Exploring the roles of prostanoids, leukotriens, and dietary fatty acids in cutaneous inflammatory diseases: Insights from pharmacological and genetic approaches.

Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2 -EP4 and LTB4 -BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine-induced migration ability into the skin and play critical roles in the priming and/or activation of antigen-specific effector T cells in the skin. In addition to these ω6 fatty acid-derived metabolites, various ω3 fatty acid-derived metabolites regulate skin immune cell functions, and some exert potent anti-inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.

Exploring oak processionary caterpillar induced lepidopterism (Part 1): unveiling molecular insights through transcriptomics and proteomics.

Lepidopterism, a skin inflammation condition caused by direct or airborne exposure to irritating hairs (setae) from processionary caterpillars, is becoming a significant public health concern. Recent outbreaks of the oak processionary caterpillar (Thaumetopoea processionea) have caused noteworthy health and economic consequences, with a rising frequency expected in the future, exacerbated by global warming promoting the survival of the caterpillar. Current medical treatments focus on symptom relief due to the lack of an effective therapy. While the source is known, understanding the precise causes of symptoms remain incomplete understood. In this study, we employed an advanced method to extract venom from the setae and identify the venom components through high-quality de novo transcriptomics, venom proteomics, and bioinformatic analysis. A total of 171 venom components were identified, including allergens, odorant binding proteins, small peptides, enzymes, enzyme inhibitors, and chitin biosynthesis products, potentially responsible for inflammatory and allergic reactions. This work presents the first comprehensive proteotranscriptomic database of T. processionea, contributing to understanding the complexity of lepidopterism. Furthermore, these findings hold promise for advancing therapeutic approaches to mitigate the global health impact of T. processionea and related caterpillars.

Exploring oak processionary caterpillar induced lepidopterism (part 2): ex vivo bio-assays unmask the role of TRPV1.

As human skin comes into contact with the tiny hairs or setae of the oak processionary caterpillar, Thaumetopoea processionea, a silent yet intense chemical confrontation occurs. The result is a mix of issues: skin rashes and an intense itching that typically lasts days and weeks after the contact. This discomfort poses a significant health threat not only to humans but also to animals. In Western Europe, the alarming increase in outbreaks extends beyond areas near infested trees due to the dispersion of the setae. Predictions indicate a sustained rise in outbreaks, fueled by global changes favoring the caterpillar's survival and distribution. Currently, the absence of an efficient treatment persists due to significant gaps in our comprehension of the pathophysiology associated with this envenomation. Here, we explored the interaction between the venom extract derived from the setae of T. processionea and voltage- and ligand-gated ion channels and receptors. By conducting electrophysiological analyses, we discovered ex vivo evidence highlighting the significant role of TPTX1-Tp1, a peptide toxin from T. processionea, in modulating TRPV1. TPTX1-Tp1 is a secapin-like peptide and demonstrates a unique ability to modulate TRPV1 channels in the presence of capsaicin, leading to cell depolarization, itch and inflammatory responses. This discovery opens new avenues for developing a topical medication, suggesting the incorporation of a TRPV1 blocker as a potential solution for the local effects caused by T. processionea.

Dendritic cells under allergic condition enhance the activation of pruritogen-responsive neurons via inducing itch receptors in a co-culture study.

BACKGROUND: Itch sensitization has been reported in patients with chronic allergic skin diseases and observed in a mouse model of allergic contact dermatitis (ACD). There is evidence suggesting that neuroimmune interactions may contribute to itch sensitization, as an increase in dendritic cells (DCs) within ganglia has been observed during allergic conditions. However, how DCs interact with sensory neurons in ganglia during allergic conditions is still not known. This study aims to investigate the role of DCs in dorsal root ganglion (DRG) under ACD conditions, specifically focusing on itch sensitization within the DRG. The tolylene-2,4-diisocyanate (TDI) mouse model for ACD and the co-culture model of DCs and DRG neurons was employed in this study. RESULTS: We successfully induced ACD by TDI, as evidenced by the development of edema, elevated total serum IgE levels, and an observed itch reaction in TDI-sensitized mice. Calcium imaging and RT-qPCR analysis revealed that TDI-sensitized mice exhibited signs of peripheral sensitization, including a higher percentage of neurons responding to pruritogens and increased activation and expression of itch receptors in excised DRG of TDI-sensitized mice. Immunofluorescence and flow cytometric analysis displayed an increase of MHCII+ cells, which serves as a marker for DCs, within DRG during ACD. The co-culture study revealed that when DRG neurons were cultured with DCs, there was an increase in the number of neurons responsive to pruritogens and activation of itch receptors such as TRPA1, TRPV1, H1R, and TRPV4. In addition, the immunofluorescence and RT-qPCR study confirmed an upregulation of TRPV4. CONCLUSIONS: Our findings indicate that there is an increase of MHCII+ cells and itch peripheral sensitization in DRG under TDI-induced ACD condition. It has been found that MHCII+ cells in DRG might contribute to the itch peripheral sensitization by activating itch receptors, as shown through co-culture studies between DRG neurons and DCs. Further studies are required to identify the specific mediator(s) responsible for peripheral sensitization induced by activated DCs.

