Acute generalized exanthematous pustulosis in cystic echinococcosis: immunological characterization.

We report the first case, to the best of our knowledge, of a woman suffering from cystic echinococcosis of the liver, who consequently developed urticaria and acute generalized exanthematous pustolosis (AGEP). Serum immunoglobulin (Ig)E and IgG4 specific to Echinococcus granulosus antigens were detected by immunoblotting. Furthermore, the intracellular cytokine analysis revealed a prevalent T-helper 2 polarization. It can be reasoned that, while the presence of IgE specific to various E. granulosus allergens may be responsible for the chronic urticarial manifestations, the detection of IgG4 specific for E. granulosus antigens, forming immunocomplexes, may be related to the development of the AGEP.

Expression of metallothioneins-I and -II isoforms at positive patch-test sites.

The expression and the distribution of metallothioneins (MT)-I and II isoforms were evaluated in 5 healthy volunteers and in 16 subjects with positive patch test reactions to various compounds. Skin specimens taken both from the healthy skin of the back and at positive patch test sites (at 48 h), were treated using a 3-step indirect immunoperoxidase procedure with a mouse monoclonal IgG1 antibody reactive against I and II isoforms of human, rat and horse MT. MT were expressed in the basal layer of the healthy skin of both controls and sensitive subjects, without any significant difference. At positive patch test sites, there was an overexpression of MT in basal and suprabasal layers of the epidermis. Overexpression of MT, related to the degree of the inflammatory reactions elicited by the penetrating compounds was observed in the dermis. The cells expressing MT in the dermis were mostly T lymphocytes and cells with dendritic morphology which positively stained in part for CD34 and in part for XIIIa markers and negatively for KP1, S100 and HLA-DR. Taken together, these results seem to indicate that MT represent a constitutive mechanism of defence expressed by different types of cells in the skin, which is triggered by contact with both metallic and non-metallic compounds. The biological significance of MT in the skin remains to be elucidated. Our preliminary findings do not permit evaluation of whether these nearly ubiquitous proteins exert their cytoprotective effects in the skin acting simultaneously as antioxidant, metal binding or zinc suppliers, or if they display these activities mainly depending on the nature of the penetrating substances.

Thimerosal positivities: patch testing to methylmercury chloride in subjects sensitive to ethylmercury chloride.

The aim of this paper was to evaluate whether methylmercury chloride (MeHgCl) aq., when patch tested in a group of thimerosal-positive subjects reacting to ethylmercury chloride (EtHgCl), might be a reliable model for the better understanding of interactions between alkylmercury compounds and the skin. 19 out of 21 consecutive patients who previously had given positive patch-test reactions to both ethylmercury chloride 0.0165% eth.(EtHgCl, 0.615 mM) and MeHgCl 0.031% aq.(1.23 mM), and negative reactions to thiosalicylic acid 0.05% (3.24 mM) aq./eth. 50/50, were repatch tested to 8 microl of MeHgCl 0.031% aq. and to 8 microl of aq. solutions containing MeHgCl mixed with cysteine, glutathione, ZnSO4, MgSO4, MnSO4, ZnCl2, MgCl2 and MnCl2, respectively. The results showed that cysteine, glutathione and Zn(II) salts were able to abolish the positive reactions, demonstrating the rôle played by both thiol groups and Zn(II) itself. Patch tests concomitantly carried out in 16 out of 19 patients to 8 microl of aqueous MeHgCl and to 8 microl of aqueous solutions containing MeHgCl and MeHgCl mixed to fragment 56-61 of metallothionein I (MT I), MT I and MT II-Zn, respectively, revealed that all the MTs tested were able to reduce or to inhibit the reactions, demonstrating the effect of the thiol groups. Due to the close chemical similarities to EtHgCl and to its water solubility, MeHgCl seems to be a suitable model for evaluating the reactivity of alkylmercury compounds in the skin. We speculate that both EtHg- and MeHg-derivatives are xenobiotics with similar reactivity. However, the lack of clinical relevance of the reactions to both alkyl compounds lead us to conclude that, since environmental exposure does not seem to play a pivotal rôle, they probably have mostly to do with compounds included in in the standard series, and are elicited by reduced function of physiological SH chelators.

The influence exerted by cutaneous ligands in subjects reacting to nickel sulfate alone and in those reacting to more transition metals.

