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.     

Immunohistochemical localization of interleukin-6-like immunoreactivity to peripheral nerve-like structures in normal and inflamed human skin

Interleukin-6-like (IL-6-like) immunoreactivity was sought in inflamed and normal human skin using the same immunohistochemical technique as for detection of neuropeptides. Such immunoreactivity was found in dermal and in a few intraepidermal nerve-like fibres in biopsy specimens from inflamed skin from patients with positive epicutaneous patchtest reactions to nickel sulphate, and in skin specimens from patients with atopic dermatitis and prurigo nodularis. However, IL-6-like immunoreactivity was also found in nerve-like fibres in specimens from nonlesional skin. In skin from patients with positive epicutaneous patch-test reactions there was a statistically significantly (P<0.01) higher number of IL-6-positive nerve fibres in the epidermis than in normal skin, in contrast to the papillary dermis, in which no difference was found. Moreover, there were clusters of nerve-like fibres with IL-6-like immunoreactivity in the dermis of prurigo nodularis lesions. In these nerve-like fibres, the colocalization of the immunoreactivities for IL-6 and calcitonin gene-related peptide was indicated. Localization of immunoreactivity to nerve-like structures surrounding the eccrine sweat glands indicates that IL-6 is present in autonomic as well as in sensory nerve fibres.     

The distribution of choline acetyltransferase- and acetylcholinesterase-like immunoreactivity in the palmar skin of patients with palmoplantar pustulosis

The distribution of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in involved skin in patients with palmoplantar pustulosis (PPP) and in normal palmar skin in healthy non-smokers and smokers has been studied by immunohistochemistry, especially in relation to the sweat gland apparatus. The sweat gland and its duct showed ChAT- and AChE-like immunoreactivity (LI) of varying intensity in all three groups and with stronger reactivity than in the epidermis. ChAT-LI was present in the coil and in the duct except in the corneal layer. Smokers and patients with PPP displayed significantly fewer ChAT+ acrosyringia than non-smokers. In the patients with PPP, the granulocytes in the pustules and in the papillary dermis displayed ChAT-LI. Western blot analysis of granulocytes from peripheral blood from healthy donors confirmed the presence of ChAT-like proteins in large amounts in neutrophils and small amounts in eosinophils. AChE-LI of varying intensity was found in all parts of the sweat gland apparatus in all three groups. The strongest AChE-LI in the acrosyringia was seen in the lowest part of the stratum corneum, where the PPP pustules are located. No significant differences in staining pattern or intensity were found between the coils, nerve fibres surrounding the coils or ducts. The number of mast cells in the papillary dermis was about four times larger in the patients with PPP than in the control subjects. AChE-LI was observed in about 25% of the mast cells in non-smoking control subjects and in patients with PPP, but only in 10% of those in the smoking control subjects. Our findings indicate that the (non-neuronal) cholinergic system may be involved in cutaneous inflammatory processes.     