Endoplasmic reticulum stress and the inflammatory response in allergic contact dermatitis.

Maintaining homeostasis is central to organismal health. Deviation is detected by a variety of sensors that react to alarm signals arising from injury, infection, and other inflammatory triggers. One important element of this alarm system is the innate immune system, which recognizes pathogen-/microbe- or damage-associated molecular patterns via pattern recognition receptors localized in the cytosol or in membranes of innate immune cells such as macrophages, dendritic cells, and mast cells but also of T cells, B cells, and epithelial cells. Activation of the innate immune system results in inflammation and is a pre-requisite for activation of the adaptive immune system. Another important element is represented by the unfolded protein response (UPR), a stress response of the endoplasmic reticulum. The UPR regulates proteostasis and also contributes to the course of inflammatory diseases such as cancer, diabetes, obesity, and neurodegenerative diseases. In addition, the UPR is instrumental in allergic contact dermatitis. This inflammatory skin disease, affecting 5-10% of the population, is caused by T cells recognizing low-molecular weight organic chemicals and metal ions. In this mini-review, we discuss the orchestration of inflammatory responses by the interplay of the innate immune system with cellular stress responses in allergic contact dermatitis, with a focus on the UPR.

CD1a and bound lipids drive T-cell responses in human skin disease.

In addition to serving as the main physical barrier with the outside world, human skin is abundantly infiltrated with resident αß T cells that respond differently to self, infectious, microbiome, and noxious stimuli.  To study skin T cells during infection and inflammation, experimental biologists track T-cell surface phenotypes and effector functions, which are often interpreted with the untested assumption that MHC proteins and peptide antigens drive measured responses.  However, a broader perspective is that CD1 proteins also activate human T cells, and in skin, Langerhans cells (LCs) are abundant antigen presenting cells that express extremely high levels of CD1a.  The emergence of new experimental tools, including CD1a tetramers carrying endogenous lipids, now show that CD1a-reactive T cells comprise a large population of resident T cells in human skin.  Here, we review studies showing that skin-derived αß T cells directly recognize CD1a proteins, and certain bound lipids, such as contact dermatitis allergens, trigger T-cell responses. Other natural skin lipids inhibit CD1a-mediated T-cell responses, providing an entry point for the development of therapeutic lipids that block T-cell responses. Increasing evidence points to a distinct role of CD1a in type 2 and 22 T-cell responses, providing new insights into psoriasis, contact dermatitis, and other T-cell-mediated skin diseases.

Contact allergic dermatitis to skin adhesive after CIED upgrade procedure.

INTRODUCTION: The utilization of skin adhesives for closure is typically secondary to its noninvasive application and aesthetic benefits. Allergic reactions to Dermabond™ can occur, though there are no reported cases in pediatric patients following cardiac implantable electronic device (CIED) implantation. The allergic reaction to skin glues is typically to cyanoacrylates, the primary component of Dermabond™. METHODS AND RESULTS: This report describes severe allergic contact dermatitis due to sensitization to cyanoacrylate in an 18-year-old with repaired congenital heart disease and postoperative atrioventricular block following CIED upgrade procedure. CONCLUSION: This demonstrates the importance of prompt diagnosis of allergic contact dermatitis, which can be confused with local infections.

Topical corticosteroids inhibit allergic skin inflammation but are ineffective in impeding the formation and expansion of resident memory T cells.

