Nickel-allergic Patients Research Articles

Neutrophil infiltration in allergic contact dermatitis to nickel.

Allergic contact dermatitis (ACD) is traditionally recognized as a T-cell-mediated delayed-type hypersensitivity reaction. However, many patients with ACD have been reported to experience rapid-onset ACD reactions within hours of re-exposure on skin areas previously exposed to the contact allergen. In this study, three nickel-allergic patients were patch tested for nickel twice at the same skin site over 21 days. The results demonstrated that neutrophils are rapidly recruited to the skin sites previously exposed to nickel, leading to the rapid onset of ACD. Considering that many patients with ACD are frequently re-exposed to contact allergens on the same skin areas in their daily lives, we propose that mechanisms involved in neutrophil recruitment could be potential targets for future ACD treatment.

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.

Nickel hypersensitivity and endovascular devices: a systematic review and meta-analysis

ObjectiveNickel allergy is common; endovascular specialists are often confronted with nickel allergic patients ahead of the implantation of endovascular devices, many of which are nickel-containing. Our aim was to elucidate...

Integrative transcriptome analysis deciphers mechanisms of nickel contact dermatitis.

BackgroundNickel‐induced allergic contact dermatitis (nACD) remains a major occupational skin disorder, significantly impacting the quality of life of suffering patients. Complex cellular compositional changes and associated immunological pathways are partly resolved in humans; thus, the impact of nACD on human skin needs to be further elucidated.MethodsTo decipher involved immunological players and pathways, human skin biopsies were taken at 0, 2, 48, and 96 hours after nickel patch test in six nickel‐allergic patients. Gene expression profiles were analyzed via microarray.ResultsLeukocyte deconvolution of nACD‐affected skin identified major leukocyte compositional changes at 48 and 96 hours, including natural killer (NK) cells, macrophage polarization, and T‐cell immunity. Gene set enrichment analysis mirrored cellular‐linked functional pathways enriched over time. NK cell infiltration and cytotoxic pathways were uniquely found in nACD‐affected skin compared to sodium lauryl sulfate–induced irritant skin reactions.ConclusionThese results highlight key immunological leukocyte subsets as well as associated pathways in nACD, providing insights into pathophysiology with the potential to unravel novel therapeutic targets.

Identification and Characterization of Circulating Naïve CD4+ and CD8+ T Cells Recognizing Nickel.

Allergic contact dermatitis caused by contact sensitizers is a T-cell-mediated inflammatory skin disease. The most prevalent contact allergens is nickel. Whereas, memory T cells from nickel-allergic patients are well-characterized, little is known concerning nickel-specific naïve T-cell repertoire. The purpose of this study was to identify and quantify naïve CD4+ and CD8+ T cells recognizing nickel in the general population. Using a T-cell priming in vitro assay based on autologous co-cultures between naïve T cells and dendritic cells loaded with nickel, we were able to detect a naïve CD4+ and CD8+ T-cell repertoire for nickel in 10/11 and 7/8 of the tested donors. We calculated a mean frequency of 0.49 nickel-specific naïve CD4+ T cells and 0.37 nickel-specific naïve CD8+ T cells per million of circulating naïve T cells. The activation of these specific T cells requires MHC molecules and alongside IFN-γ production, some nickel-specific T-cells were able to produce granzyme-B. Interestingly, nickel-specific naïve CD4+ and CD8+ T cells showed a low rate of cross-reactivity with cobalt, another metallic hapten, frequently mixed with nickel in many alloys. Moreover, naïve CD4+ T cells showed a polyclonal TCRβ composition and the presence of highly expanded clones with an enrichment and/or preferentially expansion of some TRBV genes that was donor and T-cell specific. Our results contribute to a better understanding of the mechanism of immunization to nickel and propose the T-cell priming assay as a useful tool to identify antigen-specific naïve T cells.

