Nickel Allergic Contact Dermatitis Research Articles

Nickel allergy is associated with a broad spectrum cytokine response.

Nickel-induced proliferation or cytokine release by peripheral blood mononuclear cells may be used for in vitro diagnosis of nickel allergy. Aim of this study was to explore the nickel-specific cytokine profile to further elucidate the pathogenesis of nickel allergic contact dermatitis (ACD) and to identify potential new biomarkers for nickel ACD. Peripheral blood mononuclear cells from patients and controls were cultured with T-cell skewing cytokine cocktails and/or nickel. Cytokine and chemokine concentrations were assessed in culture supernatants using validated multiplex assays. Specific cytokine production was related to history of nickel allergy and patch-test results. Twenty-one of the 33 analytes included in the analysis were associated with nickel allergy and included type1 (TNF-α, IFN-γ, TNF-β), type 2 (IL-3, IL-4, IL-5, IL-13), type 1/2 (IL-2, IL-10), type 9 (IL-9), type 17/1 (IL-17A[F], GM-CSF, IL-21) and type 22 (IL-22) derived cytokines as well as the T-cell/antigen presentation cell derived factors Thymus and activation regulated chemokine (TARC), IL-27 and IP-10. Receiver operator characteristics (ROC) analysis showed that IL-5 was the strongest biomarker for nickel allergy. A broad spectrum of 33 cytokines and chemokines is involved in the allergen-specific immune response in nickel allergic patients. IL-5 remains, next to the lymphocyte proliferation test, the strongest biomarker for nickel allergy.

METAL-INDUCED PROTEIN DENATURATION: REGULARITIES, PATHOLOGICAL MANIFESTATIONS, AND IN VITRO MODELING

the ability of various metal ions to form complexes with proteins leads to the denaturation of the latter and the development of immune response. Such hapten effects cause the well-known phenomenon of nickel-allergic contact dermatitis. No less typical are side effects of gadolinium compounds, that are used as contrasts for magnetic resonance imaging, but cause the development of fibrosis. In both cases an important role belongs to the interaction of metal ions with collagen structures. The aim of our study was to compare in vitro effects of copper and nickel ions on destabilized products of collagen cleavage. Significant difference between these metals in their ability to induce aggregation at close to physiological pH values was shown. The influence on the aggregative process of the acidification of the medium was revealed. It was shown that destabilization of protein structure leads to the formation of highly stabilized β-stacked protein aggregates. Comparison of the obtained experimental data with the literature ones makes it possible to approach the understanding of individual mechanisms of toxic effects of metal ions on the human body.

Nickel Sensitivity Is Associated with GH-IGF1 Axis Impairment and Pituitary Abnormalities on MRI in Overweight and Obese Subjects.

Nickel (Ni) is a ubiquitous metal, the exposure of which is implied in the development of contact dermatitis (nickel allergic contact dermatitis (Ni-ACD)) and Systemic Ni Allergy Syndrome (SNAS), very common among overweight/obese patients. Preclinical studies have linked Ni exposure to abnormal production/release of Growth Hormone (GH), and we previously found an association between Ni-ACD/SNAS and GH-Insulin-like growth factor 1 (IGF1) axis dysregulation in obese individuals, altogether suggesting a role for this metal as a pituitary disruptor. We herein aimed to directly evaluate the pituitary gland in overweight/obese patients with signs/symptoms suggestive of Ni allergy, exploring the link with GH secretion; 859 subjects with overweight/obesity and suspected of Ni allergy underwent Ni patch tests. Among these, 106 were also suspected of GH deficiency (GHD) and underwent dynamic testing as well as magnetic resonance imaging for routine follow up of benign diseases or following GHD diagnosis. We report that subjects with Ni allergies show a greater GH-IGF1 axis impairment, a higher prevalence of Empty Sella (ES), a reduced pituitary volume and a higher normalized T2 pituitary intensity compared to nonallergic ones. We hypothesize that Ni may be detrimental to the pituitary gland, through increased inflammation, thus contributing to GH-IGF1 axis dysregulation.

