The Involvement of Cysteine-X-Cysteine Motif Chemokine Receptors in Skin Homeostasis and the Pathogenesis of Allergic Contact Dermatitis and Psoriasis.

Members of the C-X-C motif chemokine receptor (CXCR) superfamily play central roles in initiating the innate immune response in mammalian cells by orchestrating selective cell migration and immune cell activation. With its multilayered structure, the skin, which is the largest organ in the body, performs a crucial defense function, protecting the human body from harmful environmental threats and pathogens. CXCRs contribute to primary immunological defense; these receptors are differentially expressed by different types of skin cells and act as key players in initiating downstream innate immune responses. While the initiation of inflammatory responses by CXCRs is essential for pathogen elimination and tissue healing, overactivation of these receptors can enhance T-cell-mediated autoimmune responses, resulting in excessive inflammation and the development of several skin disorders, including psoriasis, atopic dermatitis, allergic contact dermatitis, vitiligo, autoimmune diseases, and skin cancers. In summary, CXCRs serve as critical links that connect innate immunity and adaptive immunity. In this article, we present the current knowledge about the functions of CXCRs in the homeostasis function of the skin and their contributions to the pathogenesis of allergic contact dermatitis and psoriasis. Furthermore, we will examine the research progress and efficacy of therapeutic approaches that target CXCRs.

Propylene glycol, skin sensitisation and allergic contact dermatitis: A scientific and regulatory conundrum.

Propylene glycol (PG) has widespread use in pharmaceuticals, cosmetics, fragrances and personal care products. PG is not classified as hazardous under the Globally Harmonised System of Classification and Labelling of Chemicals (GHS) but poses an intriguing scientific and regulatory conundrum with respect to allergic contact dermatitis (ACD), the uncertainty being whether and to what extent PG has the potential to induce skin sensitisation. In this article we review the results of predictive tests for skin sensitisation with PG, and clinical evidence for ACD. Patch testing in humans points to PG having the potential to be a weak allergen under certain conditions, and an uncommon cause of ACD in subjects without underlying/pre-disposing skin conditions. In clear contrast PG is negative in predictive toxicology tests for skin sensitisation, including guinea pig and mouse models (e.g. local lymph node assay), validated in vitro test methods that measure various key events in the pathway leading to skin sensitisation, and predictive methods in humans (Human Repeat Insult Patch and Human Maximisation Tests). We here explore the possible scientific basis for this intriguing inconsistency, recognising there are arguably no known contact allergens that are universally negative in, in vitro, animal and human predictive tests methods.

Delayed hypersensitivity reaction from microneedling twenty years after silicone fillers.

Skin rejuvenation procedures have increasingly flooded the aesthetic market, one of which includes microneedling. In microneedling, multiple fine punctures of the skin are performed with a needle to induce neocollagenesis. Microneedling has increasingly been used to treat inflammatory acne, acne scarring, photodamaged skin, and even radiation dermatitis. We present a patient with a stable history of liquid injectable silicone (LIS) given 20 years prior who developed chronic periocular and facial hypersensitivity after undergoing microneedling at a medi-spa. Long-term steroids and immunosuppressants were needed for control. The patient's severe reaction and resistance to treatment highlights the potential complications of microneedling administered by a non-medical professional in the setting of prior injectable silicone.

High consumption of Nickel-containing foods and IBS-like disorders: late events in a gluten-free diet.

As reported in the recent literature, Nickel has become an important part of our daily life since the last decades. We can find it in skincare products, occupational exposures and foods. Only recently, research has started to show a link between Nickel and many health disorders, including adverse reactions to food containing nickel. Nowadays, the relationship between nickel-containing foods and well-being is becoming a topic of growing interest in clinical practice and will play an even larger role in the future. The use of foods with a high nickel content, largely present in a gluten free diet, could explain the lack of clinical remission in celiac patients and dispel a diagnosis of refractory celiac disease.

Treatment of MCPT8DTR mice with high- or low-dose diphtheria toxin leads to differential depletion of basophils and granulocyte-macrophage progenitors.

