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.

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.

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.

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.

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.

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.

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.

Innate Immune Regulation of Dermatitis.

Dermatitis encompasses a spectrum of inflammatory skin disorders with aberrant immune responses classified as type 1, type 2, and/or type 3. Major advances in the understanding of the pathogenesis of atopic dermatitis (AD) have shed new light on how innate immune responses critically regulate type 2 inflammation and itch. This article highlights the diverse ways by which type 2 immune cells regulate diseases beyond AD. The discovery of human Mas-related G protein-coupled receptor X2 on mast cells has revealed novel T cell-independent and immunoglobulin E-independent mechanisms of allergic contact dermatitis-associated and urticarial itch, respectively.

Mimics of Dermatitis.

Dermatitis is a common condition frequently encountered by dermatologists. The diagnosis of dermatitis can be challenging because this condition is often multifactorial, and many skin diseases that can mimic dermatitis should be considered in the differential diagnosis. It is important to recognize and be familiar with these conditions because some of them can represent signs of systemic disease or malignancies and misdiagnosis can lead to mismanagement and adverse outcomes for the patient.

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.

Contact Dermatitis: Classifications and Management.

Contact dermatitis (CD) is a common inflammatory skin disease caused by exposure to contact allergens and irritants. It is also the most common reason of occupational dermatitis and contributes greatly to hand dermatitis and facial dermatitis. Besides the two major forms of contact dermatitis: allergic contact dermatitis and irritant contact dermatitis, other subtypes of CD have been recognized including immediate skin reactions, photoinduced contact dermatitis, systemic contact dermatitis, and non-eczematous contact dermatitis. CD is a great imitator which can mimic many kinds of skin diseases, such as atopic dermatitis, lichen planus, and angioedema. For the diagnosis of CD, a complete medical history, including occupational history, is very important. It can give a clue of CD and provide a list of suspected substances. Besides the well-known diagnostic test, patch testing, there are many other diagnostic tests can be used to help diagnosis of CD and identify the causative allergens, including photopatch test, skin tests for detecting of immediate contact reactions, serum allergen-specific IgE test, and qualitative and quantitative testing of allergen in the suspected materials patients exposed to and challenge test. Before the treatment, the suspected irritants or allergens should be avoided completely. This includes both the removal of the patient from the environment that contains those substances and the promotion of the metabolism and expulsion of the allergens that have been absorbed by the body. In addition, it is also important to restore the skin barrier and reduce skin inflammation through multiple treatments, such as emollients, topical corticosteroids, and antihistamines, as well as systemic corticosteroids and immunosuppressants. Early and appropriate treatments are important to prevent further deterioration and persistence of the skin condition.

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.

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.

Irritant Contact Dermatitis.

Contact dermatitis accounts for 95% of occupational skin disorders. Irritant contact dermatitis (ICD) is often caused by cumulative exposure to weak irritants, accounting for 80% of all cases of contact dermatitis. ICD can co-exist with atopic dermatitis (AD) and allergic contact dermatitis (ACD). Patients with AD and ACD may have a lower inflammatory threshold for developing ICD. Therefore, it needs to be distinguished from lesions of AD and ACD. ICD Patients report stinging and burning in excess of pruritus. Pruritus is classically reported by patients with AD and ACD. ICD lesions are typically well-demarcated unlike AD and ACD. ICD is diagnosed by exclusion. Patients undergo testing to rule out type I and type IV hypersensitivity. Negative results suggest a diagnosis of ICD. Management consists of irritant identification and avoidance with regular emollient use. Although ICD is more common in certain occupations, genetics and environment play significant roles in its development.

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.

A highly sensitive and selective high pressure liquid chromatography with tandem mass spectrometry (HPLC/MS-MS) method for the direct peptide reactivity assay (DPRA).

While the HPLC/UV (high performance liquid chromatography coupled with ultra-violet spectrometry)-based DPRA (Direct Peptide Reactivity Assay) identifies dermal sensitizers with approximately 80% accuracy, the low selectivity and sensitivity of the HPLC/UV-based DPRA poses challenges to accurately identify the sensitization potential of certain chemicals. In this study, a high performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MS-MS)-based DPRA was developed and validated according to the test guideline (OECD TG 442C). The final results were compared with the results from the traditional HPLC/UV-based guideline DPRA. This HPLC/MS-MS-based DPRA demonstrated similar performance compared to HPLC/UV-based DPRA using known dermal sensitizers and non-sensitizers according to the test guideline (OECD TG 442C). Following the validation, a challenge set of chemicals with either overlapping retention time with peptides, or higher hydrophobicity or chemicals potentially forming non-covalent interactions with peptides were assessed for dermal sensitization potential using both methods and the results were compared to existing in vivo data. The HPLC/MS-MS-based DPRA correctly predicted these chemicals as sensitizers or non-sensitizers; however, the HPLC/UV-based DPRA resulted in false-positive predictions for hydrophobic substances, chemicals with UV peaks overlapping with those of the peptide(s), and compounds that non-covalently interact with the peptides. These findings demonstrate the broader applicability and better sensitivity and selectivity of the LC/MS-MS-based DPRA over the traditional HPLC/UV-based guideline DPRA.

Use of the LLNA:BrdU-ELISA for Skin Sensitization Hazard Assessment.

Allergic contact dermatitis (ACD) continues to be an occupational and environmental health issue. Consequently, there is a need to employ predictive tests to reduce the incidence of skin sensitization leading to clinical manifestations of ACD. For more than a decade, the murine local lymph node assay (LLNA) has been the method of choice for the identification of skin sensitizers. While the original LLNA protocol has been extensively evaluated and subjected to exhaustive validation, the use of radioisotope (i.e., tritiated thymidine; 3HTdR) has discouraged utilization of this powerful assay in some countries. To promote further utilization of this method, the original LLNA protocol was refined to use 5-bromo-2'-deoxyuridine, a nonradioactive analog of 3HTdR. The LLNA:BrdU-ELISA has been reviewed, validated, and approved for use internationally, and its performance is regarded as equivalent to the traditional LLNA. Here, we provide guidance on how to perform and interpret data from this assay.