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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. [ABSTRACT FROM AUTHOR]

This article discusses the high content of hexavalent chromium (Cr(VI)) in cement samples from three African countries: Tanzania, Ghana, and South Africa. The study found that while the total amount of chromium in the samples was relatively low compared to samples from EU and non-EU countries, the content of Cr(VI) was alarmingly high. In six out of the eight samples, the Cr(VI) content exceeded the maximal allowed concentration in the EU. The authors suggest that reducing the concentration of Cr(VI) in cement and implementing measures to prevent direct skin contact with cement could significantly reduce chromium allergy in these African countries. [Extracted from the article]

Background: CD8+ epidermal‐resident memory T (TRM) cells play central roles in local flare‐up responses to experimental contact allergens by inducing massive influx of neutrophils to the epidermis upon allergen challenge. Whether similar immunopathogenic mechanisms are involved in the responses to clinically relevant contact allergens is unknown. Methods: The immune response to cinnamal, ρ‐phenylenediamine (PPD) and methylisothiazolinone (MI) was studied in a well‐established mouse model for allergic contact dermatitis that includes formation of TRM cells by ELISA, flow cytometry, fluorescence microscopy analyses and cell depletion protocols. Results: We show that the formation of CD4+ and CD8+ epidermal TRM cells and the inflammatory response are highly allergen‐dependent. However, the magnitude of the flare‐up responses correlated with the number of epidermal CD8+ TRM cells, CXCL1/CXCL2 release and recruitment of neutrophils to the epidermis. Finally, depletion of CD4+ T cells strongly enhanced the number of epidermal CD8+ TRM cells, the flare‐up response and the epidermal infiltration of neutrophils for all allergens. Conclusion: As the first, this study demonstrates that clinically relevant contact allergens have the ability to generate pathogenic, epidermal CD8+ TRM cells that recruit neutrophils following re‐exposure to the allergen, but that this normally is counteracted by the simultaneous induction of anti‐inflammatory CD4+ T cells. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide-1 receptor (GLP-1R) plays a key role in metabolism and is an important therapeutic target in diabetes and obesity. Recent studies in experimental animals have shown that certain subsets of T cells express functional GLP-1R, indicating an immune regulatory role of GLP-1. In contrast, less is known about the expression and function of the GLP-1R in human T cells. Here, we provide evidence that activated human T cells express GLP-1R. The expressed GLP-1R was functional, as stimulation with a GLP-1R agonist triggered an increase in intracellular cAMP, which was abrogated by a GLP-1R antagonist. Analysis of CD4+ T cells activated under T helper (Th) 1, Th2, Th17 and regulatory T (Treg) cell differentiation conditions indicated that GLP-1R expression was most pronounced in induced Treg (iTreg) cells. Through multimodal single-cell CITE- and TCR-sequencing, we detected GLP-1R expression in 29–34% of the FoxP3+CD25+CD127- iTreg cells. GLP-1R+ cells showed no difference in their TCR-gene usage nor CDR3 lengths. Finally, we demonstrated the presence of GLP-1R+CD4+ T cells in skin from patients with allergic contact dermatitis. Taken together, the present data demonstrate that T cell activation triggers the expression of functional GLP-1R in human CD4+ T cells. Given the high induction of GLP-1R in human iTreg cells, we hypothesize that GLP-1R+ iTreg cells play a key role in the anti-inflammatory effects ascribed to GLP-1R agonists in humans. [ABSTRACT FROM AUTHOR]

This article, published in the British Journal of Dermatology, discusses the role of neutrophil infiltration in allergic contact dermatitis (ACD) to nickel. ACD is a common inflammatory skin disease, and it is typically observed through patch testing on the back of patients. While previous studies have not shown significant neutrophil infiltration during ACD, this study found that neutrophils do play an important role in human ACD reactions. The authors suggest that targeting the survival of allergen-specific CD8+ TRM cells or their ability to recruit neutrophils could be a novel strategy for treating ACD. The study was supported by various funding sources and the authors declare no conflicts of interest. [Extracted from the article]