BACKGROUND: Tissue-resident memory T (TRM ) cells are detrimental in allergic contact dermatitis (ACD), in which they contribute to the chronicity and severity of the disease. METHODS: We assessed the impact of a standard topical corticosteroid (TCS) treatment, triamcinolone acetonide (TA), on the formation, maintenance and reactivation of epidermal TRM cells in a preclinical model of ACD to 2,4-dinitrofluorobenzene. TA 0.01% was applied at different time points of ACD response and we monitored skin inflammation and tracked CD8+ CD69+ CD103+ TRM by flow cytometry and RNA sequencing. RESULTS: The impact of TA on TRM formation depended on treatment regimen: (i) in a preventive mode, that is, in sensitized mice before challenge, TA transiently inhibited the infiltration of effector T cells and the accumulation of TRM upon hapten challenge. In contrast, (ii) in a curative mode, that is, at the peak of the ACD response, TA blocked skin inflammation but failed to prevent the formation of TRM . Finally, (iii) in a proactive mode, that is, on previous eczema lesions, TA had no effect on the survival of skin TRM , but transiently inhibited their reactivation program upon allergen reexposure. Indeed, specific TRM progressively regained proliferative functions upon TA discontinuation and expanded in the tissue, leading to exaggerated iterative responses. Interestingly, TRM re-expansion correlated with the decreased clearance of hapten moieties from the skin induced by repeated TA applications. CONCLUSIONS: Our results demonstrate that TCS successfully treat ACD inflammation, but are mostly ineffective in impeding the formation and expansion of allergen-specific TRM , which certainly restricts the induction of lasting tolerance in patients with chronic dermatitis.

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.

Diagnosis of Allergic Dermatoses in Skin of Color.

PURPOSE OF REVIEW: This review aims to deliver a comprehensive report of the most recent knowledge on diagnosing allergic dermatoses in skin of color (SOC) patients. RECENT FINDINGS: Allergic dermatoses can affect populations of all backgrounds. However, racial/ethnic variations in epidemiology, clinical features, and associated allergens have been reported. Nuances in the approach to diagnosis, including the assessment of erythema and interpretation of patch tests, are important considerations when treating patients with SOC. In this review, we outline various manifestations of allergic dermatoses in SOC with a focus on important clinical presentations and diagnostic tools, aiming to support clinicians in accurate recognition of diseases, thereby opening avenues to improve outcomes across diverse skin types.

The role of the environment in allergic skin disease.

PURPOSE OF REVIEW: This paper explores how environmental factors influence allergic skin diseases, including atopic dermatitis (AD), contact dermatitis (CD), urticaria, angioedema, and reactions to drugs and insect bites. RECENT FINDINGS: Research indicates a significant impact of environmental elements on allergic skin diseases. High air pollution levels exacerbate symptoms, while climate change contributes to increased skin barrier dysfunction, particularly affecting AD. Allergen prevalence is influenced by climate and pollution. Irritants, like those in detergents and cosmetics, play a major role in CD. Plants also contribute, causing various skin reactions. Understanding the interplay between environmental factors and allergic skin diseases is crucial for effective management. Physicians must address these factors to support patient well-being and promote skin health amidst environmental changes.

More than just methylisothiazolinone: Retrospective analysis of patients with isothiazolinone allergy in North America, 2017-2020.

BACKGROUND: Isothiazolinones are a common cause of allergic contact dermatitis. OBJECTIVE: To examine the prevalence of positive patch test reactions to isothiazolinones from 2017-2020 and characterize isothiazolinone-allergic (Is+) patients compared with isothiazolinone nonallergic (Is-) patients. METHODS: Retrospective cross-sectional analysis of 9028 patients patch tested to methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) 0.02% aqueous, MI 0.2% aqueous, benzisothiazolinone (BIT) 0.1% petrolatum, and/or octylisothiazolinone (OIT) 0.025% petrolatum. Prevalence, reaction strength, concurrent reactions, clinical relevance, and source of allergens were tabulated. RESULTS: In total, 21.9% (1976/9028) of patients had a positive reaction to 1 or more isothiazolinones. Positivity to MI was 14.4% (1296/9012), MCI/MI was 10.0% (903/9017), BIT was 8.6% (777/9018), and OIT was 05% (49/9028). Compared with Is-, Is+ patients were more likely to have occupational skin disease (16.5% vs 10.3%, P <.001), primary hand dermatitis (30.2% vs 19.7%, P <.001), and be >40 years (73.1% vs 61.9%, P <.001). Positive patch test reactions to >1 isothiazolinone occurred in 44.1% (871/1976) of Is+ patients. Testing solely to MCI/MI would miss 47.3% (611/1292) of MI and 60.1% (466/776) of BIT allergic reactions. LIMITATIONS: Retrospective cross-sectional study design and lack of follow-up data. CONCLUSION: Sensitization to isothiazolinones is high and concurrent sensitization to multiple isothiazolinone allergens is common.

