Preservative contact allergy in occupational dermatitis: a machine learning analysis.

Occupational dermatoses impose a significant socioeconomic burden. Allergic contact dermatitis related to occupation is prevalent among healthcare workers, cleaning service personnel, individuals in the beauty industry and industrial workers. Among risk factors, the exposure to preservatives is frequent, since they are extensively added in products for occupational use. The goal of this study is to investigate the contact allergy patterns in order to understand the linkage among hypersensitivity to preservatives, occupational profiles, patients' clinical and demographic characteristics. Patch test results were collected from monosensitized patients to Formaldehyde 2%, KATHON 0.02%, thimerosal 0.1%, and MDBGN 0.5%; information was also collected for an extended MOAHLFA (Male-Occupational-Atopic-Hand-Leg-Face-Age) index. To assess the relationship between allergen group and occupational-related ACD, the chi-square test for independence was utilized. To uncover underlying relationships in the data, multiple correspondence analysis (MCA) and categorical principal components analysis (CATPCA), which are machine learning approaches, were applied. Significant relationships were found between allergen group and: occupation class, atopy, hand, leg, facial, trunk, neck, head dermatitis, clinical characteristics, ICDRG 48 h and ICDRG 72 h clinical evaluation. MCA and CATPCA findings revealed a link among allergen group, occupation class, patients' demographic and clinical characteristics, the MOAHLFA index, and the ICDRG scores. Significant relationships were identified between the allergen group and various manifestations of dermatitis. The utilization of machine learning techniques facilitated the discernment of meaningful patterns in the data.

Patch test in Brazilian children with a clinical diagnosis of atopic dermatitis: a cross-sectional study using an extended patch test battery.

INTRODUCTION: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease mainly affecting children. Similarly, Allergic contact dermatitis (ACD) is an inflammatory skin disease, but unlike AD it results from direct exposure to an external agent. Theoretically, the impaired skin barrier facilitates the penetration of potential allergens. Therefore, AD patients are at risk for an associated ACD, exacerbating their skin condition. Because eczema is similar, performing a patch test (PT) for the differential diagnosis is essential. METHODS: In this cross-sectional transversal study, we performed a PT with 30 sensitizers in 26 children with AD, selected according to established criteria for suspected ACD, and treated at an AD center of a pediatric university hospital in Rio de Janeiro. Clinical presentation, patient profile, main sensitizers, and frequency of ACD caused by therapeutic skincare products were evaluated. RESULTS: In all, 23 (88.5%) patients reacted to at least one allergen, 21 (80.7%) had a relevant positive patch test, and 15 (57.7%) were polysensitized. The main positive sensitizers were nickel (38.5%), blue disperse (30.8%), fragrance mix (30.8%), and neomycin (23.1%). Nineteen (73%) patients reacted to substances present in therapeutic or skincare products. CONCLUSION: Our data underscore the importance of performing a PT in AD children whose eczema has atypical distribution. The expressive percentage of positive tests, especially of allergens in skincare products, indicates the constant need to review the proposed treatments. Therefore, we recommend a specific and expanded PT battery for pediatric AD patients, including a negative control, to increase sensitivity for diagnosing ACD.

The new Italian SIDAPA Baseline Series for patch testing (2023): an update according to the new regulatory pathway for contact allergens.

Allergic contact dermatitis (ACD) is a common inflammatory skin disease caused by delayed hypersensitivity to chemical and biotic contact allergens. ACD significantly affects the patients' quality of life negatively impacting both occupational and non-occupational settings. Patch testing is the gold standard diagnostic in vivo test to precise the ACD etiology and to correctly perform prevention. According to the Italian Medicines Agency (AIFA) legislative decree no. 178 of 29th May 1991, allergens are defined as medicines and therefore they are subject to strict regulation. In 2017, AIFA (decree no. 2130/2017) started a procedure to regulate contact allergens on the Italian market and actually the contact allergens temporarily authorized are reported in AIFA decree no. 98/2022, valid until November 2023. The availability on the market of contact allergens to diagnose ACD and continuous updating on the basis of new epidemiological trends are mandatory, jointly with the continuous update of the baseline and integrative series for patch testing. For this reason, the scientific community represented in Italy by the Skin Allergies Study Group of SIDeMaST (Italian Society of Dermatology and Venereology) and SIDAPA (Italian Society of Allergological, Occupational and Environmental Dermatology) are constantly working, in close relationship with the European scientific communities with large expertise in this important sector of the modern Dermatology. Herein, we report the setting up of regulatory legislation by AIFA and the new Italian Adult Baseline Series for patch testing.