Short contact with nickel causes allergic contact dermatitis

Allergic contact dermatitis is a common type of eczema that causes inflammation when skin comes into contact with certain substances. Although it is well accepted that long term skin contact can cause nickel allergy and dermatitis, the significance of relatively short and repeated nickel exposure in relation to induction and elicitation (i.e. first triggering) of nickel allergy has been less explored, and it has been proposed that short skin contact with nickel is safe. A study conducted in Denmark and Sweden attempted to test this proposition by examining whether repeated skin contact with nickel over short time periods would elicit allergic contact dermatitis. 16 adults who were known to have nickel allergy were tested along with a further 10 non‐allergic control subjects (a control subject is a healthy individual used for comparison). The subjects were exposed to nickel and aluminium discs on each forearm and each earlobe for 3 x 10 minutes. Also, one arm would be treated for 24 hours beforehand with 0.5% sodium lauryl sulfate (SLS) under occlusion (meaning the solution was applied then wrapped up with plastic wrap or cloth). SLS is added to bath products and detergents to make them foam and is a common cause of skin reactions. The purpose of this was to monitor differences in reactions to nickel in skin that was either normal or already irritated (by the SLS). Each nickel and aluminium site was evaluated and blood flow measured, as increased blood flow can show that skin is reacting to nickel. 62.5% of nickel allergic subjects reacted to nickel on the SLS treated arm. The nickel exposed skin also caused significantly more blood flow than aluminium exposed skin. No change in reactivity or blood flow was seen in any non‐SLS nickel exposed arms in nickel allergic patients, or in any control subjects. This study shows that relatively short repeated contact with nickel can elicit allergic contact dermatitis in irritated skin in people who already have a nickel allergy. The results support the restrictions in current nickel regulation.

Nickel Sulfate Promotes IL-17A Producing CD4+ T Cells by an IL-23-Dependent Mechanism Regulated by TLR4 and Jak-STAT Pathways

Allergic contact dermatitis, caused by nickel, is a delayed-type hypersensitivity reaction, and 14.5% of the general population may be affected in Europe. Among a wide range of cytokines, the IL-12 family has unique structural and immunological characteristics. Whereas IL-12p70 promotes T helper (Th) 1 cell polarization, IL-23 promotes Th17 cell development and both have been isolated from nickel-allergic patients. In this work, we were interested in understanding the mechanism behind nickel-induced Th17 cell development. We showed that nickel induced an early production of IL-23 in human monocyte-derived dendritic cells along with an increase in the expression of il-23p19 and il-12p40 mRNA. However, the production of a significant level of IL-12p70 required an additional signal such as IFN-γ. Moreover, nickel-treated monocyte-derived dendritic cells induced an increase in the percentage of IL-17A+ CD4+ T cells, an effect reduced by IL-23 neutralization. We then investigated the molecular mechanism of IL-23 production. Our results showed that toll-like receptor 4, p38 mitogen-activated protein kinase, and NF-κB were involved in IL-23 production induced by nickel. However, Jak-signal transducer and activator of transcription activation seems to maintain the IL-23/IL-12p70 balance by limiting IL-23 production and promoting Th1 polarization. These results indicate that nickel-induced Th17 cell development is dependent on the production of IL-23 by human monocyte-derived dendritic cells via toll-like receptor 4, p38 mitogen-activated protein kinase, NF-κB, and Jak-signal transducer and activator of transcription pathways.

Nickel allergy in a Danish population 25 years after the first nickel regulation.

Nickel in metallic items has been regulated in Denmark since 1990; however, 10% of young Danish women are still sensitized to nickel. There is a need for continuous surveillance of the effect of regulation. To identify current self-reported metallic exposures leading to dermatitis in nickel-allergic patients, and the minimum contact time needed for dermatitis to occur. A questionnaire was sent to all patients who reacted positively to nickel sulfate 5% pet. within the last 5 years at the Department of Dermatology and Allergy, Gentofte Hospital. The response rate was 63.2%. Earrings were the foremost cause of dermatitis after the EU Nickel Directive had been implemented, followed by other jewellery, buttons on clothing, belt buckles, and wrist watches. Dermatitis reactions within 10 min of contact were reported by 21.4% of patients, and dermatitis reactions within 30 min of contact were reported by 30.7% of patients. Nickel exposures that led to the implementation of a nickel regulation seem to persist. The durations of contact with metallic items to fall under the current REACH regulation of nickel correspond well with the results of this study.

Allergic contact dermatitis pattern in Kuwait: nickel leads the pack. In-depth analysis of nickel allergy based on the results from a large prospective patch test series report.