Neuropeptide-containing nerves in painful hypertrophic human scar tissue

Specimens of hypertrophic scar tissue (n= 9). non-hypertrophic, flat scar tissue (n= 5) and control skin (n= 3) were obtained from eight adult females (aged 22–56) and three adult males (aged 22–59). The specimens were studied histologically and immunohistochemically for vasoactive intestinal polypeptide, neuropeptide Y, calcitonin gene-related peptide, substance P, somatostatin, [Met]enkephalin, [Leu]enkephalin, and the enzyme dopamine β-hydroxylase. The non-hypertrophic scar tissues were not dissimilar to the control tissue, but contained connective tissue in bundles with a greater number of collagen fibres. In the hypertrophic scar tissue of some patients, the dermis contained adipose tissue displaced upwards from the hypodermis. The connective tissue contained densely packed collagen fibres and fibroblasts; this region was devoid of hair follicles, sweat glands and blood vessels, although they were observed in the region of loosely packed connective tissue. The normal skin contained all the neuropeptides studied, except somatostatin-, and dopamine β-hydroxylase-immunoreactive nerves, which were seen as single fibres or in nerve bundles, and were associated with blood vessels in the dermis. Neuropeptide Y-immunoreactive nerves were found in the arrector pili muscle, and neuropeptide Y-, vasoactive intestinal polypeptide-, calcitonin gene-related peptide-, [Met]enkephalin- and dopamine β-hydroxylase-containing nerves were found within sweat glands. In patients with flat, non-hypertrophic scar tissue, neuropeptides and dopamine β- hydroxylase-containing nerves were absent. In patients with hypertrophic scars, the density of neuropeptide Y-, vasoactive intestinal polypeptide-, substance P-, calcitonin gene-related peptide- and dopamine β-hydroxylase-immunoreactive nerves was greater in the dermis when compared with controls. They were found at the base of the epidermis, around blood vessels, and in sweat and sebaceous glands. Only substance P-immunoreactive nerves penetrated the densely packed collagen and fibroblast matrix, whereas neuropeptide Y-, calcitonin gene-related peptide-, vasoactive intestinal polypeptide- and dopamine β-hydroxylase-containing nerves were found in the loosely packed connective tissue. [Met]enkephalin-, [Leu]enkephalin- and somatostatin-immunoreactive nerves were rarely seen in all three groups of patients. In conclusion, neuropeptide-containing nerves appear to be present in patients with painful, hypersensitive, hypertrophic scars, but absent in flat, insensitive, non-hypertrophic scars.     

Neuropeptides and general neuronal marker in psoriasis an immunohistochemical study

Nerve fibres immunoreactive to antibodies to vasoactive intestinal polypeptide (VIP) and substance P (SP) were increased in lesional psoriatic skin when assessed semi-quantitatively. Biopsies from psoriatic plaques on the arm were studied in 13 patients and compared with biopsies from non-lesional areas (in three of the same psoriatic subjects) and from normal skin in seven non-psomtic controls. Immunohistochemical methods were used on cryocut skin sections to demonstrate the neuropeptides SP, VIP, calcitonin gene-related peptide and neuropeptide Y, and the general neuronal marker protein gene product (PGP) 9.5. The immunofluorescence was examined by semiquantitative and, for PGP 9.5, by quantitative methods. VIP reactive nerve fibres were increased at areas of eccrine sweat glands throughout the dermis, at the dermo-epidermal junction, and in the epidermis, in psoriasis lesional skin. SP reactive nerve fibres were increased at the dermo-epidermal junction, where the nerves ran parallel with and perpendicularly through the junction. PGP 9.5 reactive nerve fibres showed an increase at the dermo-epidermal junction, in the papillary dermis, and at the eccrine sweat glands in lesional psoriatic skin but not in non-lesional, or in control skin. These findings support the hypothesis that neuropeptides may be involved in the pathogenesis of psoriasis.     

Identification of novel genes regulated by α-melanocyte-stimulating hormone in murine bone marrow-derived dendritic cells

The vanilloid receptor subtype 1 (VR1/TRPV1) is a non-selective cation channel that binds the vanilloid capsaicin and endogenous cannabinoids. In human skin, VR1 has recently been shown to be expressed by keratinocytes in vitro and in vivo . To determine a precise localization of VR1 in other cutaneous compartments in particular cutaneous nerve fibres, we investigated VR1 immunoreactivity as well as mRNA and protein expression in a series of normal and capsaicin-treated human skin. VR1 immunoreactivity could be observed in cutaneous sensory nerve fibres, mast cells, epidermal keratinocytes, dermal blood vessels, the inner root sheet and infundibulum of hair follicles, differentiated sebocytes, sweat gland ducts and the secretory portion of eccrine sweat glands. Upon RT-PCR and Western blot, the expression of VR1 was confirmed in primary mast cells and keratinocytes from human skin. During capsaicin therapy, VR1-receptor distribution was unchanged, while a reduction of neuropeptides (substance P, calcitonin gene-related peptide) was observed in nerve fibres. After cessation of capsaicin therapy, neuropeptides re-accumulated in skin nerves. In conclusion, VR1 is widely distributed in the skin, suggesting a central role for this receptor, e.g. in nociception and inflammation.     

