermal nerve fibre density was observed in the involved psoriatic skin. These intraepidermal nerve fibres were also mostly short and found in the basal layer. Only a few nerve fibres were found in the suprabasal layer and they were non-varicose, long fibres going straight up without branching. In the uninvolved skin of psoriatic patients, the distribution and number of the intraepidermal nerve fibres was similar to that observed in normal skin. In the dermis, the distribution and the number of the nerve fibres showed no differences between involved psoriatic skin, uninvolved psoriatic skin, and normal skin. The results support previous studies in which alterations of cutaneous nerves in psoriasis have been described.     

Intraepidermal nerve fiber expression of calcitonin gene-related peptide, vasoactive intestinal peptide and substance P in psoriasis

In order to evaluate more fully the role of neuropeptides in the pathogenesis of psoriasis, skin biopsies were obtained from 36 patients with psoriasis to identify substance P (SP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP). Lesional and nonlesional skin was examined from these biopsies and the results compared with those from biopsies taken from patients with a variety of other inflammatory dermatoses, including lichen planus, lichen simplex chronicus, spongiotic dermatitis, and seborrheic dermatitis. Also studied was a series of nine biopsies taken from patients with no known skin disorders. We found an increase in the number of SP-positive nerve fibers within the epidermis in biopsies from lesional skin of psoriasis patients (8.4 nerves per 3-mm biopsy) compared with nonlesional psoriatic skin (2.6 nerves per 3-mm biopsy) and normal skin (2.0 nerves per 3 mm biopsy). Other inflammatory disorders also demonstrated fewer SP-positive nerves than lesional psoriatic skin; lichen planus (0 nerves per 3 mm biopsy) and lichen simplex chronicus (1.3 nerves per 3 mm biopsy). The difference in SP-positive nerve expression between lesional psoriatic skin and the group comprising nonlesional skin, normal skin, lichen planus, and lichen simplex chronicus attained statistical significance ( P < 0.013). SP-positive intraepidermal nerve fibers in lesional psoriatic specimens were fewer than in spongiotic dermatitis (17.4 nerves per 3 mm biopsy). There was no significant difference in numbers of VIP- or CGRP-immunopositive intraepidermal nerve fibers between psoriatic skin and the group comprising all other material tested. However, in five patients with psoriasis, there was a marked increase in the expression of intraepidermal CGRP (up to 10.7 nerves per 3-mm biopsy) and VIP (up to 8.3 nerves per 3-mm biopsy) which was not observed in control groups. These findings suggest that neuropeptides SP, CGRP, and VIP play a role in the pathogenesis of psoriasis. Received: 3 March 1997     

Skin nerve fibres and their contacts with mast cells in patients with palmoplantar pustulosis

Abstract Patients with palmoplantar pustulosis (PPP) frequently report that stress worsens their condition. A study was therefore made of the distribution and number of nerve fibres positive for protein gene product (PGP) 9.5 (a general nerve marker) and nerve fibres with substance P- and calcitonin gene-related peptide-like immunoreactivity in involved skin from patients with PPP and in skin from healthy controls. The number of mast cells in the papillary dermis was larger (P = 0.0003) in lesional palmar PPP skin than in control skin, and the number of contacts between mast cells and nerve fibres was significantly larger (P = 0.02) in PPP skin than in control skin. Image analysis of the nerve fibres around the sweat glands showed that the positively stained area as a percentage of the total area of the sweat gland (coil + surrounding nerves) was significantly lower in PPP skin (P = 0.0006). Furthermore, the nerves seemed to be fragmented. Neutrophils within and below the pustules and in the papillary dermis showed positive substance P staining. The increased number of contacts between nerves and mast cells in PPP skin and the intense substance P-like immunoreactivity of the neutrophils indicate that neuromediation may influence the inflammation in PPP, whereas the destruction of the nerve fibres around the sweat glands might be a result of the inflammation. Received: 8 October 1999 / Revised: 25 January 2000 / Accepted: 27 January 2000     

Neuropeptides in psoriasis: an immunocytochemical and radioimmunoassay study

The present study examines the presence of neuropeptides in the skin and plasma of patients with psoriasis using the techniques of immunocytochemistry and radioimmunoassay. Immunocytochemistry failed to demonstrate differences in the pattern of neuropeptide innervation in psoriatic lesional skin when compared to normal skin. However, radioimmunoassay of skin biopsy extracts, both substance P and vasoactive intestinal polypeptide, were significantly elevated in psoriatic lesional skin when compared with both psoriatic non-lesional and normal control skin (p less than 0.001). There was no significant difference between the plasma levels of neuropeptides in psoriatic patients compared to those of control subjects, and no significant correlation among the plasma levels of neuropeptides with the surface area of involvement with psoriasis. The finding of elevated levels of substance P and vasoactive intestinal polypeptide in lesional psoriatic skin suggests that these peptides may be involved in the pathogenesis or maintenance of the psoriatic skin lesion and the development of safe and stable antagonists of these neuropeptides may have applications in the treatment of psoriasis.     