To study the influence exerted by cutaneous ligands in nickel reactions we have evaluated the patch tests responses to 4 aqueous nickel salts (sulfate, chloride, nitrate, acetate) able to form different complexes with different geometry. Two groups of respectively 71 subjects who previously reacted only to nickel sulfate 5% petrolatum (pet) and of 30 subjects who previously reacted to nickel sulfate 5% pet and to at least 1 other transition metal, were simultaneously repatch-tested to 200 microg of Ni++ contained in nickel sulfate in pet and to 47 microg of Ni++ contained in 4 different aqueous nickel salts. Another 2 groups of 25 subjects with the same characteristics were simultaneously repatch tested to 200 microg of Ni++ in pet and to 12 microg of aq Ni++ as in the first 2 groups. Visual score, total score, and mean value of the reactions were utilized in evaluating the degree of the responses. On testing to 200 microg of Ni++ in pet all the subjects were able to give positive responses. Whilst a higher percentage of the responses of 2+ degrees was found in subjects reacting to nickel sulfate 5% pet alone, a higher percentage of responses of 3+ degrees was observed in subjects reacting to more transition metals. On testing to 47 and 12 microg of aqueous Ni++ a large variability of responses to the single salts was observed in all the subjects. However, in subjects reacting to more metals there were either a greater number of multiple responses to 3 or 4 salts or responses stronger than those found in subjects reacting to nickel sulfate alone. Although patch testing cannot give us complete information about the degree of previous exposure, the results arising from the tests seem to demonstrate that the subjects allergic to nickel and other transition metals are more reactive than the subjects allergic only to nickel to the application of the same amounts of Ni++ contained in different salts. When considering the QSAR model, the difference in the sensitizing potential of the metal at the same penetration properties can depend on the possibility of combining with specific ligands. Therefore, it is likely that in subjects reacting to more metals there is a more uniform availability of cutaneous ligands which conditions the formation of complexes more immunogenic. The arising inflammatory reaction in these cases leads to a stronger but less specific response.

Thimerosal positivities: the rôle of SH groups and divalent ions.

For a better understanding of the mechanistic details of the interactions of organomercury compounds inside the skin, 32 subjects who previously had given positive patch-test reactions to thimerosal (TH) and negative reactions to thiosalicylic acid, were divided into 2 groups. 16 subjects were repatch tested to ethylmercury chloride (EtHgCl) and to solutions containing EtHgCl mixed with L-cysteine and glutathione, respectively. The remaining 16 were repatch tested to EtHgCl and to solutions containing EtHgCl mixed with chlorides of Zn, Mg, and Mn, respectively. The results showed that whilst L-cysteine, glutathione and ZnCl2 were able to abolish or to reduce the positive reactions to EtHgCl, chlorides of Mg and Mn were unable to do so. Patch tests revealed that in causing positive reactions to TH, EtHg probably interacted with thiol groups and with Zn ions, as in biological systems when causing toxic effects. The limited number of TH reactions in the general population, the constant presence of concomitant positive reactions to EtHgCl and MeHgCl, and the lack of cross-reactivity with other organic or inorganic mercury compounds, lead us to speculate that reactions to TH are due to organomercury alkyl compounds, and that positive subjects have a constitutively reduced capability to metabolize organomercury compounds, rather than to reveal previous exposure.

Multiple sensitivities to transition metals: the nickel palladium reactions.

Patch test data of 1000 consecutive patients sensitive to at least 1 substance of our standard series showed that transition metals gave associated reactions amongst themselves more frequently than they did with the remaining substances. The responses to transition metals were largely variable and seemed dependent not only upon the associated exposure to different metals or the concomitant responses of the T cell clones, as reported by others, but also upon the chemical properties of the metals and the consequent interactions inside the skin. Concomitant reactions to nickel sulfate and palladium chloride were the most frequently found associated positivities and occurred in a minority of nickel-sulfate-sensitive subjects. In 43 out of 45 of these subjects, patch tests to mixed solutions containing nickel sulfate, plus sulfates of magnesium, zinc, and manganese at higher doses, were not able to reduce the nickel sulfate reactions. This behaviour contrasted with that found in the majority of subjects sensitive only to nickel sulfate. These findings seem to demonstrate that, whilst in subjects with positive reactions to nickel sulfate alone antigen formation involves biomolecules containing ions, in those with concomitant reactions to palladium chloride, other structures are involved.

Nickel chloride/chlorides of divalent metal interactions in nickel-sensitive subjects.