Subclinical immune responses to nickel in sensitized individuals-a dose-response study.

BACKGROUND: Nickel is the leading cause of contact allergy in Europe, with 14.5% of the adult population being sensitized. Despite regulations limiting nickel release from consumer items, the incidence and prevalence of nickel allergy remain high. OBJECTIVE: To investigate the clinical and subclinical immune response to low-dose nickel exposure on nickel pre-exposed skin to assess the adequacy of current regulatory limits. METHOD: Nickel-allergic and healthy controls were patch tested with nickel twice with a 3-4 weeks interval. The first exposure used the diagnostic concentration of 2000 µg/cm2 nickel sulphate, and the same skin areas were then re-exposed to 0.2, 0.5, 12.8 and 370 µg/cm2 nickel sulphate. After 48 h, the patch reactions were examined for clinical signs of eczema, and skin biopsies were collected. The transcriptomic immune profile was analysed with Nanostring nCounter and quantitative polymerase chain reaction. RESULTS: Two nickel-allergic participants (15%) had clinical reactions to the regulatory limiting doses for nickel (0.2/0.5 µg/cm2) following re-exposure. There was immune activation in all skin areas following re-exposure to nickel, predominantly mediated by up-regulation of cytokines and chemokines. In all nickel re-exposed skin areas, 81 genes were up-regulated independent from the clinical response. In skin areas exposed to 0.2 µg/cm2, 101 immune-related genes were differentially expressed, even when no clinical response was observed. Healthy controls showed up-regulation of three genes in response to nickel re-exposures without any clinical reactions. CONCLUSION: Immune activation can be induced in skin with local memory to nickel upon challenge with nickel doses within the regulatory limits. Our findings suggest that the regulatory limits in the European nickel regulation may not provide sufficient protection for consumers against low-dose exposures.

Contact allergens responsible for eyelid dermatitis in adults.

Allergic contact dermatitis has been established as the most frequent cause of eyelid dermatitis, but it is often misdiagnosed. The purpose of this study was to evaluate the characteristics of patients with eyelid dermatitis who were referred for patch testing. The patients were divided into three subgroups in this retrospective study: patients with only eyelid involvement, patients with involvement of eyelids and other areas, and patients without eyelid involvement. Data was collected on diagnoses, medical history, personal care products and make-up use, occupational dermatitis, and positive allergens. An independent t-test, one-way ANOVA, and chi-squared test were used to analyze the data. A total of 427 patients who referred for patch tests were included in the study. Of these, 139 patients had eyelid dermatitis. Allergic contact dermatitis (ACD) was the most common diagnosis in all three groups referred for patch tests. Use of shaving cream and hair conditioner was significantly higher in patients with only eyelid involvement and nickel sulfate was the most common allergen among them. Patch testing is the gold standard tool in the evaluation of eyelid contact dermatitis, and it is a necessity in the treatment of eyelid dermatitis, for the accurate identification of responsible allergens.

CD1a and skin T cells: a pathway for therapeutic intervention.

The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex-peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.

Exploring the relationship between allergic contact dermatitis and atopic dermatitis in children: insights from a retrospective patch testing analysis.