Background: Allergic contact dermatitis (ACD) is classically described as a delayed‐type hypersensitivity reaction. However, patients often experience flare‐ups characterized by itching erythema, edema, and often vesicles occurring within hours after re‐exposure of previously sensitized skin to the specific contact allergen. Recent studies have indicated that skin‐resident memory T (TRM) cells play a central role in ACD. However, the pathogenic role of TRM cells in allergen‐induced flare‐ups is not known. Methods: By the use of various mouse models and cell depletion protocols, we investigated the role of epidermal TRM cells in flare‐up reactions to the experimental contact allergen 1‐fluoro‐2,4‐dinitrobenzene. The inflammatory response was measured by changes in ear thickness, and the cellular composition in epidermis was determined by flow cytometry and confocal microscopy. Finally, adaptive transfer and inhibitors were used to determine the role of TRM cells, neutrophils, and CXCL1/CXCL2 in the response. Results: We show that CD8+ TRM cells initiate massive infiltration of neutrophils in the epidermis within 12 h after re‐exposure to the contact allergen. Depletion of neutrophils before re‐exposure to the allergen abrogated the flare‐up reactions. Furthermore, we demonstrate that CD8+ TRM cells mediate neutrophil recruitment by inducing CXCL1 and CXCL2 production in the skin, and that blockage of the C‐X‐C chemokine receptor type 1 and 2 inhibits flare‐up reactions and neutrophil infiltration. Conclusion: As the first, we show that epidermal CD8+ TRM cells cause ACD flare‐ups by rapid recruitment of neutrophils to the epidermis. [ABSTRACT FROM AUTHOR]

Interleukin‐1β (IL‐1β) is an important pro‐inflammatory cytokine that has an effect on almost every cell lineage in the body. By blocking IL‐1β and investigating the IL‐1β signaling pathway, several studies have demonstrated a central role of IL‐1β in the response to contact allergens. This review summarizes the current literature regarding the basic immunological mechanisms mediated by IL‐1β in the different phases of allergic contact dermatitis (ACD) and highlights potential IL‐1β‐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‐1β in ACD are lacking. [ABSTRACT FROM AUTHOR]

Approximately 25% of the population suffers from skin diseases. The most common forms of skin diseases are the inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis. These diseases are described as T cell–mediated diseases induced by either allergens or autoantigens. Classically, the focus has been on the role of αβ T cells, but it is becoming increasingly clear that γδ T cells play a central role in inflammatory skin diseases. In particular, an important role of IL‐17A–producing γδ T cells in these inflammatory skin diseases has been shown in various disease models in mice. Interestingly, various epidermal proteins, which appear to be linked to inflammatory conditions in the skin by yet undescribed mechanisms, are expressed by specific subsets of thymic epithelial cells and mutations in these proteins seem to affect γδ T cell development. The focus of this review is how mutations in epidermal proteins affect γδ T cell development and how γδ T cells, and in particular of IL‐17A–producing γδ T cells, contribute to inflammatory skin diseases such as allergic contact dermatitis, psoriasis, and atopic dermatitis. [ABSTRACT FROM AUTHOR]

Allergic contact dermatitis (ACD) is a common inflammatory skin disease with a prevalence of approximately 20% in the European population. ACD is caused by contact allergens that are reactive chemicals able to modify non-immunogenic self-proteins to become immunogenic proteins. The most frequent contact allergens are metals, fragrances, and preservatives. ACD clinically manifests as pruritic eczematous lesions, erythema, local papules, and oedema. ACD is a T cell-mediated disease, involving both CD4+ and CD8+ T cells. In addition, γδ T cells appear to play an important role in the immune response to contact allergens. However, it is debated whether γδ T cells act in a pro- or anti-inflammatory manner. A special subset of γδ T cells, named dendritic epidermal T cells (DETC), is found in the epidermis of mice and it plays an important role in immunosurveillance of the skin. DETC are essential in sensing the contact allergen-induced stressed environment. Thus, allergen-induced activation of DETC is partly mediated by numerous allergen-induced stress proteins expressed on the keratinocytes (KC). Several stress proteins, like mouse UL-16-binding protein-like transcript 1 (Mult-1), histocompatibility 60 (H60) and retinoic acid early inducible-1 (Rae-1) α-ε family in mice and major histocompatibility complex (MHC) class I—chain-related A (MICA) in humans, are upregulated on allergen-exposed KC. Allergen-induced stress proteins expressed on the KC are consequently recognized by NKG2D receptor on DETC. This review focuses on the role of γδ T cells in ACD, with DETC in the spotlight, and on the role of stress proteins in contact allergen-induced activation of DETC. [ABSTRACT FROM AUTHOR]

Background: Nickel allergy and dermatitis have been associated with filaggrin gene mutations in epidemiological studies, but the mechanisms mediating these associations are unknown. Objectives: To investigate whether filaggrin‐deficient flaky tail (ft/ft) mice show increased immune reactivity to nickel and elucidate the mechanisms mediating this. Methods: The immune responses to nickel, 2,4‐dinitrofluorobenzene (DNFB), cinnamal and p‐phenylenediamine were assessed in ft/ft and wild‐type (WT) mice. The amounts of nickel in the skin of ft/ft and WT mice were determined 20 hours after nickel exposure. The effect of blocking either the interleukin (IL)‐17A pathway or the IL‐1 pathway on the response to nickel in ft/ft mice was evaluated. Results: Increased responsiveness to nickel, DNFB and cinnamal was observed in ft/ft mice as compared with controls. A reduced amount of nickel was found in the skin of ft/ft mice as compared with WT mice, suggesting increased nickel absorption by the skin of ft/ft mice. Blocking either the IL‐17A pathway or the IL‐1 pathway reduced nickel responsiveness in ft/ft mice. Conclusions: These findings suggest that the increased nickel responsiveness associated with epidermal filaggrin deficiency is mediated by a combination of increased nickel penetration and the steady‐state inflammation found in the skin of filaggrin‐deficient mice. [ABSTRACT FROM AUTHOR]