IntroductionContact dermatitis is a relatively common dermatosis reported among several population groups from all around the globe. However, the data from Kuwait is unavailable. Patch tests are essential for the diagnosis of contact sensitization.AimTo determine a relative frequency and pattern of sensitizers to different allergens in patients of suspected contact dermatitis in Kuwait and, also to study the role of the commonest sensitizer in detail.Material and methodsPatch tests were performed in 2461 consecutive patients with a clinical diagnosis of contact dermatitis seen at our hospital between September 1, 2014 and August 31, 2015. Out of the total of 1381 (56.1%) patients with positive patch test results to at least one allergen, 546 (22.2%) patients with a single positive reaction to nickel only (single largest sensitizer) were selected as the study population for further detailed analysis.ResultsAt least one positive patch test reaction was found in 1381 (56.12%) patients. Nickel was found to be the most common sensitizer seen in 546 (40%) patients. The mean age was 37.3 ±13.8 years and the mean duration of disease was 27.3 ±13.8 months. Most (387/546) patients sensitized were females. The forearms/hands and wrists were the most prevalent sites (52.56% of the participants). In 58.91% of women, dermatitis was more often confined to other sites, mostly ears and the neck due to earrings and necklaces. Just more than half of the number (51.09%) of nickel allergic patients were found in the age group of 15–25 years. Hairdressers/beauticians were the most affected group followed by house workers (housewives, cleaners, housekeepers).ConclusionsNickel is the single most common sensitizer found in our patients, and female sex, young age, occupation with long hours of contact to nickel are high risk factors. We recommend that a directive, which limits the release of nickel from products with extended skin contact, be approved in Kuwait.

The reactivity of the back revisited. Are there differences in reactivity in different parts of the back?

In the contact dermatitis literature, it is regularly stated that the patch test reactivity on various areas of the back differs, which might have a large impact on the reproducibility of patch testing. To investigate the reproducibility of patch testing on the upper back with regard to the left as opposed to the right side, and the medial as opposed to the lateral part of the upper back. The reproducibility over time and with regard to the reactivity pattern was also investigated. Thirty-one subjects with contact allergy to the metals gold (n = 19) or nickel (n = 12) were patch tested with serial dilutions, in triplicate applications, on different locations on the upper back. The Friedman test was used for statistical calculations. No significant differences in the reactivity of the back were found. In all gold-allergic patients and 11 of 12 nickel-allergic patients, the allergy could be reproduced with regard to previous patch testing, but the degree of reactivity differed. When a high level of standardization of the patch test technique with the same test system was used, there were no differences in patch test reactions and sites of application on the upper back.

Oral nickel exposure may induce Type I hypersensitivity reaction in nickel-sensitized subjects.

Little is known about the clinical and immunological changes in the nickel allergic patients with systemic symptoms. We aimed to evaluate T helper cell responses of patients with different clinical presentations due to nickel. Patients having various allergic symptoms and positive patch test results to nickel and 20 controls underwent skin prick tests with nickel. IL-10, IL-4, IL-5 and IFN-gamma were measured in the culture supernatants of PBMC stimulated by nickel during lymphocyte proliferation test (LTT). 69 patients (56 female, mean age: 49.2 ± 13.1), 97% having nickel containing dental devices and 20 controls (8 female, mean age 34.9 ± 12.06) were evaluated. Skin prick tests with nickel were positive in 70% of the patients (p<0.001), being significantly higher in the patients with urticaria/angioedema (p=0.02). The LTT stimulation index (p<0.0001), IL-4 (p=0.002), IFN-gamma (p=0.01), IL-5 (p=0.04) and IL-10 (p=0.003) were higher in the patient group. LTT stimulation index, IL-4 and IL-10 were significantly elevated in patients having urticaria, angioedema and respiratory symptoms when compared to those who had only oral symptoms or systemic dermatitis (p=0.004, p=0.002 and p=0.01, respectively). This study suggests the presence of Type I hypersensitivity in addition to a Type IV immune reaction in patients with chronic systemic symptoms related to nickel. Nickel containing dental alloys and oral nickel intake seem to trigger systemic symptoms in previously nickel sensitized patients.