Basophils have been recently recognized to play important roles in type 2 immune responses during allergies and parasitic infection, largely due to the development of novel tools for the in vivo study of these cells. As such, the genetically-engineered MCPT8DTR mouse line has been used to specifically deplete basophils following treatment with diphtheria toxin (DT). In this study, we showed that DT-injected MCPT8DTR mice exhibited a striking decrease of eosinophils and neutrophils in skin when subjected to a hapten fluorescein isothiocyanate (FITC)-induced allergic contact dermatitis (ACD) experimental protocol. Unexpectedly, we found that loss of skin eosinophils and neutrophils was not due to a lack of basophil-mediated recruitment, as DT injection caused a systemic reduction of eosinophils and neutrophils in MCPT8DTR mice in a time-dependent manner. Furthermore, we found that hematopoietic stem-cell-derived granulocyte-macrophage progenitors (GMPs) expressed MCPT8 gene, and that these cells were depleted upon DT injection. Finally, we optimized a protocol in which a low-dose DT achieved a better specificity for depleting basophils, but not GMPs, in MCPT8DTR mice, and demonstrate that basophils do not play a major role in recruiting eosinophils and neutrophils to ACD skin. These data provide new and valuable information about functional studies of basophils.

Computational approaches for skin sensitization prediction.

Drugs, cosmetics, preservatives, fragrances, pesticides, metals, and other chemicals can cause skin sensitization. The ability to predict the skin sensitization potential and potency of substances is therefore of enormous importance to a host of different industries, to customers' and workers' safety. Animal experiments have been the preferred testing method for most risk assessment and regulatory purposes but considerable efforts to replace them with non-animal models and in silico models are ongoing. This review provides a comprehensive overview of the computational approaches and models that have been developed for skin sensitization prediction over the last 10 years. The scope and limitations of rule-based approaches, read-across, linear and nonlinear (quantitative) structure-activity relationship ((Q)SAR) modeling, hybrid or combined approaches, and models integrating computational methods with experimental results are discussed followed by examples of relevant models. Emphasis is placed on models that are accessible to the scientific community, and on model validation. A dedicated section reports on comparative performance assessments of various approaches and models. The review also provides a concise overview of relevant data sources on skin sensitization.

Multivariate models for prediction of human skin sensitization hazard.

One of the Interagency Coordinating Committee on the Validation of Alternative Method's (ICCVAM) top priorities is the development and evaluation of non-animal approaches to identify potential skin sensitizers. The complexity of biological events necessary to produce skin sensitization suggests that no single alternative method will replace the currently accepted animal tests. ICCVAM is evaluating an integrated approach to testing and assessment based on the adverse outcome pathway for skin sensitization that uses machine learning approaches to predict human skin sensitization hazard. We combined data from three in chemico or in vitro assays - the direct peptide reactivity assay (DPRA), human cell line activation test (h-CLAT) and KeratinoSens™ assay - six physicochemical properties and an in silico read-across prediction of skin sensitization hazard into 12 variable groups. The variable groups were evaluated using two machine learning approaches, logistic regression and support vector machine, to predict human skin sensitization hazard. Models were trained on 72 substances and tested on an external set of 24 substances. The six models (three logistic regression and three support vector machine) with the highest accuracy (92%) used: (1) DPRA, h-CLAT and read-across; (2) DPRA, h-CLAT, read-across and KeratinoSens; or (3) DPRA, h-CLAT, read-across, KeratinoSens and log P. The models performed better at predicting human skin sensitization hazard than the murine local lymph node assay (accuracy 88%), any of the alternative methods alone (accuracy 63-79%) or test batteries combining data from the individual methods (accuracy 75%). These results suggest that computational methods are promising tools to identify effectively the potential human skin sensitizers without animal testing. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Prediction of skin sensitization potency using machine learning approaches.

The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non-sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non-animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave-one-out cross-validation. A one-tiered strategy modeled all three categories of response together while a two-tiered strategy modeled sensitizer/non-sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two-tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one-tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non-animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd.

Evaluation of occupational allergic contact dermatitis and its related factors in Iran.