Mast cells,nerves and neuropeptides in atopic dermatitis and nummular eczema

The association between mast cells and sensory nerves and the distribution of the neuropeptides substance P (SP), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) were studied immunohistochemically in lesional and nonlesional skin of 26 atopic dermatitis (AD) and 23 nonatopic nummular eczema (NE) patients. Mast cell-nerve contacts were counted morphometrically and confirmed by confocal laser scanning microscopy. Neuropeptide positivity was assessed semiquantitatively. Dermal contacts between mast cells and nerves were increased in number in both lesional and nonlesional samples of AD and NE when compared to those in normal controls, although only the values in lesional AD reached statistical significance ( P<0.05). Nerve-mast cell contacts in the basement membrane zone were seen practically only in lesional NE. SP and CGRP fibres were prominently increased in lesional samples when compared to their nonlesional controls both in AD and NE in the epidermis and in the papillary dermis. In both AD and NE, only small differences were found regarding VIP positivity in lesional and nonlesional biopsies. The epidermis was devoid of VIP positivity. In conclusion, SP and CGRP but not VIP fibres were more frequent in lesional than in nonlesional papillary dermis of both AD and NE. Since mast cells are also increased in number in lesions of AD and NE, they are able to maintain neurogenic inflammation through activation by SP and CGRP. The increased SP/CGRP nerves in the epidermis of AD and NE lesions may stimulate keratinocytes to release cytokines which affect various cell types enhancing inflammation.     

Depletion of cutaneous peptidergic innervation in HIV-associated xerosis

Severe xerosis occurs in approximately 20% of human immunodeficiency virus seropositive patients. Changes in cutaneous innervation have been found in various inflammatory skin diseases and in xerotic skin in familial amyloid. We have therefore carried out a quantitative examination of the cutaneous peptidergic innervation in human immunodeficiency virus-associated xerosis. Immunohistochemistry and image analysis quantitation were used to compare total cutaneous innervation (protein gene product 9.5), calcitonin gene-related peptide, substance P, and vasoactive intestinal peptide peptidergic fibers, at two sites in the skin of human immunodeficiency virus-associated xerosis patients (upper arm, n = 12; upper leg, n = 11) and site-matched seronegative controls (upper arm, n = 10; upper leg, n = 10). Measurement of lengths of fibers of each type was carried out for each subject in the epidermis and papillary dermis, and around the sweat glands. Immunostained mast cells in these areas were counted. Epidermal integrity and maturation were assessed by immunostaining for involucrin. There were significant (Mann-Whitney U test; p < 0.02) decreases in total lengths of protein gene product 9.5 fibers in both epidermis/papillary dermis and sweat gland fields; of calcitonin gene-related peptide innervation in the epidermis/papillary dermis; and of substance P innervation of the sweat glands. There were no differences in the distribution of mast cells, or in the epidermal expression of involucrin. Depletion of the calcitonin gene-related peptide innervation may affect the nutrient blood supply of the upper dermis, and the integrity and function of basal epidermis and Langerhans cells. Diminished substance P innervation of the sweat glands may affect their secretory activity. Both of these changes may be implicated in the development of xerosis.     

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     

Vasoactive intestinal polypeptide in allergic contact dermatitis: an immunohistochemical and radioimmunoassay study

Abstract Vasoactive intestinal polypeptide (VIP) is a neuropeptide with immunomodulatory properties. To elucidate the possible role of VIP in the pathophysiology of cutaneous contact hypersensitivity, we compared involved with uninvolved skin of allergic contact dermatitis (ACD) from nickel-allergic patients. Assays included quantification of VIP-immunoreactive (VIP-IR) nerve fibres and cells bearing immunoreactivity for VIP1 and VIP2 receptors in skin biopsy specimens, and of the concentration of VIP-like immunoreactivity (VIP-LI) in extracts of biopsy specimens. VIP-IR nerve fibres were found in the deeper part of the dermis close to sweat glands and hair follicles. No difference in the presence of VIP-IR nerve fibres was found between involved and uninvolved skin of ACD. VIP1 and VIP2 receptor immunoreactivity was seen on keratinocytes in the basal layer of the epidermis, with no difference between involved and uninvolved skin. Staining was also seen on vessel walls and mononuclear cells in the dermis. The highest staining intensity in the mononuclear cells was noted with the antibodies against the VIP2 receptor. While most of the mononuclear cells were stained in uninvolved skin, a minority of the cells showed a positive signal in involved skin. The concentration of VIP-LI in uninvolved skin was 1.53 ± 0.790 pmol/g and in involved skin 1.41 ± 0.735 pmol/g. It is concluded that there is no significant difference in either the distribution of VIP-IR fibres or the concentration of VIP-LI between involved and uninvolved skin of ACD. However, the number of dermal mononuclear cells showing VIP2 receptor immunoreactivity in skin of ACD was reduced. Received: 4 May 1998 / Received after revision: 12 October 1998 / Accepted: 16 October 1998     