First case of congenital idiopathic hypohidrosis in China

A 43-year-old Chinese man presented with generalized hypohidrosis, which he had had since birth, without obvious abnormalities of other skin appendages except a sparse beard and axillary hairs. The sweat test revealed localized sweating on the face, axillae and palms. Histopathologic examination showed that the sweat glands were absent in the forearm and thigh, but some eccrine and apocrine sweat glands were present in the right axilla. S-100 was expressed in the nerve terminals surrounding the acini and ducts of the eccrine sweat glands, while PGP9.5 was positive in the acini of apocrine glands and the nerve terminals surrounding the eccrine glands in the axilla. To our knowledge, this is the first case of congenital idiopathic hypohidrosis in China.     

Double-labeled immunofluorescence study of cutaneous nerves in psoriasis

Background and objective In recent years, many reports have suggested an active role of neuropeptides in the pathogenesis of psoriasis. Increased numbers of neuropeptide-containing nerves positive for substance P (SP), vasoactive intestinal polypeptide (VIP), and calcium gene-related peptide (CGRP) have been reported in psoriatic tissue. As psoriatic epidermis has a larger mass/volume, however, it is expected to have more nerves and a higher number of neuropeptergic fibers. Therefore, instead of demonstrating a larger number of neuropeptergic fibers, a more significant study is to investigate whether the neuropeptergic fibers are denser in psoriatic tissue. In this study, we applied a double labeled immunofluorescence technique. This method allows the identification of the total number of nerve fibers and the number of nerves positive for specific neuropeptides. Materials and methods We obtained biopsies from nine lesional and seven non-lesional psoriatic skins and six normal controls. Biopsies were snap frozen and then cut into 14 μm cryosections. The tissues were first treated with anti-microtubule associated protein (MAP)2 antibody to stain the nerves. This was followed by a second set of stainings for SP, VIP, and CGRP. Primary antibodies were used in dilutions of 1 : 200 for anti-MAP2, 1 : 200 for anti-SP, 1 : 800 for anti-VIP, and 1 : 400 for anti-CGRP. Results We found that the percentage of SP-positive fibers was twofold greater and the percentage of CGRP-positive fibers was 2.5 times greater in the psoriatic epidermis than in the epidermis of normal skin. Psoriatic epidermis had 30.1 ± 3.9% SP-positive nerve fibers compared with 15.7 ± 3.7% in the normal control. The corresponding values for CGRP-positive nerve fibers were 30.1 ± 3.9% and 12.0 ± 4.2%. Conclusions The results of our study suggest that SP- and CGRP-containing neuropeptide nerve fibers are more dense in the psoriatic epidermis. Both SP and CGRP are chemotactic to neutrophils and mitogenic to keratinocytes and endothelial cells. In addition, SP activates T lymphocytes and induces adhesion molecules on the endothelial cells. Our observations suggest that neuropeptides may play a significant role in the inflammatory and proliferative process of psoriasis.     

Studies on fibronectin in the skin

Fibronectin is a glycoprotein mediating contact between cellular elements and collagen. As judged by indirect immunofluorescence studies fibronectin is abundantly present in normal human skin. It is located in the dermo-epidermal junction area, in the papillary and reticular dermis, about epidermal appendages (pilosebaceous units and eccrine sweat glands) and in the vascular and neural structures.     

银屑病患者表皮及真皮中Bcl-X、Bcl-2、Bax表达的免疫组化研究

目的 探讨银屑病患者细胞增殖与凋亡的调节。方法 用免疫组化ＳＰ法检测银屑病皮损及非皮损中Ｂｃｌ－Ｘ、Ｂｃｌ－２、Ｂａｘ的表达情况。结果 银屑病皮损中,Ｂｃｌ－Ｘ在表皮各层、真皮炎症细胞及血管内皮的表达均较正常明显增高;Ｂａｘ在颗粒层与棘层的表达轻度增高。上述异常在非皮损中已经部分存在,且隍未完全恢复正常。而Ｂｃｌ－２表达与正常相似,局限于基底层黑素细胞,角质形成细胞未是性。结论 银屑病中角质形成细     

Occurrence and distribution of neuropeptides in the human skin. An immunocytochemical and immunochemical study on normal skin and blister fluid from inflamed skin