Child of steel

Allergic reactions to metal implants have been on the rise reaching an incidence of 10-17% in the general population. In Asia, nickel ranks among the top five most common source of metal sensitivity. We present a case of nickel allergic contact dermatitis secondary to an orthopaedic implant. 12/M with chronic osteomyelitis of the left tibia presented with non-union of the bones necessitating an Ilizarov fixator implant using conventional SAE 16 stainless steel plate and bone graft. After 9 months, there was paucity of the bone allograft necessitating adjustment of the Ilizarov fixator and repeat bone allograft. 2 weeks after the second revision of the metal implant, the child manifested with pruritic wheals on both his flanks lasting for a week. Months later, the wheals developed along the pin tracts with serous exudate. Orthopaedics entertained a possible hypersensitivity to the metal implant and the fixator was removed. For further work-up, the child was referred to dermatology and allegro-immunology service whereupon further history revealed that he has a prior undocumented allergy to metal accessories when he was 6 years old. A patch test was later performed revealing +1 reaction to nickel. Failure of the union of the left tibia and decreasing function of the left leg necessitated a below-knee amputation and subsequent application of a prosthetic limb. This is a rarely reported case of metal implant allergy in a pediatric patient presenting as failure in wound healing and non-union of tibial fracture. This case further emphasizes the importance of a complete medical history in assessing a patient with possible metal allergy and its proper diagnosis and management. This case also highlights the possible role of metal exposure and the patient’s chronic infection in the pathogenesis of bone non-union.

Nickel Allergic Contact Dermatitis: Identification, Treatment, and Prevention.

Nickel is a ubiquitous metal added to jewelry and metallic substances for its hardening properties and because it is inexpensive. Estimates suggest that at least 1.1 million children in the United States are sensitized to nickel. Nickel allergic contact dermatitis (Ni-ACD) is the most common cutaneous delayed-type hypersensitivity reaction worldwide. The incidence among children tested has almost quadrupled over the past 3 decades. The associated morbidities include itch, discomfort, school absence, and reduced quality of life. In adulthood, individuals with Ni-ACD may have severe disabling hand eczema. The increasing rate of Ni-ACD in children has been postulated to result from early and frequent exposure to metals with high amounts of nickel release (eg, as occurs with ear piercing or with products used daily in childhood such as toys, belt buckles, and electronics).To reduce exposure to metal sources with high nickel release by prolonged and direct contact with human skin, Denmark and the European Union legislated a directive several decades ago with the goal of reducing high nickel release and the incidence of Ni-ACD. Since then, there has been a global reduction in incidence of Ni-ACD in population-based studies of adults and studies of children and young adults being tested for allergic contact dermatitis. These data point to nickel exposure as a trigger for elicitation of Ni-ACD and, further, provide evidence that legislation can have a favorable effect on the economic and medical health of a population.This policy statement reviews the epidemiology, history, and appearances of Ni-ACD. Examples of sources of high nickel release are discussed to highlight how difficult it is to avoid this metal in modern daily lives. Treatments are outlined, and avoidance strategies are presented. Long-term epidemiological interventions are addressed. Advocacy for smarter nickel use is reviewed. The American Academy of Pediatrics supports US legislation that advances safety standards (as modeled by the European Union) that protect children from early and prolonged skin exposure to high-nickel-releasing items. Our final aim for this article is to aid the pediatric community in developing nickel-avoidance strategies on both individual and global levels.

Does clinical testing support the current guidance definition of prolonged contact for nickel allergy?

BackgroundThe European Chemical Agency (ECHA) definition of prolonged contact was introduced in 2014 and has not been evaluated clinically.ObjectivesTo assess whether nickel‐sensitized individuals react on patch testing with high nickel‐releasing metal discs for short and repetitive periods.Materials and methodsWe patch tested 45 nickel‐sensitized individuals double‐blind with 2 different types of high nickel‐releasing discs for 10, 30 and 60 minutes on 3 occasions over a period of 2 weeks, and for 1 longer period. Discs were tested for nickel release.ResultsNickel release from both discs significantly exceeded the 0.5 μg Ni/cm2/week limit of the EU REACH nickel restriction. However, only 1 individual tested had a largely dose‐dependent allergic reaction.ConclusionsThe majority of nickel‐allergic subjects did not react to nickel discs after 2 hours or after repetitive exposures of up to 30 minutes on 3 occasions over a period of 2 weeks. The length of time needed to cause nickel allergic contact dermatitis in most nickel‐allergic individuals is longer than the ECHA guidance definition. Longer test times are needed to define the time required to cause dermatitis in most nickel‐allergic individuals. As a limitation, the test conditions did not adequately assess real‐life factors such as friction, which is relevant for some uses of nickel.