BACKGROUND: Recent years have seen significant exploration into the potential link between allergic contact dermatitis and atopic dermatitis, yielding contradictory findings. METHODS: A retrospective cohort analysis of children aged 2 to 18 who underwent patch testing at the pediatric dermatology clinic at a tertiary medical center in Israel was conducted. RESULTS: Overall, 367 patients were included in the study, 31.6% of whom were diagnosed with atopic dermatitis. 160 children (43.6%) exhibited a positive reaction to at least one compound in the European baseline series. There was no statistically significant difference in reactivity between children with atopic dermatitis and those without (P = 0.848). Sub-analyses based on ethnicity, gender, and age did not reveal significant differences in overall European baseline series reactivity (P = 0.612, P = 0.446, P = 0.488, respectively). Sensitivity was notably higher when patch readings were conducted 72 h after application compared to 48 h [0.95 (CI: 0.91-0.97) vs. 0.60 (CI: 0.55-0.66)]. CONCLUSIONS: Patch testing is imperative for suspected cases of allergic contact dermatitis in all children, regardless of their atopic background. Further research is warranted to potentially replace the traditional 48-h reading with a single 72-h reading in future guidelines, contributing to enhanced efficiency and cost-effectiveness in clinical practice.

Regulation of immune response genes in the skin of allergic and clinically tolerant individuals exposed to p-phenylenediamine.

BACKGROUND: p-Phenylenediamine (PPD) is a potent contact allergen found in many hair colour products. However, not all individuals develop allergic contact dermatitis (ACD) although they are regularly exposed to PPD. It is unclear whether these asymptomatic individuals are true non-responders to PPD or whether they mount a response to PPD without showing any symptoms. METHODS: Skin biopsies were collected from 11 asymptomatic hairdressers regularly exposed to PPD and from 10 individuals with known ACD on day 4 after patch testing with 1% PPD in petrolatum and petrolatum exclusively as control. RNA sequencing and confocal microscopy were performed. RESULTS: T cell activation, inflammation and apoptosis pathways were up-regulated by PPD in both asymptomatic and allergic individuals. Compared to asymptomatic individuals with a negative patch test, individuals with a strong reaction to PPD strongly up-regulated both pro- and anti-inflammatory cytokines genes. Interestingly, PPD treatment induced significant up-regulation of several genes for chemokines, classical type 2 dendritic cell markers and regulatory T cell markers in both asymptomatic and allergic individuals. In addition, apoptosis signalling pathway was activated in both non-responders and allergic individuals. CONCLUSION: This study demonstrates that there are no true non-responders to PPD but that the immune response elicited by PPD differs between individuals and can lead to either tolerance, subclinical inflammation or allergy.

Contact allergies to dental materials in patients.

BACKGROUND: Concerns regarding contact allergies and intolerance reactions to dental materials are widespread among patients. Development of novel dental materials and less frequent amalgam use may alter sensitization profiles in patients with possible contact allergy. OBJECTIVES: To analyse current sensitization patterns to dental materials in patients with suspected contact allergy. METHODS: This retrospective, multicentre analysis from the Information Network of Departments of Dermatology (IVDK) selected participants from 169 834 people tested in 2005-2019 and registered with (i) an affected area of 'mouth' (and 'lips'/'perioral'), (ii) with the dental material in question belonging to one of three groups (dental filling materials, oral implants or dentures or equivalents) and (iii) with patch-testing done in parallel with the German baseline series, (dental) metal series and dental technician series. RESULTS: A total of 2730 of 169 834 tested patients met the inclusion criteria. The patients were predominantly women (81.2%) aged ≥ 40 years (92.8%). The sensitization rates with confirmed allergic contact stomatitis in women (n = 444) were highest for metals (nickel 28.6%, palladium 21.4%, amalgam 10.9%), (meth)acrylates [2-hydroxyethyl methacrylate (HEMA) 4.8%] and the substances propolis (6.8%) and 'balsam of Peru' (11.4%). The most relevant acrylates were HEMA, 2-hydroxypropyl methacrylate, methyl methacrylate, ethylene glycol dimethacrylate and pentaerythritol triacrylate. Few men were diagnosed with allergic contact stomatitis (n = 68); sensitization rates in men were highest for propolis (14.9%) and amalgam (13.6%). CONCLUSIONS: Allergic contact stomatitis to dental materials is rare. Patch testing should not only focus on metals such as nickel, palladium, amalgam and gold, but also (meth)acrylates and the natural substances propolis and 'balsam of Peru'.