Quantitative analysis of contact sites between mast cells and sensory nerves in cutaneous psoriasis and lichen planus based on a histochemical double staining technique

Summary The aim of the present study was to test further our previous hypothesis that the inflammatory reaction in psoriasis is neurogenic. For this purpose, contact sites between mast cells and sensory nerves were morphometrically analysed in the basement membrane zone, papillary dermis and three dermal zones of lesional/non-lesional psoriatic and lichen planus skin as well as in healthy control skin. The analyses were made on sections stained with a histochemical double stain developed for this study. With the double stain, active mast cell tryptase was stained blue enzyme histochemically, and the sensory nerves black using specific monoclonal anti-neurofilament antibodies with immunogold. In psoriatic lesions, both mast cells and mast cell — nerve contacts were markedly more frequent in the basement membrane zone and in the papillary dermis when compared with the corresponding areas in the other groups. Mast cell numbers were increased in both lesional and symptom-free skin in lichen planus, but no increase was found in the mast cell — nerve contacts. Increased contacts between mast cells and sensory nerves indicate that the elements exist for neurogenic inflammation in psoriatic lesions. These increased contacts are not due to the extensive inflammatory reaction only, because they were not observed in lichen planus lesions.     

Increased nerve growth factor and its receptors in atopic dermatitis: an immunohistochemical study

Evidence suggests that neurotrophins may regulate certain immune functions and inflammation. In the present study, the localization and distribution of nerve growth factor (NGF) and its receptors were explored using immunohistochemical methods, with the aim of detecting the cause of the neurohyperplasia in early lesions of atopic dermatitis (AD). In AD involved skin, strong NGF-immunoreactive (IR) cells were observed in the epidermis. In some cases, a huge number of infiltrating cells with stronger NGF immunoreactivity was seen mainly in the dermal papillae. Some trkA immunoreactivity was observed in the outer membrane of cells in the basal and spinal layers of the epidermis. In the papillary dermis, a larger number of cells demonstrated strong trkA immunoreactivity. The p75 NGFr-IR nerve fibre profiles were increased (900 per mm²; p<0.001) compared to normal [the involved skin also differed from the uninvolved skin (p<0.05)] in the dermal papillae. These nerve fibres were larger, coarser and branched, some of them terminated at p75 NGFr-IR basal cells, and also revealed a stronger fluorescence staining than the controls or the uninvolved skin. In normal healthy volunteers and AD uninvolved skin, the NGF immunoreactivity was weak in the basal layer of epidermis. Only a few trkA positive cells were seen in the basal layer of the epidermis and upper dermis. The IR epidermal basal cells revealed a striking patchy arrangement with strong p75 NGFr immunostaining in the peripheral part of the cells, and short and thick NGFr-IR nerve fibre profiles appeared as smooth endings scattered in the dermis including the cutaneous accessory organs. Using NGF and p75 NGFr double staining, both immunoreactivities showed a weak staining in the epidermis and dermis in normal and uninvolved skin. In the involved dermis of AD, the intensity of p75 NGFr-IR nerves was stronger in areas where there were also increased numbers of NGF-IR cells. These findings indicate that NGF and its receptors may contribute to the neurohyperplasia of AD.     

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.     