Background: Occupational contact dermatitis, especially in hand, is one of the most common occupational disorders. The present study aimed at evaluating patients with occupational allergic contact dermatitis (ACD) caused by common allergens based on occupation type and disease history. Methods: This cross-sectional study aimed at evaluating the data of the patients with probable diagnosis of ACD in Center for Research and Training in Skin Diseases and Leprosy (CRTSDL) in Iran. In the present study, 946 patients were assessed from different regions of Iran. One hundred fifty-one cases with positive patch test and relevant exposure were entered into the study; data related to their occupation and disease activity history were evaluated and recorded. Then, factors related to disease activity history were assessed considering the occupational groups and common exposures. Results: Nickel sulphate was the most common allergen in the 151 patients. Disease activity was constant in 29.8% of the patients; it increased in 27.8%, and decreased just before doing the patch test in 42.4%. Of the patients, 52.3% were getting worse during the working days. Occupational groups were significantly different in age and gender. Disease duration was also different in the occupational groups (p=0.001). The least disease duration was observed in healthcare workers, and the most in service workers. Lesions in the foot were related to period of employment. In administrative work group, (teachers, technicians and housewives) disease activity was decreased in the most cases, while it was increased in most patients of service workers (p=0.086). Conclusion: The present study, similar to previous reports, revealed that nickel sulphate is the most common allergen in ACD cases. Moreover, it was found that the symptoms of disease activity remained constant or increased in a significant proportion of the cases during the working days. Therefore, these workers should seriously follow up on this matter and change their occupation, or limit the exposure to allergens.

Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor.

Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD.

Assessing skin sensitization hazard in mice and men using non-animal test methods.

Sensitization, the prerequisite event in the development of allergic contact dermatitis, is a key parameter in both hazard and risk assessments. The pathways involved have recently been formally described in the OECD adverse outcome pathway (AOP) for skin sensitization. One single non-animal test method will not be sufficient to fully address this AOP and in many cases the use of a battery of tests will be necessary. A number of methods are now fully developed and validated. In order to facilitate acceptance of these methods by both the regulatory and scientific communities, results of the single test methods (DPRA, KeratinoSens, LuSens, h-CLAT, (m)MUSST) as well for a the simple '2 out of 3' ITS for 213 substances have been compiled and qualitatively compared to both animal and human data. The dataset was also used to define different mechanistic domains by probable protein-binding mechanisms. In general, the non-animal test methods exhibited good predictivities when compared to local lymph node assay (LLNA) data and even better predictivities when compared to human data. The '2 out of 3' prediction model achieved accuracies of 90% or 79% when compared to human or LLNA data, respectively and thereby even slightly exceeded that of the LLNA.

Allergic Contact Dermatitis in Refractory Brick Production Worker: A Case Report.

In this study, we investigated a 42-year-old man working in a refractory brick (RB) production line who had allergic contact dermatitis (ACD) due to skin exposure to chromium (Cr). He had visited a dermatologist several times over a five-month period and although he had been medically treated, the symptoms reappeared after he returned to work and resumed exposure. Finally, with the announcement of the definite diagnosis of ACD through a patch test, it was decided to exclude him from exposure, and after 20 days, the symptoms went through the recovery process. No new recurring episodes were reported during the six-month follow-up period.

A Mysterious Recurrent Urticarial Rash and a Life-Altering Metal.

Allergic contact dermatitis is a common manifestation in individuals who have a contact hypersensitivity to nickel. Direct exposure to nickel triggers an adaptive immune response that mediates a localized inflammatory reaction of the skin, typically resulting in an erythematous and pruritic rash at the site of contact. We present a distinct case in which nickel was systemically introduced via a carotid stent into an individual with an unidentified allergy to nickel. This case emphasizes the potentially life-threatening risks associated with implantable hardware containing metals, such as nickel. Moreover, this case highlights the potential benefit that screening for metal allergies may have before surgically implanting permanent metal-based devices.

Mechanisms of impairment in hair and scalp induced by hair dyeing and perming and potential interventions.

With the rapid growth of beauty and personal care industries, many hair-relevant products, hair dyes and hair perms in particular, are increasingly prevalent in both women and men, regardless of being young or old as they frequently change hair color or shape to enhance youthfulness and beauty and to follow fashion trends. Hair dyes and perms alter hair color and/or shape by mechanically changing the physical structure and chemical substances of the hair shaft. However, treatment of hair with chemical formulations has been potentially ascribed to adverse outcomes in the hair shaft including structure damage, chemical constituent disorder, and impaired physical properties, although hair cosmetics procedures are intrinsically safe. Nevertheless, the mechanisms of impairment in the hair shaft and scalp induced by hair dyeing and perming remain elusive. Additionally, adverse reactions activated by exposure to specific chemical ingredients including skin irritation, allergic contact dermatitis (ACD), and even cancer risk have been reported clinically, but existing evidence is not consistent enough in the case of human studies. Herein, the review aims to give an overview of hair cosmetics, especially concerning the basic knowledge about various hair dyes and perms, the consequences for hair shafts and the scalp resulting from the application of hair cosmetics mentioned above, mechanisms of hazardous outcomes, and potential desirable interventions to alleviate the impairment.