The content and distribution of substance P (SP), somatostatin, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) in human skin were investigated. Radioimmunoassay was performed on pooled tissue samples from several regions (fingers, toes, axillas and thighs) and on tissue fluid from spontaneous blisters on inflamed skin. Immunocytochemical localization showed all peptides examined except somatostatin to be present in nerve fibers. Nerve fibers storing SP and CGRP, which were found to coexist, were mostly present as free nerve endings in the superficial part of dermis and in epidermis. SP/CGRP fibers were most abundant in fingers and toes. VIP fibers and NPY fibers were localized in the deeper parts of dermis around blood vessels and acini of sweat glands. Also fibers containing these neuropeptides were most common in fingertips and toes. VIP occurred in relatively high amounts also in skin from axilla whereas NPY in this region was below detection limit. Immunoreactive somatostatin was found in low concentrations in tissue extracts and was not present in amounts sufficient for reliable immunostaining. Fluid from spontaneous blisters on inflamed skin contained detectable amounts of all neuropeptides.     

Pruritogenic mediators in psoriasis vulgaris: comparative evaluation of itch-associated cutaneous factors

BACKGROUND: Although some patients with psoriasis vulgaris also complain of severe pruritus, the data available regarding pruritus in psoriasis are sparse. OBJECTIVES: To clarify the mechanism and mediators involved in the pruritus of psoriasis vulgaris, we compared itch-associated factors in lesional skin from psoriatic patients vs. skin without pruritus quantitatively using a panel of histological and immunohistological parameters. PATIENTS AND METHODS: Biopsied specimens were obtained from 38 patients with psoriasis vulgaris who were divided into two groups according to the presence or absence of pruritus. RESULTS: When compared with psoriatic patients devoid of pruritus, lesional skin from patients with pruritus showed the following characteristic features: (i) a rich innervation both in the epidermis and in the papillary dermis; (ii) an increase in neuropeptide substance P-containing nerve fibres in perivascular areas; (iii) decreased expression of neutral endopeptidase in the epidermal basal layer as well as in the endothelia of blood vessels; (iv) many mast cells showing degranulating processes in the papillary dermis; (v) a strong immunoreactivity for nerve growth factor (NGF) throughout the entire epidermis and an increased NGF content in lesional skin homogenates; (vi) an increase in the expression of high-affinity receptors for NGF (Trk A) in basal keratinocytes and in dermal nerves; (vii) an increased population of interleukin-2-immunoreactive lymphocytes; and (viii) a strong expression of E-selectin on vascular endothelial cells. A significant correlation was observed between the severity of pruritus and protein gene product 9.5-immunoreactive intraepidermal nerve fibres, NGF-immunoreactive keratinocytes, expression of Trk A in the epidermis and the density of immunoreactive vessels for E-selectin. These findings indicate that possible pruritogenic mediators in psoriatic lesional skin are neurogenic factors including innervation, neuropeptide substance P, neuropeptide-degrading enzymes and NGF, activated mast cells, one or more cytokines and endothelial-leucocyte adhesion molecules. CONCLUSIONS: These data document for the first time itch-related local markers in psoriasis, and suggest complex and multifactorial mechanisms of pruritus in the disease. These results provide the groundwork for further studies to evaluate the efficacy of antipruritic treatment for psoriatic patients.     

Detection of nitric oxide and nitric oxide synthases in psoriasis

Biopsies from psoriasis lesions and clinically uninvolved skin of eight patients and five normal subjects were studied by immunocytochemistry with computerized image analysis for the presence of endothelial, neuronal and inducible isoforms of nitric oxide synthase. Endothelial nitric oxide synthase was expressed in the endothelium and weakly in some keratinoctyes. Its expression was not significantly different in psoriasis. Inducible nitric oxide synthase, however, was absent from normal skin but was significantly upregulated in psoriatic lesional skin, focally in keratinocytes but to the greatest extent in the papillary dermis and to a lesser extent in clinically uninvolved psoriatic skin. Inducible nitric oxide synthase staining was greatest in the more severe lesions and correlated with the inflammatory infiltrate (CD3-positive cells) and with keratinocyte proliferation (Ki-67-positive cells). In normal skin, neuronal nitric oxide synthase was expressed only in keratinocytes in the granular layer and eccrine sweat glands. However, in psoriasis and clinically uninvolved skin the neuronal form was present through all levels of the epidermis. Direct measurement of nitric oxide production from the skin surface revealed a tenfold increase in the lesions of 16 psoriatic patients compared with their nonlesional skin, and this nitric oxide production was inhibited by topical betamethasone. Received: 4 March 1996