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The study investigated whether patients with atopic dermatitis (AD) have an altered response to contact allergens compared to those without AD. The researchers compared the response to a contact allergen in mice with different skin conditions. They found that mice with impaired skin barrier and pre-existing skin inflammation had a reduced inflammatory response to the allergen compared to mice with healthy skin or impaired skin barrier without inflammation. The study suggests that pre-existing skin inflammation can suppress immune responses to new allergens, which may have implications for future research in contact allergy and dermal vaccine development. [Extracted from the article]

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]

Cutaneous T-cell lymphoma (CTCL) is characterized by the proliferation of malignant T cells in inflamed skin lesions. Mycosis fungoides (MF)—the most common variant of CTCL—often presents with skin lesions around the abdomen and buttocks ("bathing suit" distribution), i.e., in skin areas devoid of sun-induced vitamin D. For decades, sunlight and vitamin D have been connected to CTCL. Thus, vitamin D induces apoptosis and inhibits the expression of cytokines in malignant T cells. Furthermore, CTCL patients often display vitamin D deficiency, whereas phototherapy induces vitamin D and has beneficial effects in CTCL, suggesting that light and vitamin D have beneficial/protective effects in CTCL. Inversely, vitamin D promotes T helper 2 (Th2) cell specific cytokine production, regulatory T cells, tolerogenic dendritic cells, as well as the expression of immune checkpoint molecules, all of which may have disease-promoting effects by stimulating malignant T-cell proliferation and inhibiting anticancer immunity. Studies on vitamin D treatment in CTCL patients showed conflicting results. Some studies found positive effects, others negative effects, while the largest study showed no apparent clinical effect. Taken together, vitamin D may have both pro- and anticancer effects in CTCL. The balance between the opposing effects of vitamin D in CTCL is likely influenced by treatment and may change during the disease course. Therefore, it remains to be discovered whether and how the effect of vitamin D can be tilted toward an anticancer response in CTCL. [ABSTRACT FROM AUTHOR]

Background: Allergic contact dermatitis (ACD) is a common skin disease caused by the recognition of haptens by the immune system. Keratinocytes play an important role in the initiation and facilitation of inflammatory responses in ACD. Immune responses are associated with major changes in metabolism. However, metabolic re‐programming is not well studied in ACD; specifically, knowledge of metabolic alterations in structural cells is lacking. Methods: Metabolic re‐programming in ACD was studied using publicly available transcriptome datasets. Primary pooled keratinocytes and a keratinocyte cell line (HaCaT) were stimulated with contact allergens, and inflammatory responses and expression of metabolic markers were measured by qPCR and flow cytometry, respectively. Results: ACD is characterized by metabolic re‐programming with a metabolic profile similar to atopic dermatitis. Exposure to contact allergens causes a wide array of metabolic alterations. Stimulation of keratinocytes with contact allergens induced inflammatory responses typical for ACD and was associated with an up‐regulation of proteins representative for glucose uptake, fatty acid metabolism, oxidative phosphorylation and to some extent arginine biosynthesis. Changes in these metabolic pathways were also observed when comparing lesional with non‐lesional contact dermatitis skin. Conclusions: ACD is, similarly to other inflammatory skin diseases, characterized by metabolic re‐programming. Contact allergen exposure induces expression of a wide array of metabolic pathways, which is at least in part mediated through metabolic re‐programming of keratinocytes. [ABSTRACT FROM AUTHOR]

Only few studies on contact allergy in African countries have been published. The aim of the present study was to provide an overview of the most common contact allergens identified by the use of patch tests in African countries based on a review of the existing literature. A total of twenty‐four publications from eight African countries were initially identified by search in PubMed. The abstracts and method sections were screened, and 15 studies in which patch tests were actually used to identify the allergen causing the allergic contact dermatitis (ACD) were finally selected. Nickel, cobalt, chromium, fragrance mix and p‐tert‐butylphenol‐formaldehyde resin were the dominating contact allergens responsible for 40%–90% of the positive patch test reactions. This study indicates that a targeted effort directed towards prevention, avoidance and regulation of reliably identified contact allergens could reduce the disease burden of ACD considerable in some African countries. [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: Allergic contact dermatitis (ACD) is an inflammatory disease with a complex pathophysiology in which epidermal‐resident memory CD8+ T (TRM) cells play a key role. The mechanisms involved in the activation of CD8+ TRM cells during allergic flare‐up responses are not understood. Methods: The expression of CD100 and its ligand Plexin B2 on CD8+ TRM cells and keratinocytes before and after allergen exposure was determined by flow cytometry and RT‐qPCR. The role of CD100 in the inflammatory response during the challenge phase of ACD was determined in a model of ACD in CD100 knockout and wild‐type mice. Results: We show that CD8+ TRM cells express CD100 during homeostatic conditions and up‐regulate it following re‐exposure of allergen‐experienced skin to the experimental contact allergen 1‐fluoro‐2,4‐dinitrobenzene (DNFB). Furthermore, Plexin B2 is up‐regulated on keratinocytes following exposure to some contact allergens. We show that loss of CD100 results in a reduced inflammatory response to DNFB with impaired production of IFNγ, IL‐17A, CXCL1, CXCL2, CXCL5, and IL‐1β and decreased recruitment of neutrophils to the epidermis. Conclusion: Our study demonstrates that CD100 is expressed on CD8+ TRM cells and is required for full activation of CD8+ TRM cells and the flare‐up response of ACD. [ABSTRACT FROM AUTHOR]