Low Nickel Diet: A Patient-Centered Review

Nickel allergic contact dermatitis (ACD) has become a more widely recognized disease process over the last three decades in the United States. A subpopulation of ACD patients will manifest with systemic contact dermatitis (SCD). Specifically, those cases of widespread recalcitrant nickel ACD with only partial clinical relief after strict nickel avoidance, suggest SCD. Evidence indicates that application of the low nickel diet has the highest efficacy in patients with SCD, and that a targeted, points-based approach is most meaningful. Furthermore, as the immunologic pathways of how oral nickel provokes cutaneous dermatitis are complex, involving interplay between the Th2 and Th1 response, more specific investigative work in this area is much needed.

Nickel Allergy and Our Children's Health: A Review of Indexed Cases and a View of Future Prevention.

Nickel is the leading cause of allergic contact dermatitis (ACD) from early childhood through adolescence. Studies have shown that skin piercings and other nickel-laden exposures can trigger the onset of nickel ACD in those who are susceptible. Nickel ACD causes a vast amount of cutaneous disease in children. Cases of nickel ACD in children have been reported in peer-reviewed literature from 28 states. Common items that contain inciting nickel include jewelry, coins, zippers, belts, tools, toys, chair studs, cases for cell phones and tablets, and dental appliances. The diagnosis of nickel ACD has been routinely confirmed by patch testing in children older than 6 months suspected of ACD from nickel. Unlike in Europe, there are no mandatory restrictions legislated for nickel exposure in the United States. Denmark has demonstrated that regulation of the nickel content in metals can lower the risk of ACD and the associated health care-related costs that arise from excess nickel exposure. To further awareness, this article reviews the prominent role of nickel in pediatric skin disease in the United States. It discusses the need for a campaign by caretakers to reduce nickel-related morbidity. Lastly, it promotes the model of European legislation as a successful intervention in the prevention of nickel ACD.

Clinical-Epidemiological Features of Nickel Hypersensitivity

Nickel is a chemical element found ubiquitously in the environment and is used with a high frequency worldwide. Nickel hypersensitivity could give rise both to contact dermatitis and to systemic contact dermatitis, the latter, as expression of ingestion or other systemic exposure to a contact allergen. The common clinical presentation of nickel allergic contact dermatitis (ACD) is more often a vesicular pruritic dermatitis in sites of prolonged skin contact with nickel-containing items. Patients can develop acute (bright red rash, edema and vesicle), subacute (less erythematous and edematous lesions, minimal vesiculation, and excoriation) and chronic manifestations (fissuring, scaling, excoriation and mild form of erythema). Systemic contact dermatitis is induced in sensitized individuals when they are exposed to a hapten systemically. In the detection of contact allergy, and in the diagnosis of ACD, patch test is the generally accepted method of choice and the “gold standard”. Their execution increases the probability of correct diagnosis, shortens the time lapse between first visit and final diagnosis, increases the chance for full remission, and reduces therapy costs. Management of nickel allergy is still complex for dermatologists. Between 1994 and 2009, nickel allergy showed a decreased in morbidity; however, after 2000, there was no significant decrease. Exposure to nickelcontaining products exceeding the permitted limit may explain the high persistence of nickel contact allergy in population. In 2001 the European Union, to reduce the exposure to nickel, introduced standards for the productions of tools intended for prolonged skin contact. Keywords: Allergy, hypersensitivity, metal ions, nickel, nickel dermatitis, secondary eruption, RCLM.