To verify if the counter-ion Cl- permits the same interactions between nickel and divalent metals with physicochemical similarities as the counter-ion SO4- does, 50 sensitive subjects to nickel sulfate 5% pet. who previously gave positive patch test reactions either to 8 mu 1 of aq. nickel sulfate 0.1 M or to 8 mu 1 of aq. nickel chloride 0.1 M, or to both, were patch retested simultaneously to 8 mu 1 of, respectively, aq. nickel sulfate 0.1 M and aq. nickel chloride 0.1 M, and to 8 mu 1 of aq. mixed solutions containing, respectively, nickel chloride 0.1 M+magnesium chloride 0.3 M, nickel chloride 0.1 M+zinc chloride 0.3 M, nickel chloride 0.1 M+zinc chloride 0.5 M, nickel chloride 0.1 M+manganese chloride 0.3 M, and nickel chloride 0.1 M+manganese chloride O.5 M. Whilst 4 subjects gave a positive patch test response to only nickel sulphate, 8 gave a positive response to nickel chloride alone and the remaining 38 gave a concomitant positive response to both. In all subjects who gave positive responses to nickel chloride, the chlorides of divalent metals were not able to inhibit or reduce the positive reaction. 25 healthy subjects patch tested to both single salts and mixed solutions, and all gave negative responses. 9 of the 50 subjects, 4 who previously gave positive reactions to only nickel chloride 0.1 M, and 5 with concomitant reactions of equal intensity to both nickel chloride and nickel sulfate 0.1 M, were patch retested simultaneously to 8 mu 1 of, respectively, aq. nickel sulfate 0.1 M, aq. nickel chloride 0.1 M and aq. mixed solutions containing nickel sulfate (0.1 M) mixed with sulfates (0.3 M) and nickel chloride (0.1 M) mixed with chlorides of Mg, Zn, Mn (0.3 M). Whilst the mixed sulfate solutions were able to reduce nickel sulfate, 0.1 M patch test positive reactions, those containing chlorides, at all concentrations tested, did not inhibit the nickel chloride reactions in any of the subjects. The results of the tests to chlorides, compared to those reached on testing to sulfates of the same metals, lead us to hypothesize that the anion probably affects the uptake and local tissue distribution of the metal, modulating in this way, together with the individual cutaneous ligands, its effects.

Interactions of sulfates of divalent metals in nickel-sulfate-sensitive patients.

70 nickel-sensitive subjects who previously gave positive patch test response to 10 microliters of nickel sulfate 0.1 M, were patch tested to 10 microliters of mixed aqueous solutions containing nickel sulfate 0.1 M+magnesium sulfate 0.3 M, nickel sulfate 0.1 M+zinc sulfate, 0.3 and 0.5 M, respectively, nickel sulfate 0.1 M+ manganese sulphate 0.3 and 0.5 M, respectively nickel sulphate 0.1 M+ cadmium sulfate 0.1 and 0.3 M, respectively, nickel sulfate 0.1 M+iron sulfate (III) 0.1 and 0.3 M, respectively, and to 10 microliters of aq. cadmium sulfate 0.1 M, aq. cadmium sulfate 0.3 M, aq. iron sulfate 0.1 M, aq. iron sulfate 0.3 M. The results showed that, whilst sulfates of divalent metals with similar size and redox properties (Mg, Zn and Mn) were able to reduce or to suppress, in a dose-dependent way, the majority (75%) of nickel reactions, those with large radius and different oxidation state(Fe III), generally gave an increase in the reactions. In about 15% of the tested subjects, an increase in all the positive reactions to the mixed solutions was found. The findings seem to demonstrate that in only a majority but not all of nickel sulfate allergic reactions, is Ni(II) able to substitute for divalent ions with similar properties at the ion sites of some proteins. This tendency reproduces the results of experimental systems, in which nickel toxicity and cancerogenity are considered responsible. In contrast, in about 15% of the tested subjects, there was a general enhancement of the reactions. In these cases, either the occurrence of a "hyper-irritable" skin caused by the adopted test system or, more likely, the formation of Ni complexes with different geometries, is hypothesized.

Nickel/magnesium interactions in nickel-sensitive patients.