Neuroimmune mechanisms in patients with atopic dermatitis during chronic stress

Objective To identify pathoaetiological neuroimmune mechanisms in patients with atopic dermatitis (AD) and chronic stress, focusing at nerve density, sensory neuropeptides, and the serotonergic system. Methods Eleven patients with AD with histories of stress worsening were included. Biopsies from involved and non‐involved skin were processed for immunohistochemistry. Salivary cortisol test was done as a marker for chronic stress. Results There were more acanthosis and fewer nerve fibres in epidermis and papillary dermis of involved compared with non‐involved skin. Whereas there was no significant change in the number of substance P and calcitonin gene‐related peptide–positive nerve fibres between the involved and non‐involved skin, there was an increase in the epidermal fraction of 5‐hydroxtrytamine 1A (5‐HT1A) receptor and serotonin transporter protein (SERT) immunoreactivity in the involved skin. The number of 5‐HT2AR, CD3‐positive cells, and SERT‐positive cells, most of them being CD3 positive, was increased in involved skin. There was an increase in mast cells in the involved skin, and these cells were often located close to the basement membrane. There was a strong tendency to a correlation between 5‐HT2AR positive cells in the papillary dermis of involved skin and low cortisol ratios, being an indicator of chronic stress. Conclusion A changed innervation and modulation of the serotonergic system are indicated in chronic atopic eczema also during chronic stress.     

The occurrence of cutaneous nerve endings and neuropeptides in vitiligo vulgaris: a case-control study

Pioneering studies both in humans and animals have demonstrated an association between the peripheral nervous system and epidermal melanocyte destruction. The presence of certain neuropeptides and neuronal structural markers in peripheral nerve fibres was investigated in involved and uninvolved vitiligo skin and compared with normal healthy skin. A group of 18 vitiligo vulgaris patients and matched healthy volunteers participated in the investigation. The indirect immunofluorescence technique was employed. There was a tendency for a reduction in the number and intensity of low affinity (p75) nerve growth factor receptor immunoreactive (NGFr-IR) basal keratinocytes in involved vitiliginous skin (P<0.06) compared with control skin, while the number of NGFr-IR nerve fibres was significantly increased (P<0.01). The number of calcitonin gene-related peptide (CGRP)-IR nerve fibres in the epidermis and papillary dermis was dramatically increased in involved skin as compared with control skin (P<0.01) and with uninvolved skin (P<0.05). No clear difference could be found in the distribution of vasoactive intestinal polypeptide (VIP)-and neuropeptide tyrosine (NPY)-IR nerve fibres. A different structural appearance of the peripheral nervous system as well as a changed balance of neuropeptides in vitiliginous skin point to a critical role of the nervous system in the pathogenesis of vitiligo. Work was supported by funds from the Medical Faculty of the Karolinska Institute     

Somatostatin receptors are strongly expressed in palmoplantar sweat glands and ducts: studies of normal and palmoplantar pustulosis skin

Background. The acrosyringium is the target for inflammation in the chronic and intensely inflammatory skin disease palmoplantar pustulosis (PPP). The sweat‐gland apparatus seems to be an immunocompetent structure that probably contributes to skin defence. Furthermore, the sweat gland and duct may be a hitherto unrecognized neuroendocrine organ. Aim. To obtain further information about the neuroendocrine properties of the sweat‐gland apparatus by examining expression of the somatostatin receptors (SSTRs) 1–5 in healthy palmar skin and in PPP skin. Methods. Biopsy specimens were taken from 25 patients with PPP and 25 healthy controls. Immunohistochemical analysis was used to investigate expression of SSTRs 1–5. Results. SSTRs 1–5 were expressed in both epidermal and endothelial structures. The staining intensity of the sweat‐gland apparatus was more pronounced than that of the epidermis. Expression differed significantly between lesional PPP and normal plantar skin, with increased expression of SSTRs 3 and 4 in ducts in epidermis, and decreased expression of SSTR 1 in ducts in both papillary and reticular dermis. In specimens with pronounced inflammation, numerous dendritic cells with strong expression of SSTRs 1, 2 and 4 were seen, especially in the papillary dermis. Conclusions. The presence of SSTRs in palmoplantar skin, and specifically at high density in the sweat glands and ducts, might be of particular importance in skin neuroimmunoendocrinology. Although the relevance of the changes in SSTR expression in PPP skin compared with normal skin is unclear, our hypothesis is that these differences might influence the function of both the neuroendocrine and neuroimmunological properties of palmoplantar skin, especially in the sweat‐gland apparatus.     