Systemic Nickel Allergy Syndrome: Nosologic Framework and Usefulness of Diet Regimen for Diagnosis

Systemic (gastrointestinal and skin) reactions to ingestion of nickel rich foods in patients with nickel allergic contact dermatitis characterize Systemic Nickel Allergy Syndrome (SNAS). The objective of the study was to describe the nosologic framework of the syndrome and to compare sensibility and specificity for SNAS diagnosis between two different low nickel diets - BraMa-Ni and the usually prescribed list of forbidden foods - along with patient adherence to diet. One hundred forty-five patients with suspected SNAS (by history and benefit from nickel dietary restrictions) were selected and orally challenged with nickel for a definite diagnosis. Specificity and sensibility of the diets were calculated in relation to the results of nickel challenges. The nosologic framework of SNAS was deduced from the clinical pictures of 98 patients with positive nickel challenge and characterized essentially by skin and gastrointestinal symptoms, whereas all other symptoms (dizziness, headache etc.) were never elicited by the oral nickel challenge. The specificity and sensibility of BraMa-Ni in detecting SNAS were significantly higher than the forbidden food list diet, with an excellent patient adherence. Therefore, BraMa-Ni diet can be prescribed for the treatment of the syndrome other than for the diagnosis, the gold standard of which remains the oral nickel challenge.

English

Association between atopy and development of allergic contact dermatitis (ACD) remains controversial. T cell disfunctions in a patient with atopy complicate the process of nickel sensitization. On the other, the decrease of the skin barrier function and overexpression of Langerhans cells in the patient facilitate the sensitization. This study aimed to evaluate the association between atopy and incidence of nickel ACD. A case-control study was carried out in Allergic and Immunology Sub Department of Dermato-Venereology Policlinic, Dr. Sardjito General Hospital, Yogyakarta, involving 54 nickel ACD patients as case group and 74 healthy subjects as control group. All subjects underwent prick test allergens i.e. house dust, dust mite, cockroach, mixed fungi, nuts and egg white. The skin reaction was considered as a positive result if a wheal diameter of at least 3 mm larger than the negative control or a minimum of half of the positive control. The relationship between atopy and the nickel ACD incidence was analyzed using Chi-Square test with confidence interval (CI) of 95%. A significant association between atopy and the nickel ACD incidence was observed in this study. Subjects with atopy to ≥1 allergen had risk of nickel ACD 3.74 higher than subjects without atopy (odds ratio/OR=3.74; 95%CI = 1.64-8.53). Furtheremore, subjects with atopy to ≥2 allergens had risk of nickel ACD 3.74 higher than subjects without atopy (OR=2.08; 95%CI = 1.01-4.29). In conclusion, atopy is a risk factor of nickel ACD.

Visual Diagnosis: 13-Year-Old Girl With Pink Papules

1. Meghan M. Dickman, MD 2. Ilona J. Frieden, MD 1. University of California, San Francisco (UCSF), San Francisco, CA. A 13-year-old girl presents to the clinic with pink papules on her abdomen, legs, arms, and the lateral aspects of her cheeks. The lesions have been present for 4 years, always appearing in the same area, with satellite lesions surrounding the primary site. The rash blanches on palpation. The papules are primarily located on her abdomen and become more prominent and pruritic with sun exposure. The rash is most noticeable in the periumbilical region, where the patient’s metal pants button comes in contact with her skin. The papules are accompanied by pruritus for which she gets mild relief by taking oral antihistamines and applying topical corticosteroids. However, she has been unable to completely get rid of the rash with this regimen. The patient has an unremarkable medical history and is developing appropriately. There are no similar skin lesions on any close contacts. On physical examination, the patient has multiple pink papules on the bilateral aspects of her cheeks, upper arms, elbows, knees, and lower legs (Fig 1). All vital signs are within normal limits. There are papules that have coalesced into plaques surrounding her umbilicus (Fig 2), with lichenification. There is evidence of excoriation, without any ulcerations or bleeding. The remainder of the physical examination findings are unremarkable. Figure 1. Multiple papules were noted on the arms (left) and legs (right) of the patient. Figure 2. The initial location …

Palladium‐induced Th2 cytokine responses reflect skin test reactivity

Recently, a crucial role of Th2 responses in nickel allergic contact dermatitis (ACD) was demonstrated. As palladium allergy is an issue of growing interest, the diagnostic potential of Th2 parameters for palladium sensitization was investigated. Palladium (Na(2) [PdCl(4)])-induced lymphocyte proliferation (LPT), Th1 and Th2 cytokine production were correlated with skin test (ST) reactivity in 16 positive and 21 negative controls. Furthermore, the diagnostic potential of these assays was evaluated using receiver operating characteristics (ROC) analysis. For comparison, same experiments were carried out for nickel (NiSO(4)). Correlation coefficients between palladium ST reactivity and IFN-γ, LPT, IL-5, and IL-13 were 0.34, 0.51, 0.69, and 0.78, and overall test accuracies were 68%, 81%, 89%, and 95%, respectively. Both palladium- and nickel-mediated Th2 responses tightly correlate with ST reactivity, supporting recent findings on the crucial role of Th2 involvement in ACD. Therefore, these assays may have great potential as diagnostic tools for future in vitro sensitization testing.