Positive Reactions to Nickel on a Patch Test Do Not Predict Clinical Outcome of Nickel Alloy-Based Atrial Septal Defect Occluder Implantation

Background: Patch testing is thought to be necessary prior to metal device implantation to rule out metal allergy-related complications; however, there are controversies over the effects of nickel allergy on the outcome of nickel alloy-based device implantation. Objective: This study aimed to evaluate the adverse events in a Korean population of nickel allergy patients who underwent atrial septal defect (ASD) closure with a nickel-titanium alloy-based device. Methods: We retrospectively reviewed the medical records of patients who underwent ASD closure with a nitinol device. Results: Among 38 patients who had ASD closure, 4 of 5 nickel-allergic patients and 10 of the 33 non-nickel-allergic patients had post-closure complications. All patients fared well, without device failure culminating in device removal. Conclusion: In this study, positive reactions to nickel in a patch test were not associated with adverse early or late outcomes following ASD closure with a nickel alloy-based device.

Comparative evaluation of nickel discharge from brackets in artificial saliva at different time intervals.

Objectives:To determine and compare the potential difference of nickel release from three different orthodontic brackets, in different artificial pH, in different time intervals.Materials and Methods:Twenty-seven samples of three different orthodontic brackets were selected and grouped as 1, 2, and 3. Each group was divided into three subgroups depending on the type of orthodontic brackets, salivary pH and the time interval. The Nickel release from each subgroup were analyzed by using inductively coupled plasma-Atomic Emission Spectrophotometer (Perkin Elmer, Optima 2100 DV, USA) model. Quantitative analysis of nickel was performed three times, and the mean value was used as result. ANOVA (F-test) was used to test the significant difference among the groups at 0.05 level of significance (P < 0.05). The descriptive method of statistics was used to calculate the mean, standard deviation, minimum and maximum. SPSS 18 software ((SPSS.Ltd, Quarry bay, Hong Kong, PASW-statistics 18) was used to analyze the study.Result:The analysis shows a significant difference between three groups. The study shows that the nickel releases from the recycled stainless steel brackets have the highest at all 4.2 pH except in 120 h.Conclusion:The study result shows that the nickel release from the recycled stainless steel brackets is highest. Metal slot ceramic bracket release significantly less nickel. So, recycled stainless steel brackets should not be used for nickel allergic patients. Metal slot ceramic brackets are advisable.

IL-9 Regulates Allergen-Specific Th1 Responses in Allergic Contact Dermatitis

The cytokine IL-9, derived primarily from T-helper (Th)-9 lymphocytes, promotes expansion of the Th2 subset and is implicated in the mechanisms of allergic asthma. We hypothesize that IL-9 also plays a role in human allergic contact dermatitis (ACD). To investigate this hypothesis, skin biopsy specimens of positive patch test sites from non-atopic patients were assayed using qPCR and immunohistochemistry. Along with Th2 associated cytokines, IFN-γ, IL-4, and IL-17A, expression of IL-9, and PU.1, a Th9-associated transcription factor, were elevated when compared to paired normal skin. Immunohistochemistry on ACD skin biopsies identified PU.1+CD3+, and PU.1+CD4+ cells, consistent with Th9 lymphocytes, in the inflammatory infiltrate. PBMC from nickel-allergic patients, but not non-allergic controls, show significant IL-9 production in response to nickel. Blocking studies with monoclonal antibodies to HLA-DR (but not HLA-A, B, C) or chloroquine significantly reduced this nickel-specific IL-9 production. Additionally, blockade of IL-9 or IL-4 enhanced allergen-specific IFN-γ production. A contact hypersensitivity model using IL-9−/− mice, shows enhanced Th1 lymphocyte immune responses, when compared to WT mice, consistent with our human in vitro data. This study demonstrates that IL-9, through its direct effects on Th1 and ability to promote IL-4 secretion, has a regulatory role for Th1 lymphocytes in ACD.

Percutaneous closure of patent foramen ovale with Atriasept II device in nickel allergic patients

There are concerns about percutaneous closure of patent foramen ovale (PFO) using nitinol-alloys devices in patients with nickel hypersensitivity. We describe our experience with Atriasept II (Cardia Eagan, Minnesota, USA) used in four patients with known nickel allergy. No intraprocedural or in-hospital adverse events occurred. The follow-up was negative for allergic manifestations, without complications, as assessed by echocardiography. Because of the risk of adverse outcomes in nickel-allergic patients, devices with higher biocompatibility, low-profile, and low nickel content should be preferred in cases of known hypersensitivity. Atriasept II, containing less metallic material, appears to be a safe option in allergic patients undergoing PFO closure.