Regulation of the immune response to contact sensitizers by Nrf2.

The skin is frequently exposed to chemical stress by organic chemicals or metal ions that can directly or indirectly challenge its immune components and may lead to T-cell-mediated delayed-type hypersensitivity reactions. The disruption of the skin's homeostasis by exposure to contact sensitizers (CSs) can trigger an inflammatory immune response that results in eczema and allergic contact dermatitis. The recognition of these chemicals depends on the expression of pattern recognition receptors on sentinel skin cells, mainly the innate resident immune cells orchestrating the skin's immune response and involving both oxidative and inflammatory pathways. The main driver of these both pathways is the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress, activated in various innate immune cells of the skin, including keratinocytes and epidermal Langerhans cells in the epidermis and dermal dendritic cells in the dermis. Nrf2 also shows a strong protective capacity by downregulating inflammatory pathways. In this review, the important role of Nrf2 in the regulation of the immune response to CSs will be discussed and highlighted.

Enzymes and sensitization via skin exposure: A critical analysis.

Some proteins, including enzymes, can induce allergic sensitization of various types, including allergic sensitization of the respiratory tract. There is now an increased understanding of the role that the skin plays in the development of IgE-mediated allergy and this prompts the question whether topical exposure to enzymes used widely in consumer cleaning products could result in allergic sensitization. Here, the evidence that proteins can interact with the skin immune system and the way they do so is reviewed, together with a consideration of the experience gained over decades of the use of enzymes in laundry and cleaning products. The conclusion drawn is that although transcutaneous sensitization to proteins can occur (typically through compromised skin) resulting in IgE antibody-mediated allergy, in practice such skin contact with enzymes used in laundry and cleaning products does not appear to pose a significant risk of allergic disease. Further, the evidence summarized in this publication support the view that proteins do not pose a risk of allergic contact dermatitis.

Type 2 immunity plays an essential role for murine model of allergic contact dermatitis with mixed type 1/type 2 immune response.

BACKGROUND: Both human and mouse allergic contact dermatitis (ACD) frequently demonstrates a combined type 1 and type 2 immune response. However, the relative importance of type 2 immunity in this setting has been incompletely understood yet. OBJECTIVE: To explore an effector function of type 2 immunity in ACD with mixed type 1/type 2 immune response. METHODS: Gene expression characteristics of contact hypersensitivity (CHS) model was examined by quantitative polymerase chain reaction. Cytokine profile of T cells was analyzed by flow cytometry. The involvement of type 2 immunity was assessed by antibody-mediated cytokine neutralization and cell depletion. The role of specific subset of cutaneous dendritic cells was evaluated using diphtheria toxin-induced cell-depleting mouse strains. RESULTS: Oxazolone-induced CHS revealed a combination of type 1/type 2 gene expression. The severity of oxazolone-induced CHS was ameliorated by neutralization of IL-4 but not of IFN-γ, indicating that type 2 immunity plays a dominant effector function in this mixed type 1/type 2 model. Mechanistically, type 2 effector immunity was mounted by CD301b+Langeirn- dermal dendritic cells in part through thymic stromal lymphopoietin-interleukin 7 receptor alpha signaling-dependent manner. CONCLUSION: Our findings suggest the clinical rationale for targeting type 2 immunity as a relevant therapeutic strategy for the mixed immune phenotype of ACD.

Quantitative assessment of sensitizing potency using a dose-response adaptation of GARDskin.

Hundreds of chemicals have been identified as skin sensitizers. These are chemicals that possess the ability to induce hypersensitivity reactions in humans, giving rise to a condition termed allergic contact dermatitis. The capacity to limit hazardous exposure to such chemicals depends upon the ability to accurately identify and characterize their skin sensitizing potency. This has traditionally been accomplished using animal models, but their widespread use offers challenges from both an ethical and a scientific perspective. Comprehensive efforts have been made by the scientific community to develop new approach methodologies (NAMs) capable of replacing in vivo assays, which have successfully yielded several methods that can identify skin sensitizers. However, there is still a lack of new approaches that can effectively measure skin sensitizing potency. We present a novel methodology for quantitative assessment of skin sensitizing potency, which is founded on the already established protocols of the GARDskin assay. This approach analyses dose-response relationships in the GARDskin assay to identify chemical-specific concentrations that are sufficient to induce a positive response in the assay. We here compare results for 22 skin sensitizers analyzed using this method with both human and LLNA potency reference data and show that the results correlate strongly and significantly with both metrics (rLLNA = 0.81, p = 9.1 × 10-5; rHuman = 0.74, p = 1.5 × 10-3). In conclusion, the results suggest that the proposed GARDskin dose-response methodology provides a novel non-animal approach for quantitative potency assessment, which could represent an important step towards reducing the need for in vivo experiments.