New Insights and Evidence on "Food Intolerances": Non-Celiac Gluten Sensitivity and Nickel Allergic Contact Mucositis.

The clinical examination of patients often includes the observation of the existence of a close relationship between the ingestion of certain foods and the appearance of various symptoms. Until now, the occurrence of these events has been loosely defined as food intolerance. Instead, these conditions should be more properly defined as adverse food reactions (AFRs), which can consist of the presentation of a wide variety of symptoms which are commonly identified as irritable bowel syndrome (IBS). In addition, systemic manifestations such as neurological, dermatological, joint, and respiratory disorders may also occur in affected patients. Although the etiology and pathogenesis of some of them are already known, others, such as non-celiac gluten sensitivity and adverse reactions to nickel-containing foods, are not yet fully defined. The study aimed to evaluate the relationship between the ingestion of some foods and the appearance of some symptoms and clinical improvements and detectable immunohistochemical alterations after a specific exclusion diet. One hundred and six consecutive patients suffering from meteorism, dyspepsia, and nausea following the ingestion of foods containing gluten or nickel were subjected to the GSRS questionnaire which was modified according to the "Salerno experts' criteria". All patients underwent detection of IgA antibodies to tissue transglutaminase, oral mucosal patch tests with gluten and nickel (OMPT), and EGDS, including biopsies. Our data show that GSRS and OMPT, the use of APERIO CS2 software, and the endothelial marker CD34 could be suggested as useful tools in the diagnostic procedure of these new pathologies. Larger, multi-center clinical trials could be helpful in defining these emerging clinical problems.

Metal Allergy: State-of-the-Art Mechanisms, Biomarkers, Hypersensitivity to Implants.

Metal allergy is mainly an environmental disorder which can cause allergic contact dermatitis. Environmental metal exposures include jewelry, everyday metal items, mobile phones, leather, metal-rich food and implants, including stents or anchors. While consumer exposure is liable for the majority of metal hypersensitivity cases, the significance of occupational exposure to metals remains relevant. Although the most common metal allergens are nickel, chromium, and cobalt; however, lately, gold, palladium, titanium, and some others have also attracted attention. This review highlights advances in metal allergy mechanisms, biomarkers for potential patients' stratification as well as biological treatments. The most recent evidence of human exposure to metal for risk assessment is discussed, as well as the relationship between the occurrence of metal hypersensitivity and implanted devices, including non-characteristic symptoms. The latest data on the diagnosis of metal hypersensitivity are also reported.

Effects of thermal therapy combined with blue light-emitting diode irradiation on trimellitic anhydride-induced acute contact hypersensitivity mouse model.

BACKGROUD: The biological effect of phototherapy, which involves using visible light for disease treatment, has attracted recent attention, especially in dermatological practice. Light-emitting diode (LED) irradiation increases dermal collagen level and reduces inflammation. It has been suggested that thermal therapy and LED irradiation can modulate inflammatory processes. However, little is known about the molecular mechanism of the anti-inflammatory effects of thermal therapy and LED irradiation. OBJECTIVE: This study was to determine the anti-inflammatory effect of thermal therapy combined with LED irradiation on trimellitic anhydride (TMA)-induced acute contact hypersensitivity (CHS) mouse model. METHODS: Twenty-four BALB/c mice were randomly divided into the following groups: Vehicle group, TMA group, TMA + alternating thermal therapy group (Alternating group), and TMA + alternating + LED group (LED group). Ear swelling was measured based on the thickness of ear before and after each TMA challenge. Vascular permeability was evaluated by the extravasation of Evans blue dye. Serum IgE level, Th1/Th2/Th17 cytokines, and related transcription factors were measured using ELISA kits, and histological examination was illustrated in ear tissue. RESULTS: The LED group showed reduction in ear swelling response, vascular permeability, serum IgE levels, Th2/Th17 cytokine levels, and inflammatory cell infiltration. Moreover, the LED group showed increased Th1 cytokine levels. CONCLUSIONS: These results indicate that thermal therapy combined with LED irradiation alleviated TMA-induced acute CHS in the mouse model. Thermal therapy and phototherapy should be considered as a novel therapeutic tool for the treatment of skin inflammation.

Haptenation of Macrophage Migration Inhibitory Factor: A Potential Biomarker for Contact Hypersensitivity.