Nickel dental alloys can induce laryngeal edema attacks: A case report

Nickel is a strong immunological sensitizer and may result in contact hypersensitivity. Case reports of allergic reactions to intraoral nickel have occasionally been reported in the published work and these allergic reactions are generally of a delayed type (type IV). Here, we present a case of a nickel allergic patient displaying frequent laryngeal edema attacks which required treatment with epinephrine injections followed by parenteral corticosteroid doses. Her complaints ceased after the removal of the dental bridge and the foods containing nickel. In summary, we propose that in the case of recurrent laryngeal edema attacks without any explainable cause, an allergic reaction due to nickel exposure should be taken into consideration.

CD4+ T cells producing interleukin (IL)‐17, IL‐22 and interferon‐γ are major effector T cells in nickel allergy

It has been suggested that interleukin (IL)-17 and IL-22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL-17 and IL-22 in human allergic contact dermatitis are unknown. To determine the frequencies of CD4(+) , CD8(+) and γδ T cells producing IL-17, IL-22 and interferon (IFN)-γ in the blood and skin from nickel-allergic patients. Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6 controls, and analysed by immunohistochemistry and flow cytometry of skin lymphocytes. We found an increased frequency of γδ T cells in the blood, but no differences in the distribution of cytokine-producing CLA(+) T cell subtypes in nickel-allergic patients as compared with controls. In nickel-allergic patients, there was massive cellular infiltration dominated by CD4(+) T cells producing IL-17, IL-22 and IFN-γ in nickel-challenged skin but not in vehicle-challenged skin. CD4(+) T cells producing IL-17, IL-22 and IFN-γ are important effector cells in the eczematous reactions of nickel-induced allergic contact dermatitis in humans.

Coin exposure may cause allergic nickel dermatitis: a review

Nickel is used in coins because the metal has beneficial properties, including price, colour, weight, and corrosion resistance, and also because it is easy to stamp. It has often been claimed that the duration of skin contact with coins is too short to cause nickel release and dermatitis. However, it is well known by dermatologists specialized in occupational skin diseases, and by their nickel-allergic patients, that hand eczema in cashiers and other professionals who handle coins may be caused or aggravated by nickel release from coins. In this review, we present evidence from past studies showing that nickel-containing coins can indeed pose a risk for those who handle them. For protection of the health of consumers, cashiers, and other workers who handle coins, it is suggested that coins without nickel release should be used as a substitute for the high nickel-releasing coins currently in widespread use. The key risk factor in this situation is the ability of metal alloys in coins to release nickel and contaminate the skin after repeated contact from coin handling.

Nickel Allergy

Nickel allergy is the second most common form of allergic contact dermatitis skin allergy, second only to poison ivy. There is no cure for a nickel allergy. The best treatment is to avoid contact with all products known to have nickel content. Because nickel is present in a vast amount of items used every day in the gastroenterology endoscopy setting, it is not possible to have a nickel-free environment. Nurses need to be aware of items in their facility, which could affect the nickel-allergic patient in an adverse way. The focus should be to limit patient exposure as much as possible. This article provides an overview of nickel allergy and areas of risk for patients in the gastroenterology endoscopy setting.

The Sino-American Belt Study

Nickel and cobalt are common causes of metal allergy. The objective of this study was to investigate nickel and cobalt exposure in belt buckles by testing 701 belts purchased in China and the United States and to consider the prevalence of nickel allergy and its relevance among Chinese patients. Seven hundred one belt buckles purchased in China and the United States were tested for nickel and cobalt release. Six hundred thirty-one Chinese patients with suspected allergic contact dermatitis were patch tested and interviewed to determine clinical relevance of results. The Chinese and American literature was reviewed to investigate trends in nickel prevalence over the past decades. Sixty percent (n = 219) of belts purchased in China (n = 365) released nickel, and 0.5% (n = 2) released cobalt; 55.7% (n = 187) in the United States (n = 336) released nickel, and 0.9% (n = 3) released cobalt. Belt dermatitis was a significant clinical finding in 34.8% of Chinese nickel-allergic patients. Literature review suggests increasing nickel allergy prevalence in the United States and China. Metallic belt buckles are an important source of nickel exposure to consumers. Belts from lowest socioeconomic vendors were more likely to release nickel. Belts with silver color and dark metallic color were more likely to release nickel and cobalt, respectively. Clinical findings show belt dermatitis in China to be a problem.