Evidence for gamma-melanocyte stimulating hormone containing nerves and neutrophilic granulocytes in the human skin by indirect immunofluorescence

gamma-melanocyte stimulating hormone (gamma-MSH)-like immunoreactivity has been found by indirect immunofluorescence in nerve fibers and terminals as well as in neutrophilic granulocytes of normal human skin. A preferential localization to sensory nerves was seen; abundant nerve fibers displaying gamma-MSH immunoreactivity were observed as free nerve endings in the basal layer of the epidermis and in the upper dermis, close to the Merkel cells, in Meissner's corpuscles, around the external root sheath of the lower part of the hair follicles, and in nerve bundles of the deeper parts of the dermis. Very few fibers were seen to be associated with sweat glands and most blood vessels, although arterioles were densely innervated. Thus, gamma-MSH should be considered for possible role as a sensory or axon-reflex chemical messenger. Furthermore, the presence of gamma-MSH in neutrophilic granulocytes raises the possibility that gamma-MSH may play a role in the genesis of post-inflammatory hyperpigmentation, nevi, and melanomas.     

Generalized argyria with low ceruloplasmin and copper levels in the serum. A case report with clinical and microscopical findings and a trial of penicillamine treatment

This paper describes a 45-year-old man with generalized argyria and low ceruloplasmin and copper levels in the serum. During a trial of penicillamine treatment the urine excretion of silver rose markedly although after 6 months therapy no change in skin colour was noted. Light and electronmicroscopy of the skin both before and after penicillamine showed that silver particles were deposited especially in the basement membrane around eccrine sweat glands and elastic fibres of the papillary dermis. The epidermis and sebaceous glands were free from silver deposits.     

Mast cell tryptase and chymase in developing and mature psoriatic lesions

The number and distribution of mast cells in nonlesional and lesional skin samples from 13 psoriatic patients were analyzed enzyme- and immunohistochemically. Mast cell tryptase was stained with the sensitive substrate Z-Gly-Pro-Arg-4-methoxy-2-naphthylamide, and chymase with Suc-Val-Pro-Phe-MNA and monoclonal B7 anti-chymase antibody. In addition, healthy-looking skin from 27 psoriatic patients was tape-stripped resulting in induction of the Köbner response in 9 patients. Sequential biopsies were taken before and after (7, 14 and 21 days) tape-stripping, and both tryptase and chymase were stained enzyme-histochemically. In nonlesional psoriatic skin, 70 ± 24% (mean ± SD) of the mast cells contained chymase enzyme activity, and 78 ± 18% chymase immunoreactivity. About 10% of the chymase-immunoreactive cells lacked chymase activity. In lesional psoriatic skin, tryptase-positive cells were increased in number throughout the dermis but especially beneath the epidermis. Chymase immunoreactivity paralleled the tryptase activity, whereas chymase activity was strongly diminished both in terms of mast cell numbers and in staining intensity in the papillary dermis. The apparent inactivation of chymase may be due to the action of the chymase inhibitors, ₁-antitrypsin and ₁-antichymotrypsin, localized immunohistochemically in mast cells of lesional and nonlesional psoriatic skin. In the developing psoriatic lesion, mast cells displaying chymase activity were already 27–38% decreased in number in the upper dermis on day 7 after tape-stripping, along with the first clinical signs of psoriasis. Earliest alterations in tryptase-positive cells were observed on day 14 as increased mast cell contacts with the epidermis combined with only a slight increase in mast cell numbers in the upper dermis. During the development of a psoriatic lesion, TC mast cells (tryptase⁺, chymase⁺) increase in number in the upper dermis, but chymase becomes inactive at an early stage. The abundant presence of active trypase but inactive chymase in the upper dermis may have a potential role in psoriasis since both of these enzymes can process several biologically active peptides and proteins.