Identification of the pigments used in permanent makeup and their ability to elicit allergic contact dermatitis.

BACKGROUND: Decorative tattoos are known to contain ingredients that may elicit allergic contact dermatitis; it is less well-known if permanent makeup pigments carry the same risk. OBJECTIVE: Identify pigments used in permanent makeup inks sold in the United States and review cases of allergic contact dermatitis to these pigments. METHODS: Using internet searches, permanent makeup inks sold in the United States were identified. Safety data sheets were used to catalog pigments used in permanent makeup. A subsequent literature search was performed to identify cases of allergic contact dermatitis to these pigments. RESULTS: A total of 974 permanent makeup inks were reviewed, and 79 unique pigments were identified. The average product contained 4 pigments. Twenty of the pigments were inorganic metals, including carbon, iron, chromium, manganese, and molybdenum. Fifty-nine pigments were organic, of which most were azo, quinacridone, or anthraquinone dyes. A literature search revealed that 10 of the 79 pigments were associated with allergic contact dermatitis. CONCLUSION: Permanent makeup primarily uses organic pigments, although some metallic pigments are still used. Physicians should also be aware that some of these pigments-both organic and inorganic-are known causes of allergic contact dermatitis. Of note, patch testing to these ingredients can be negative.

Cost-effectiveness of patch testing allergens within the same group: A computational approach to optimize formaldehyde-related allergen selection.

BACKGROUND: Patch testing for multiple cross-reactive allergens for allergic contact dermatitis (ACD) may not be necessary because of copositivity. OBJECTIVES: We evaluated the formaldehyde group allergens to determine the optimal, most cost-effective allergens to test. METHODS: A retrospective analysis of Mayo Clinic (1997-2022) examined the well-established copositive formaldehyde group: formaldehyde, quaternium 15, hexahydro-1,3,5-tris(2-hydroxyethyl)triazine, diazolidinyl urea, imidazolidinyl urea, toluenesulphonamide formaldehyde resin, DMDM hydantoin, and ethyleneurea melamine formaldehyde mix. Patch Optimization Platform identified which single formaldehyde-related allergen optimally captures patients with clinically relevant ACD. Next, Patch Optimization Platform determined the optimal additional 1, 2, 3, etc. allergens. Cost per patch test was $5.19 (Medicare 2022). RESULTS: A total of 9832 patients were tested for all listed allergens, with 830 having positive patch test results. Patch Optimization Platform determined that quaternium 15 alone captures 53% of patients with ACD to the formaldehyde group; adding the optimal second allergen (formaldehyde 1%) captures 78%; the optimal 5 top allergens capture >94% of patients. The incremental cost per additional diagnosis increased up to 44-fold as the number of allergens tested increased. LIMITATIONS: Data are from a single institution, and the cost per test was fixed according to Medicare Part B in 2022. CONCLUSIONS: For diagnosing ACD, we recommend considering an optimized allergen selection algorithm.

Gene profiling in active dermatitis lesions strengthens the diagnosis of allergic contact dermatitis.

BACKGROUND: Distinguishing between allergic and nonallergic forms of Contact Dermatitis (CD) is challenging and requires investigations based on patch-testing. Early detection of allergy biomarkers in active CD lesions could refine and simplify the management of CD patients. OBJECTIVE: To characterize the molecular signatures of active CD lesions. METHODS: We studied the expression of 12 allergy biomarkers by qRT-PCR in active lesions of 38 CD patients. Allergic CD (ACD) was diagnosed based on patch test (PT) results and exposure assessment. Molecular signatures of active lesions, as well as positive PT reactions, were compared with those of reference chemical allergens and irritants. RESULTS: Nineteen of the 38 CD patients reacted positively upon patch-testing and exposure assessment confirmed ACD diagnosis for 17 of them. Gene profiling of active CD lesions revealed 2 distinct molecular patterns: patients harboring signatures similar to reference allergens (n = 23) or irritants (n = 15). Among the 23 patients with an "allergy signature," we found the 17 patients with confirmed ACD, while no culprit allergen was identified for the 6 other patients. Interestingly, the 15 patients without biomarker induction had negative PT, suggesting that they developed nonallergic CD reactions. CONCLUSION: Molecular signatures from active skin lesions may help to stratify CD patients and predict those suffering from ACD.

A sticky mess-Are moisturizers overused in dermatitis care?