Background: The junctional adhesion molecule‐like protein (JAML) plays important roles in wound healing and activation of epidermal γδ T cells in mice. Whether JAML plays a role in contact hypersensitivity (CHS), the animal model of allergic contact dermatitis (ACD), is not known. Methods: To examine the role of JAML in CHS, we used various mouse models of CHS in JAML knockout (KO) and wild‐type (WT) mice. Furthermore, the expression of the JAML ligand coxsackievirus and adenovirus receptor (CXADR) on keratinocytes was accessed in vitro and in vivo. Results: JAML KO mice had a diminished inflammatory response during both the sensitization and elicitation phase of CHS and had reduced numbers of CD8+ and CD4+ T cells in the epidermis. Furthermore, interferon γ (IFNγ), interleukin 1β (IL‐1β) and CXCL10 production were significantly reduced in JAML KO mice during the elicitation phase. We found that CD8+ T cells express JAML and that JAML is essential for rapid flare‐up responses to contact allergens. Finally, we show that keratinocytes up‐regulate the JAML ligand CXADR following exposure to contact allergens. Conclusion: Our study is the first to show a central role of JAML in CHS and reveals a potential new target for the treatment of ACD in humans. [ABSTRACT FROM AUTHOR]

Differentiation of naive CD4+ T cells into effector T cells is a dynamic process in which the cells are polarized into T helper (Th) subsets. The subsets largely consist of four fundamental categories: Th1, Th2, Th17, and regulatory T cells. We show that human memory CD4+ T cells can produce hepatocyte growth factor (HGF), a pleiotropic cytokine which can affect several tissue types through signaling by its receptor, c-Met. In vitro differentiation of T cells into Th-like subsets revealed that HGF producing T cells increase under Th1 conditions. Enrichment of HGF producing cells was possible by targeting cells with surface CD30 expression, a marker discovered through single-cell RNA-sequencing. Furthermore, pharmacological inhibition of PI3K or mTOR was found to inhibit HGF mRNA and protein, while an Akt inhibitor was found to increase these levels. The findings suggest that HGF producing T cells could play a role in disease where Th1 are present. [ABSTRACT FROM AUTHOR]

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]

Tuberculosis (TB) presents a serious health problem with approximately a quarter of the world's population infected with Mycobacterium tuberculosis (M. tuberculosis) in an asymptomatic latent state of which 5-10% develops active TB at some point in their lives. The antimicrobial protein cathelicidin has broad antimicrobial activity towards viruses and bacteria including M. tuberculosis. Vitamin D increases the expression of cathelicidin in many cell types including macrophages, and it has been suggested that the vitamin Dmediated antimicrobial activity against M. tuberculosis is dependent on the induction of cathelicidin. However, unraveling the immunoregulatory effects of vitamin D in humans is hampered by the lack of suitable experimental models. We have previously described a family in which members suffer from hereditary vitamin D-resistant rickets (HVDRR). The family carry a mutation in the DNAbinding domain of the vitamin D receptor (VDR). This mutation leads to a nonfunctional VDR, meaning that vitamin D cannot exert its effect in family members homozygous for the mutation. Studies of HVDRR patients open unique possibilities to gain insight in the immunoregulatory roles of vitamin D in humans. Here we describe the impaired ability of macrophages to produce cathelicidin in a HVDRR patient, who in her adolescence suffered from extrapulmonary TB. The present case is a rare experiment of nature, which illustrates the importance of vitamin D in the pathophysiology of combating M. tuberculosis. [ABSTRACT FROM AUTHOR]

The CD3 subunits of the T-cell antigen receptor (TCR) play a central role in regulation of surface TCR expression levels. Humans who lack CD3g (g--) show reduced surface TCR expression levels and abolished phorbol ester (PMA)-induced TCR down-regulation. The response to PMA ismediated by a double leucine motif in the intracellular (IC) domain of CD3g. However, the molecular cause of the reduced TCR surface expression in g-- lymphocytes is still not known. We used retroviral vectors carrying wild type CD3g or CD3d or the following chimeras (ECextracellular, TM-transmembrane and IC): dECgTMgIC (dgg for short), ggd, gdd and gg-. Expression of ggg, ggd, gdd or gg-in the g-- T cell line JGN, which lacks surface TCR, demonstrated that cell surface TCR levels in JGN were dependent on the EC domain of CD3g and could not be replaced by the one of CD3d. In JGN and primary g-- patient T cells, the tested chimeras confirmed that the response to PMA maps to the IC domain of CD3g. Since protein homology explains these results better than domain structure, we conclude that CD3g contributes conformational cues that improve surface TCR expression, likely at the assembly or membrane transport steps. In JGN cells all chimeric TCRs were signalling competent. However, an IC domain at CD3g was required for TCR-induced IL-2 and TNF-a production and CD69 expression, indicating that a TCR without a CD3g IC domain has altered signalling capabilities. [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]