Experimentally demonstrated interactions between Ni2+ and Mg2+ were examined in human beings. 110 subjects patch-test-positive to 10 microliters aq. NiSO4 0.1 M were subdivided into groups of 30, 50 and 30 people. Each subgroup was tested to 10 microliters NiSO4 0.1 M solution as a control and to mixed solutions containing NiSO4 0.1 M together with, respectively MgSO4 0.1 and 0.3, 0.3 and 0.5 and 0.5 and 1 M. On increasing the applied concentrations of MgSO4, the % of patients with reduced or suppressed nickel reactions, with 1 exception, proportionally increased. The exception concerned testing with 0.5 M, where a paradoxically exacerbating increase in nickel reactions was seen in a majority of nickel-sensitive subjects. MgCl2 aq. at 0.3, 0.5 and 1 M concentrations was not able to reduce the cutaneous patch test positive reactions to NiCl2 0.1 M in 25 sensitive patients. On increasing the applied concentrations of MgCl2, both the number and intensity of patch test reactions to NiCl2 proportionally increased. A supposed rôle of the sulfate and chloride counterions in the penetration of nickel was examined in 30 NiSO4 5% patch-test-positive patients, testing to 10 microliters of aq. NiSO4 0.1 M, NiCl2 0.1 M, NiSO4 0.1 M + MgCl2 0.3 M, NiCl2 0.1 M + MgSO4 0.3 M, Na2SO4 0.3 M, NaCl 0.3 M, NiSO4 0.1 M + Na2SO4 0.3 M, NiCl2 0.1 M + NaCl 0.3 M. The findings suggest that the addition of sulfate or chloride to nickel could determine the formation of different Ni complexes directed toward different targets, one Mg(2+)-dependent, the other Mg(2+)-independent.

Serum and urine concentrations in nickel-sensitive patients after prolonged oral administration.

8 nickel-sensitive subjects were given a gradually increasing daily oral intake of NiSO4 in water. The exposure lasted from between 91 and 178 days and the total intake ranged from between 113 and 278 mg of Ni++. While 6 subjects were continuously exposed over the entire period, the other 2 were exposed for 2 shorter periods with an interval between the 2 exposures of 84 and 63 days, respectively. Nickel exposure was well tolerated by all subjects, and there was no worsening of the cutaneous manifestations. Ni++ serum and urine concentrations were repeatedly assayed. A reduction of intestinal adsorption and an activation of the renal excretion were shown through an evaluation of the ratios of Ni++ serum concentration/Ni++ cumulative oral intake, Ni++ urinary amount/nickel cumulative oral intake and Ni++ serum amount/Ni++ urine amount. The course of Ni++ faecal amounts, calculated indirectly, increased rapidly in time and was consistent with the other courses. In many subjects, the decrease in serum concentrations was followed by a slight increase. It is likely that this phenomenon is due to the release of epidermally stored nickel. These data seem to indicate that in some sensitive subjects, prolonged oral exposure to NiSO4 in water reduces the intestinal adsorption of nickel and activates its renal excretion, also promoting the mobilization of accumulated element.

Interaction of metals in nickel-sensitive patients.

Nickel (Ni) dermatitis is thought to involve the formation of complexes between Ni ions and suitable proteins. 4 groups of 30 subjects who gave positive patch test responses to NiSO4 2.9% aq. were each retested to 1 of 4 different solutions containing equimolar (0.1 M) amounts of NiSO4 plus MgSO4, NiSO4 plus CuSO4, NiSO4 plus ZnSO4, and NiSO4 plus Li2SO4, respectively. The results, evaluated at 2 days by visual scoring only, demonstrated that the 4 metals exerted a different influence on the nickel reactions, perhaps interfering with one or more factors affecting the formation of Ni+ + complexes.

Contact dermatitis in hairdressers: the Italian experience. Gruppo Italiano Ricerca Dermatiti da Contatto e Ambientali.

A multicenter study was performed in 9 Italian centers by members of the GIRDCA, to evaluate the frequency and source of contact sensitization in a group of 302 hairdressers with dermatitis. Occupational habits and use of preventive measures were specifically investigated both in these 302 hairdressers and in a further group of 240 hairdressers who answered a questionnaire. The results showed the presence of an occupationally relevant sensitization in 60.9% of the 302 hairdressers. This proportion included 52 hairdressers who had negative patch tests to the hairdressers' series but showed positive reactions to other allergens, such as nickel, rubber additives, preservatives and fragrances, which were judged relevant to their occupation. Among hair dyes, PPD caused 73 reactions (24.2%), PAP 32 reactions (10.6%), ONPPD 24 reactions (7.9%), and PTD 40 reactions (13.2%). A low incidence of sensitization was detected in our hairdressers to resorcinol and pyrogallol (1.3% for each substance). Among permanent wave allergens, positive reactions to GMTG were found in 11.3% of patients, while ATG gave a lower rate of positive reactions (5.0%). Allergic contact dermatitis due to APS was also relatively common (11.3%). 4 hairdressers in this study gave a positive reaction 30 min after a provocative test with latex gloves, patch testing to the rubber series being negative. Enquiry regarding preventive measures revealed that the majority of hairdressers use gloves when doing hair dyeing, but rarely use them for washing dyed hair or for doing permanent waving. The infrequent use of preventive measures by Italian hairdressers was confirmed by the results of the questionnaire, and possibly explains the high frequency of skin problems (12.5%) in the hairdressing population that was specifically interviewed.