Nickel and cobalt allergy before and after nickel regulation – evaluation of a public health intervention

Over the 20th century, the frequent use of nickel in consumer products resulted in an increasing prevalence of nickel allergy. Risk items included suspenders in the 1950s-1960s; buttons, zippers and rivets in the 1970s; and ear-piercing jewellery in the 1980s. When subjects allergic to nickel were exposed to nickel in high concentrations, it often resulted in allergic nickel contact dermatitis and hand eczema. In 1990, the Danish government began to regulate consumer nickel exposure as a response to the increasing nickel allergy problem. In 1994, the EU Nickel Directive was passed, a regulation that was based on the Danish and Swedish nickel regulations. These major public health interventions were expected to change the epidemiology of nickel allergy and dermatitis in Europe. Furthermore, it was debated whether nickel would be replaced by cobalt in inexpensive jewellery and result in higher prevalence of cobalt allergy. An evaluation of the possible effects of the European nickel regulations is of importance to ensure protection of consumers and dermatitis patients. This doctoral thesis aimed to evaluate the effects of regulatory interventions on nickel exposure by investigating the development of nickel allergy and dermatitis before and after nickel regulation. Furthermore, a change in the association between nickel allergy and hand eczema was evaluated. The nickel spot test was validated to determine its value when used for screening purposes. Possible explanations for the persistence of nickel allergy were explored including genetic predisposition and consumer nickel exposure from jewellery and accessories. A cobalt spot test was developed and validated. Finally, it was evaluated whether a cobalt allergy epidemic had replaced the nickel allergy epidemic after nickel regulation in terms of increasing cobalt sensitization and cobalt exposure. The thesis showed that the prevalence of nickel allergy decreased significantly after nickel regulation in young Danish women from the general population (18-35 years) and in young Danish female dermatitis patients from a university patch test clinic (0-30 years). Stratification by ear-piercing status revealed that women ear pierced before 1990 had a significantly higher prevalence of nickel allergy and dermatitis than women ear pierced after 1990. Furthermore, the association between hand eczema and nickel allergy decreased in young women aged 18-35 years when a comparison was made between women who were patch tested and questioned in, respectively, 1990 and 2006. Despite the decreasing prevalence of nickel allergy, this condition remains prevalent in young Danish women, as about 10% are nickel allergic. Genetic predisposition to nickel allergy was evaluated by investigating the possible association between filaggrin null mutation status and nickel allergy. A positive association was found but it was also concluded that environmental nickel exposure is of much greater importance. Thus, of 354 consumer items purchased from 36 different stores in Copenhagen, 22% released nickel in concentrations that may result in nickel dermatitis in sensitized subjects. Therefore excessive consumer nickel exposure remains common in Denmark and may be an important explanation for the persistence of nickel allergy. Excessive nickel release was also frequent when samples of earrings purchased in Warsaw and London were examined with the nickel spot test, in particular earrings purchased from street markets and shops with independent ownership. Only very weak indications of an emerging cobalt allergy epidemic were found, as the prevalence of cobalt allergy has not yet increased in young people and only four of 354 consumer items purchased in Copenhagen released cobalt in concentrations that may result in cobalt dermatitis in sensitized individuals. The specificity of the nickel spot test was 98% and the sensitivity 59%. Also, a cobalt spot test was developed and validated and seemed to be a useful diagnostic tool. In conclusion, the Danish nickel regulation and the EU Nickel Directive have changed the epidemiology of nickel allergy in Denmark. However, the Nickel Directive and its reference methods need to be revised to better protect consumers and dermatitis patients.