The immunological response in contact hypersensitivity is incited by small electrophilic compounds, known as haptens, that react with endogenous proteins after skin absorption. However, the identity of hapten-modified proteins seen as immunogenic remains as yet largely unknown. In a recent study, we have for the first time identified a hapten-modified protein in the local lymph nodes of mice treated topically with the model hapten tetramethylrhodamine isothiocyanate (TRITC). The TRITC modification was located on the N-terminal proline of the protein macrophage migration inhibitory factor (MIF). The focus of the current study was to investigate the presence of the same hapten-protein conjugate in blood samples from mice treated topically with TRITC. Furthermore, TRITC modifications of the two major blood proteins, namely hemoglobin (Hb) and albumin (Alb), as well as TRITC modifications of MIF other than the N-terminal proline, were examined. Following incubation with different molar ratios of TRITC, a proteomic approach was applied to characterize conjugate formation of the three aforementioned proteins, using high resolution mass spectrometry (HRMS). The targeted screening of the TRITC-treated mice blood and lymph node samples for these sites led to the identification of only the same TRITC-MIF conjugate previously detected in the lymph nodes. No Hb and Alb conjugates were detected. Quantification of both the TRITC-modified and unmodified N-terminal peptide of MIF in blood and lymph node samples gave interesting insights of MIF's role in murine contact hypersensitivity. Incubation of MIF with four different haptens encompassing different reactivity mechanisms and potencies, showed adduct formation at different amino acid residues, suggesting that MIF can be the preferred target for a wide variety of haptens. The present study provides essential progress toward understanding of hapten-protein conjugate formation in contact hypersensitivity and identifies hapten-modified MIF as a potential biomarker for this condition. Further investigation of MIF as a target protein can be a next step to determine if MIF is a biomarker that can be used to develop better diagnostic tools and targeted therapeutics for individuals with allergic contact dermatitis.

Animal Models of Contact Dermatitis: 2,4-Dinitrofluorobenzene-Induced Contact Hypersensitivity.

Allergic contact dermatitis (ACD) is a common skin disease with high prevalence in work environments. Human allergic contact dermatitis is triggered by the exposure to haptens that leads to an initial phase known as sensitization. During this phase, hapten-protein complexes presented by antigen-presenting cells activate a T-cell-mediated response, leading to the generation of memory cells against the hapten. Upon re-exposure to the same hapten, the elicitation phase is initiated. This phase is characterized by a quicker acute inflammatory response involving activation and/or infiltration of a variety of immune cell populations. Human ACD can be studied through the use of animal models of contact hypersensitivity (CHS). The 2,4-dinitrofluorobenzene (DNFB)-induced CHS model is a commonly used mouse model that has been helpful in the study of the mechanisms as well as potential therapeutic interventions of ACD. In this chapter I will provide a detailed protocol to develop acute DNFB-induced CHS in mice in a period of 7 days. In addition, I will discuss several key considerations for experimental design including best controls, potential expected outcomes, and sample collection.

Contact Dermatitis and Medical Adhesives: A Review.

In more recent years, the use of medical adhesives in lieu of sutures or staples has become increasingly common for the closure of post-surgical and traumatic incisions in areas of the skin where tension is low. While medical adhesives possess many advantages and little risk of adverse side effects, there are increasing numbers of accounts in the medical literature of allergic contact dermatitis (ACD) caused by specific components contained within the medical adhesives. The goal of this paper is to provide physicians with a differential diagnosis when faced with complications after the use of medical adhesives for wound closure. Additionally, this paper aims to delineate the differences among the most commonly used adhesives, provide a rationale for assessing an individual's personal risk of developing ACD, and to highlight the unique advantages and disadvantages of each adhesive.  Dermabond® appears to be the most versatile adhesive with the lowest risk of ACD. However, because of its high cost, it may not be appropriate for all patients. While Mastisol® can only be utilized in combination with a dressing, such as Steri-Strips®, it is much more affordable than Dermabond and is still capable of providing an effective wound closure. Due to these factors, it is our recommendation that Dermabond is considered the first-line medical adhesive due to its versatility and strength, while Mastisol can be readily employed in situations with financial consideration. As the number of patients treated with medical adhesives continues to grow, physicians should anticipate an increase in the number of cases of ACD secondary to adhesive sensitization. It is imperative for physicians to be able to differentiate between a case of ACD and another potentially more serious complication, such as cellulitis. We hope that this paper will assist providers in distinguishing adhesive-induced ACD and other complications, identifying patients at risk of ACD from adhesive use, and provide a basis for which adhesives are most appropriate for any given patient.