Nickel-keratinocyte interaction: a possible role in sensitization.

Normal human keratinocytes and the keratinocyte-derived cell lines NCTC 2544 and A 431, were exposed for different periods (1-5 days) to various concentrations (0.023-46.6 micrograms/ml) of nickel (Ni2+). A dose- and time-dependent inhibition of cell growth and viability was observed. Cultures exposed to 2.3 micrograms Ni2+/ml showed approximately 50% cell survival at 5 days. An increase in release of interleukin 1 by keratinocytes was detected following culture for 24 h with a Ni2+ concentration of 2.3-11.5 micrograms/ml. Short periods of incubation (30 min) with these concentrations induced an activation of lipoxygenase in leucocytes from healthy subjects, without modifying cell viability. The results suggest that the percutaneous penetration of small amounts of Ni2+ can result in damage to keratinocytes and can initiate sensitization.

Serum concentrations in nickel-sensitive patients after prolonged oral administration.

11 nickel-sensitive subjects were given a gradually increasing daily oral intake of NiSO4 in water. The treatment lasted from between 49 and 152 days and the total intake ranged from 56.43 to 271.70 mg of Ni++. Ni serum concentrations were repeatedly assayed. While the values varied irregularly in the first assessments, they then tended to diminish and to be lower than those found at basal level. The ratio of Ni serum concentration to oral intake demonstrated that, as the doses administered increased, the absorption of nickel decreased. We hypothesize that this trend might be due to an intestinal adaptivity that reduces nickel absorption.

Epidermolytic hyperkeratosis: generalized form in children from parents with systematized linear form.

Two unrelated families are presented in both of which a child with generalized epidermolytic hyperkeratosis (congenital bullous ichthyosiform erythroderma) had a parent with linear epidermolytic hyperkeratosis (epidermolytic epidermal naevus). Light and electron microscopy of skin biopsies of lesions from the children and parents showed typical epidermolytic hyperkeratosis. Gonadal mosaicism in patients with linear epidermolytic hyperkeratosis may be responsible for transmission of the abnormality to the offspring.

Nickel dermatitis from cheap earrings.

In 1988, 64% of our patients patch test positive to at least 1 allergen of the ICDRG standard series were nickel sensitive. In 70% of 300 patients evaluated, dermatitis started on the earlobes and was related to the regular wearing of cheap earrings. At the same time, 62% of 735 young schoolgirls were found to have dermatitis of their earlobes and all regularly wore cheap earrings. 9 clasps and clips commonly used in earrings released high quantities of nickel ions (between 49 and 103 micrograms/12 h), having been stored in synthetic sweat. A round piece cut from a clasp was taped to the skin of 30 nickel-sensitive patients, previously tested with 20 microliters of NiSO4 5%, 2.5%, 1% aq. solutions, giving a response similar to that caused by the 5% solution. High daily absorption of Ni ions through the skin follows its repetitive exposure to cheap earrings, causing, firstly, a direct inflammatory reaction, then followed, in our opinion, by sensitization.

Nickel sensitivity: effects of prolonged oral intake of the element.

25 nickel-sensitive females were given 10 mg NiSO4 in water in a single dose. 18 experienced generalized or localized flare-ups. 15 days later, 17 of the 25 patients were given gradually increasing daily doses of NiSO4 in water for 3 months. 14 ended the trial without flare-up, 3 had to stop because of intense worsening of cutaneous manifestations. A relationship does exist between the daily oral intake of nickel and its clinical manifestations, but it is not uniform and depends on the changing quantities and, above all, on the manner of intake. It would seem that a 10 mg NiSO4 oral challenge represents a sudden and large intake of the element to which the majority of sensitized subjects are not able to adapt. On the other hand, a gradual intake permits a majority of subjects to adapt to the element. We hypothesize that this behaviour is more likely due to intestinal adaptivity than to immunological tolerance.