Nickel Allergy: Localized, Id, and Systemic Manifestations in Children

Nickel is the most common allergen causing allergic contact dermatitis in patch-tested children, especially in female children. Allergy to this metal can manifest in a variety of ways. In this case series, we present four children to illustrate the different presentations of nickel allergy confirmed by patch testing. Localized, id, and systemic nickel reactions are reviewed, as well as the diagnosis and management of nickel allergic contact dermatitis. While localized dermatitis in areas of direct contact to the allergen is the most common and easiest form of nickel allergy to identify, recognition of varying presentations is critical as these can result in more chronic and severe symptoms, and can be misdiagnosed as atopic dermatitis.

Oral Hyposensitization to Nickel Induces Clinical Improvement and a Decrease in TH1 and TH2 Cytokines in Patients with Systemic Nickel Allergy Syndrome

Some patients with nickel (Ni) allergic contact dermatitis suffer from systemic (intestinal or cutaneous) symptoms after ingestion of Ni-rich foods and experience symptoms reduction with low-Ni diet, a condition termed Systemic Ni Allergy Syndrome (SNAS). We aimed at evaluating whether oral administration of low nickel doses improved clinical conditions and modulated immunological aspects of SNAS, without significant side effects. Thirty-six SNAS patients were enrolled. Treatment started after 1-month of low-Ni diet and consisted in an incremental oral NiOH dose phase (0.3ng to 1.5 microg/week) followed by a 12-months maintenance phase (1.5 microg/week). Randomly, twenty-four patients added Ni therapy to low-Ni diet and 12 remained with diet alone. All patients were allowed rescue medications (antihistamines and topical steroids). After 4 months, Ni-rich foods were gradually reintroduced. In vitro allergen-driven IL13, IL5 and IFN-gamma release by peripheral blood mononuclear cells was evaluated before and after treatment. Twenty-three patients receiving NiOH and the 12 control patients completed the study. Evaluation of SNAS clinical severity (by VAS and drug consumption) showed a significant difference in favor of NiOH-treated patients compared to controls. Twenty of 23 patients in the NiOH group and none in the control group tolerated Ni-rich food reintroduction. Release of all studied cytokines in culture supernatants was significantly lower after NiOH treatment. In conclusion NiOH is effective in reducing symptoms and drug consumption in SNAS and is able to modulate inflammatory parameters.

Serum levels of protein oxidation products in patients with nickel allergy

Nickel sensitization can not only induce allergic contact dermatitis (ACD), but also can induce an overlapping disease referred to as "systemic nickel allergy syndrome" (SNAS), characterized by urticaria/angioedema and gastrointestinal symptoms correlated to the ingestion of nickel-containing foods. This study was designed to determine if oxidative stress occurs in patients with nickel allergy. Thirty-one female patients (mean age 31.26 + 13.04 years, range 16-64 years) with confirmed nickel CD underwent oral nickel challenge because of clinically suspected SNAS; serum concentrations of protein carbonyl groups (PCGs) and nitrosylated proteins (NPs; biomarkers of oxidative stress) were measured before and after oral nickel challenge as well as in healthy female controls. Twenty-three of these 31 patients were diagnosed with SNAS because they had a positive reaction to the oral nickel challenge, and 8 patients had no reaction and therefore were classified as patients with contact nickel allergy only. Although both nickel-allergic patients and controls presented similar serum levels of PCGs, NP values in nickel-allergic patients appeared higher than in controls and tended to decrease after the challenge; furthermore, serum levels of NPs in patients affected by SNAS were higher (although not significantly) than in patients with nickel ACD only. The involvement of specific biomarkers of oxidative stress such as NPs and the lack of involvement of other biomarkers such as PCGs may help to better understand the alteration of the redox homeostasis occurring in nickel ACD and particularly in SNAS.

Prevention of Nickel Allergy: The Case for Regulation?

Nickel is the most common allergen detected in patch-tested patients. Nickel allergy is highest among females and patients under the age of 18, affecting 35.8% of patients patch-tested in this demographic. Nickel allergic contact dermatitis is a T-cell-mediated immune reaction which most commonly presents as a skin rash in areas exposed to nickel; however, more serious reactions to nickel in medical devices and more widespread eruptions to dietary nickel can occur. In contrast to Europe, where regulations have resulted in a decreasing prevalence of nickel allergy, the incidence of nickel allergic contact dermatitis in North America is increasing. This article summarizes primary prevention strategies as well as management of patients already sensitized to nickel.