Allergic contact dermatitis is one of the most frequent forms of skin inflammation. Very often, we are exposed to mixtures of allergens with varying potencies, doses/areas, and exposure times. Therefore, improved knowledge about immune responses to combinations of contact allergens is highly relevant. In this article, we provide a general introduction to immune responses to contact allergens, and discuss the literature concerning immune responses to mixtures of allergens. According to the existing evidence, increased responses are induced following sensitization with combinations of allergens as compared with single allergens. The response to a mixture of allergens can be both additive and synergistic, depending on the dose and combination of allergens. Importantly, sensitization with combinations of either fragrance allergens or metal salts can result in increased challenge responses to specific allergens within the mixture. Taken together, the immune responses to mixtures of allergens are complex, and further studies are required to obtain the necessary knowledge to improve consumer safety. [ABSTRACT FROM AUTHOR]

Background. Perfumes are complex mixtures composed of many fragrance ingredients, many of which are known to be only weak allergens when tested individually. It is therefore surprising that fragrance contact allergy is one of the most common forms of contact allergy. Objectives. To investigate whether mixing different fragrance allergens leads to increased sensitization potency, and to examine the difference in the challenge response to one chemical in mice sensitized either with the mixture of allergens or with only the relevant allergen. Methods. CBA mice were sensitized with three different concentrations of three fragrance allergens alone or as a mixture. The sensitization and elicitation responses were measured by ear thickness plus infiltration of B and T cells and T cell proliferation in the draining lymph nodes. Results. We found a dose-dependent sensitization response for each of the allergens. An increased response was seen when the allergens were mixed. A stronger challenge response to cinnamal was seen in mice sensitized with the allergen mixture than in mice sensitized with cinnamal alone. Conclusions. Our findings suggest that mixtures of allergens increase the primary response that potentiates the generation of memory T cells in response to the specific allergen. Thus, allergen mixtures enhance both induction and elicitation of contact allergy. [ABSTRACT FROM AUTHOR]

Background: IL-17–producing TH (TH17) cells are key mediators of chronic inflammation in mice. Recent studies have implicated TH17-mediated inflammation in the pathogenesis of human autoimmune diseases; however, the involvement of TH17 cells in allergic disorders remains largely elusive. Objective: To investigate TH17-mediated inflammation in human beings with allergic contact dermatitis; in particular, the innate response of keratinocytes to contact allergen, the induction of allergen-specific TH17 cells, and the presence of TH17-related effector cells in inflamed skin. Methods: Human keratinocytes were stimulated with nickel in vitro followed by measurements of IL-23 and IL-12 production by quantitative PCR and ELISA. Allergen-specific memory T cells from the blood of individuals with nickel allergy and healthy controls were identified and characterized by using a short-term ex vivo assay. Nickel patch test lesions and normal skin were analyzed for the expression of TH17-related cells and molecules by using immunohistochemistry. Results: Keratinocytes were found to produce IL-23, but no detectable IL-12, in a response to nickel stimulation. Memory T cells isolated from peripheral blood of individuals with nickel allergy, but not healthy controls, contained TH17 and TH1 cells proliferating in response to nickel-pulsed DCs. Inflamed skin of nickel-challenged allergic individuals contained infiltrating neutrophils and cells expressing IL-17, IL-22, CCR6, and IL-22R. Conclusion: Our results demonstrate the involvement of TH17-mediated immunopathology in human allergic contact dermatitis, including both innate and adaptive immune responses to contact allergens. [Copyright &y& Elsevier]

Background: The different role of various immunological effector cells in contact hypersensitivity (CHS) is receiving increased attention. During the past decade, the involvement of different cell types in CHS has been investigated by the use of antibody-induced depletion of specific subtypes of immunological cells and by studying knockout mice lacking one or more of these immunological cell populations. Objectives: To develop a method for studying the collective cellular dynamics of immune cells in the draining lymph nodes during CHS in intact animals. Patients/Methods: Mice were sensitized and/or challenged with 2,4-dinitrofluorobenzene or oxazolone. Using multi-parameter flow cytometry we determined the proliferation, activation state, and absolute number of helper T cells, cytotoxic T cells, B cells, and natural killer cells in the draining lymph nodes. Results: The presented method can be applied to evaluate the effect of different contact allergens on various cell populations of the immune system. Conclusions: Our study support recent findings that several cell types seem to be involved in CHS. [ABSTRACT FROM AUTHOR]