Microbial dysbiosis is increasingly understood to influence allergic sensitization and skin barrier defects in dermatitis. Occlusion, such as from moisturizers, fosters microbial dysbiosis, and increases itch in many patients with dermatitis. Nevertheless, use of moisturizers in dermatitis remains part of dermatologic guidelines. This is a review of the evidence of benefits and adverse effects of moisturizers in dermatitis and a proposal for moderation in their clinical use.

Petroleum jelly: A comprehensive review of its history, uses, and safety.

Petrolatum, also known as petroleum jelly, is a widely used topical agent, with a variety of uses in dermatology. Despite its popularity, many myths surround this ubiquitous dermatologic staple. This review details the history of petrolatum and how it is manufactured as well as how its biologic properties make it a great moisturizer. Additionally, data on its potential for flammability, allergenicity, and comedogenicity are detailed, dispelling misconceptions about petrolatum use around oxygen and as a cause of acne. The uses and benefits of petrolatum in dermatology are wide-ranging-a patch test instrument, a vehicle for medicated ointments, and a wound care essential. Given its ubiquitous presence, it is important for dermatologists to understand the history, safety profile, and myths surrounding this humble skincare staple.

Sunscreens Part 2: Regulation and Safety.

The second part of this CME article discusses sunscreen regulation and safety considerations for humans and the environment. First, we provide an overview of the history of the United States Food and Drug Administration's regulation of sunscreen. Recent Food and Drug Administration studies clearly demonstrate that organic ultraviolet filters are systemically absorbed during routine sunscreen use, but to date there is no evidence of associated negative health effects. We also review the current evidence of sunscreen's association with vitamin D levels and frontal fibrosing alopecia, and recent concerns regarding benzene contamination. Finally, we review the possible environmental effects of ultraviolet filters, particularly coral bleaching. While climate change has been shown to be the primary driver of coral bleaching, laboratory-based studies suggest that organic ultraviolet filters represent an additional contributing factor, which led several localities to ban certain organic filters.

Illuminating characteristic patterns of inflammatory dermatoses: A comprehensive dual-imaging approach using Optical coherence tomography and Line-field confocal optical coherence tomography.

BACKGROUND: Inflammatory skin diseases, such as psoriasis, atopic eczema, and contact dermatitis pose diagnostic challenges due to their diverse clinical presentations and the need for rapid and precise diagnostic assessment. OBJECTIVE: While recent studies described non-invasive imaging devices such as Optical coherence tomography and Line-field confocal OCT (LC-OCT) as possible techniques to enable real-time visualization of pathological features, a standardized analysis and validation has not yet been performed. METHODS: One hundred forty lesions from patients diagnosed with atopic eczema (57), psoriasis (50), and contact dermatitis (33) were imaged using OCT and LC-OCT. Statistical analysis was employed to assess the significance of their characteristic morphologic features. Additionally, a decision tree algorithm based on Gini's coefficient calculations was developed to identify key attributes and criteria for accurately classifying the disease groups. RESULTS: Descriptive statistics revealed distinct morphologic features in eczema, psoriasis, and contact dermatitis lesions. Multivariate logistic regression demonstrated the significance of these features, providing a robust differentiation between the three inflammatory conditions. The decision tree algorithm further enhanced classification accuracy by identifying optimal attributes for disease discrimination, highlighting specific morphologic criteria as crucial for rapid diagnosis in the clinical setting. CONCLUSION: The combined approach of descriptive statistics, multivariate logistic regression, and a decision tree algorithm provides a thorough understanding of the unique aspects associated with each inflammatory skin disease. This research offers a practical framework for lesion classification, enhancing the interpretability of imaging results for clinicians.

Tattoo-induced allergic contact dermatitis presents diagnostic challenge as a cellulitis mimic.

Allergic contact dermatitis (ACD) is a prevalent condition associated with numerous potential allergen exposures. Tattoo ink is variable and may contain allergens that can be overlooked in patient education and diagnosis. We present a 27-year-old female with ACD following a new tattoo. The patient was repeatedly misdiagnosed with cellulitis by three different clinicians and treated with multiple antibiotics without improvement. The correct diagnosis was eventually made in the emergency department (ED). Although the patient was aware of her allergies to nickel and cobalt from patch testing, she was not aware of the potential for tattoo ink to contain these allergens because prior tattoos had not provoked an allergic reaction. Consequently, the appropriate care was delayed by a month, resulting in significant morbidity. This case demonstrates the potential for ACD to present similarly to cellulitis in an ED setting and the need for clinical vigilance in diagnosis of ACD. It also highlights the importance of detailed patient education on potential allergen sources particularly in the context of tattooing, which is performed with unregulated and variable ink products.