Increased serum levels of IL‐22 in patients with nickel contact dermatitis

Nickel can elicit both Th1-type andTh2-type responses in vitro (1) inpatients with nickel allergic contactdermatitis,butthiscomplexcytokinecascade has still to be clarified. Therecently discovered Th17 subset,which has crucial functions in hostdefence against infections and hasbeen implicated in the developmentofautoimmunediseases(2),hasbeensupposed to play an important rolein some inflammatory and autoim-mune skin disorders, such as contacthypersensitivity(3)andpsoriasis(4),respectively. Th17 cells are charac-terized by expression of interleukin(IL)-6, tumour necrosis factor-a,granulocyte–macrophage colony-stimulating factor, IL-17A, IL-17F,IL-21, IL-22, and IL-26 (5).Among these cytokines, IL-22,a member of the IL-10 cytokine fam-ily, described as having proinflam-matory activities on liver, pancreas,intestine, and skin (reviewed in 6),has been demonstrated to have a cru-cial function in the development ofdermal inflammation and epidermalacanthosis induced by IL-23 in mice(4). Moreover, IL-22 seems to beinvolved in the pathogenesis of psori-asis in humans, as demonstrated bythehighserumlevelsshowedbypsori-atic patients and the high levels pro-duced by T cells isolated by psoriaticskin (6), where the IL-22 receptor isexpressed on a variety of epithelialtissues(4).However,nodataareavail-ableon thepossibleroleplayed byIL-22in nickel contacthypersensitivityinhumans, thus we measured the circu-latinglevelsofthiscytokineinpatientswith allergic nickel contact dermatitis.We enrolled 31 female patientsaffected by allergic contact dermatitisto nickel (mean age 31.9 years; range17–64 years) diagnosed followingpatch testing in accordance withthe International Contact DermatitisResearch Group guidelines. Bloodsamples were collected after patchtesting during a period of clinicalremission 1 month after nickel con-tact avoidance.15 sex- and age-matched blooddonors, with no contact dermatitisand negative patch tests, were re-cruited as controls. Each subject gavepreviously used written, informedconsent to the study.Serum IL-22 was measured usingan enzyme-linked immunosorbentassay kit (R&D System Europe,Abingdon, UK). All samples wereanalysed in duplicate.Differences in IL-22 blood levelswere assessed by the Student’s t-testfor unpaired comparison, assumingunequal variances. Data were ex-pressed as mean standard devia-tion. A P value <0.05 was consideredto be significant.IL-22 serum levels were signifi-cantly higher in patients affected bycontact dermatitis compared withcontrols (17.10 9.50 pg/ml versus8.61 7.25 pg/ml, P ¼ 0.002)(Fig. 1). No correlation between IL-22 levels and age was found.About 10 years ago, it was demon-stratedthatnickel-specificCD4Tcellsexpressing the cutaneous lymphocyte-associated antigen skin-homingrecep-tor can synthesize and release IL-17and that IL-17 modulates variousproinflammatory functions of kerati-nocytes, especially when actingtogether with interferon-g and IL-4(7). Zheng et al. have recently demon-strated that the injection of IL-23(a Th17-inducing cytokine) into miceears induces a model of psoriasis-likelesions characterized by epidermalacanthosis with inflammatory cellularinfiltration mediated by IL-17 andIL-22. These features decrease inIL-22-deficient mice (4), and theadministration of IL-22 neutralizingautoantibodies reduces acanthosis,inflammatory infiltrates, and expres-sion of Th17 cytokines (8). However,thehistologicalfeaturesfoundinthesemurine models are not exclusivelycharacteristic of psoriasis but of aller-gic contact dermatitis as well.*Theseauthorscontributedequallytothis work.

Genetics of Nickel Allergic Contact Dermatitis

Nickel sulfate is the most frequently detected cause of allergic contact dermatitis in the world; the prevalence of nickel allergic contact dermatitis is between 8 and 11% in the general female population. Although it is well recognized that environmental factors are important in the pathogenesis of this dermatitis, some investigators have hypothesized that genetic factors are important as well. This review summarizes animal and human studies evaluating genetic factors in the development of allergic contact dermatitis from nickel.