Melatonin prevents allergic airway inflammation in epicutaneously sensitized mice.

PURPOSE: The pathological process of atopic dermatitis (AD) progressing into other types of allergic diseases such as asthma and allergic rhinitis during the first several years of life is often referred to as the atopic march. Although the phenomenon of atopic march has been recognized for decades, how asthma stems from AD is still not fully understood, confounding a universal strategy to effectively protect people from the atopic march. METHODS: We established experimental atopic march mice by first inducing allergic dermatitis with 0.5% fluorescein isothiocyante (FITC) applied to the skin, followed by an ovalbumin (OVA) airway challenge. In addition, by examining serum immunoglobulin (Ig) concentrations, airway cytokines, the levels of oxidative stress markers, histopathological changes in lung tissue and airway hyperresponsiveness (AHR), we were able to validate the successful establishment of the model. Furthermore, by detecting the attenuating effects of melatonin (MT) and the levels of oxidative stress in the atopic march mice, we explored the potential molecular mechanisms involved in the development of atopic march. RESULTS: By successfully establishing an experimental atopic march mouse model, we were able to demonstrate that overproduction of oxidative stress in the lung significantly up-regulated the activation of nuclear factor-κB (NF-κB) signaling pathways causing thymic stromal lymphopoietin (TSLP) release, which further promotes the development of atopic march. CONCLUSIONS: To mitigate the development of the atopic march, antioxidants such as MT may be imperative to inhibit NF-κB activation in the lung, especially after the onset of AD.

Selenium Modulates the Allergic Response to Whey Protein in a Mouse Model for Cow's Milk Allergy.

Cow's milk allergy is a common food allergy in infants, and is associated with an increased risk of developing other allergic diseases. Dietary selenium (Se), one of the essential micronutrients for humans and animals, is an important bioelement which can influence both innate and adaptive immune responses. However, the effects of Se on food allergy are still largely unknown. In the current study it was investigated whether dietary Se supplementation can inhibit whey-induced food allergy in an animal research model. Three-week-old female C3H/HeOuJ mice were intragastrically sensitized with whey protein and cholera toxin and randomly assigned to receive a control, low, medium or high Se diet. Acute allergic symptoms, allergen specific immunoglobulin (Ig) E levels and mast cell degranulation were determined upon whey challenge. Body temperature was significantly higher in mice that received the medium Se diet 60 min after the oral challenge with whey compared to the positive control group, which is indicative of impaired anaphylaxis. This was accompanied by reductions in antigen-specific immunoglobulins and reduced levels of mouse mast cell protease-1 (mMCP-1). This study demonstrates that oral Se supplementation may modulate allergic responses to whey by decreasing specific antibody responses and mMCP-1 release.

The role of interleukin-1ß in the immune response to contact allergens.

Interleukin-1ß (IL-1ß) is an important pro-inflammatory cytokine that has an effect on almost every cell lineage in the body. By blocking IL-1ß and investigating the IL-1ß signaling pathway, several studies have demonstrated a central role of IL-1ß in the response to contact allergens. This review summarizes the current literature regarding the basic immunological mechanisms mediated by IL-1ß in the different phases of allergic contact dermatitis (ACD) and highlights potential IL-1ß-targeted treatment options, which in the future may be relevant in the treatment of patients with ACD. This review is based primarily on studies using various mouse models and human in vitro studies, since clinical studies on the effect of IL-1ß in ACD are lacking.