Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces.

Epithelial tissues continually undergo apoptosis. Commensal organisms that inhabit the epithelium influence tissue homeostasis, in which regulatory T cells (Treg cells) have a central role. However, the physiological importance of epithelial cell apoptosis and how the number of Treg cells is regulated are both incompletely understood. Here we found that apoptotic epithelial cells negatively regulated the commensal-stimulated proliferation of Treg cells. Gut commensals stimulated CX3CR1(+)CD103(-)CD11b(+) dendritic cells (DCs) to produce interferon-ß (IFN-ß), which augmented the proliferation of Treg cells in the intestine. Conversely, phosphatidylserine exposed on apoptotic epithelial cells suppressed IFN-ß production by the DCs via inhibitory signaling mediated by the cell-surface glycoprotein CD300a and thus suppressed Treg cell proliferation. Our findings reveal a regulatory role for apoptotic epithelial cells in maintaining the number of Treg cell and tissue homeostasis.

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.

Contact allergies to dental materials in patients.

BACKGROUND: Concerns regarding contact allergies and intolerance reactions to dental materials are widespread among patients. Development of novel dental materials and less frequent amalgam use may alter sensitization profiles in patients with possible contact allergy. OBJECTIVES: To analyse current sensitization patterns to dental materials in patients with suspected contact allergy. METHODS: This retrospective, multicentre analysis from the Information Network of Departments of Dermatology (IVDK) selected participants from 169 834 people tested in 2005-2019 and registered with (i) an affected area of 'mouth' (and 'lips'/'perioral'), (ii) with the dental material in question belonging to one of three groups (dental filling materials, oral implants or dentures or equivalents) and (iii) with patch-testing done in parallel with the German baseline series, (dental) metal series and dental technician series. RESULTS: A total of 2730 of 169 834 tested patients met the inclusion criteria. The patients were predominantly women (81.2%) aged ≥ 40 years (92.8%). The sensitization rates with confirmed allergic contact stomatitis in women (n = 444) were highest for metals (nickel 28.6%, palladium 21.4%, amalgam 10.9%), (meth)acrylates [2-hydroxyethyl methacrylate (HEMA) 4.8%] and the substances propolis (6.8%) and 'balsam of Peru' (11.4%). The most relevant acrylates were HEMA, 2-hydroxypropyl methacrylate, methyl methacrylate, ethylene glycol dimethacrylate and pentaerythritol triacrylate. Few men were diagnosed with allergic contact stomatitis (n = 68); sensitization rates in men were highest for propolis (14.9%) and amalgam (13.6%). CONCLUSIONS: Allergic contact stomatitis to dental materials is rare. Patch testing should not only focus on metals such as nickel, palladium, amalgam and gold, but also (meth)acrylates and the natural substances propolis and 'balsam of Peru'.

CD1a and skin T cells: a pathway for therapeutic intervention.

The CD1 and MR1 protein families present lipid antigens and small molecules to T cells, complementing well-studied major histocompatibility complex-peptide mechanisms. The CD1a subtype is highly and continuously expressed within the skin, most notably on Langerhans cells, and has been demonstrated to present self and foreign lipids to T cells, highlighting its cutaneous sentinel role. Alteration of CD1a-dependent T-cell responses has recently been discovered to contribute to the pathogenesis of several inflammatory skin diseases. In this review, we overview the structure and role of CD1a and outline the current evidence implicating CD1a in the development of psoriasis, atopic dermatitis and allergic contact dermatitis.

Subclinical immune responses to nickel in sensitized individuals-a dose-response study.

BACKGROUND: Nickel is the leading cause of contact allergy in Europe, with 14.5% of the adult population being sensitized. Despite regulations limiting nickel release from consumer items, the incidence and prevalence of nickel allergy remain high. OBJECTIVE: To investigate the clinical and subclinical immune response to low-dose nickel exposure on nickel pre-exposed skin to assess the adequacy of current regulatory limits. METHOD: Nickel-allergic and healthy controls were patch tested with nickel twice with a 3-4 weeks interval. The first exposure used the diagnostic concentration of 2000 µg/cm2 nickel sulphate, and the same skin areas were then re-exposed to 0.2, 0.5, 12.8 and 370 µg/cm2 nickel sulphate. After 48 h, the patch reactions were examined for clinical signs of eczema, and skin biopsies were collected. The transcriptomic immune profile was analysed with Nanostring nCounter and quantitative polymerase chain reaction. RESULTS: Two nickel-allergic participants (15%) had clinical reactions to the regulatory limiting doses for nickel (0.2/0.5 µg/cm2) following re-exposure. There was immune activation in all skin areas following re-exposure to nickel, predominantly mediated by up-regulation of cytokines and chemokines. In all nickel re-exposed skin areas, 81 genes were up-regulated independent from the clinical response. In skin areas exposed to 0.2 µg/cm2, 101 immune-related genes were differentially expressed, even when no clinical response was observed. Healthy controls showed up-regulation of three genes in response to nickel re-exposures without any clinical reactions. CONCLUSION: Immune activation can be induced in skin with local memory to nickel upon challenge with nickel doses within the regulatory limits. Our findings suggest that the regulatory limits in the European nickel regulation may not provide sufficient protection for consumers against low-dose exposures.

Patch test in Brazilian children with a clinical diagnosis of atopic dermatitis: a cross-sectional study using an extended patch test battery.

INTRODUCTION: Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease mainly affecting children. Similarly, Allergic contact dermatitis (ACD) is an inflammatory skin disease, but unlike AD it results from direct exposure to an external agent. Theoretically, the impaired skin barrier facilitates the penetration of potential allergens. Therefore, AD patients are at risk for an associated ACD, exacerbating their skin condition. Because eczema is similar, performing a patch test (PT) for the differential diagnosis is essential. METHODS: In this cross-sectional transversal study, we performed a PT with 30 sensitizers in 26 children with AD, selected according to established criteria for suspected ACD, and treated at an AD center of a pediatric university hospital in Rio de Janeiro. Clinical presentation, patient profile, main sensitizers, and frequency of ACD caused by therapeutic skincare products were evaluated. RESULTS: In all, 23 (88.5%) patients reacted to at least one allergen, 21 (80.7%) had a relevant positive patch test, and 15 (57.7%) were polysensitized. The main positive sensitizers were nickel (38.5%), blue disperse (30.8%), fragrance mix (30.8%), and neomycin (23.1%). Nineteen (73%) patients reacted to substances present in therapeutic or skincare products. CONCLUSION: Our data underscore the importance of performing a PT in AD children whose eczema has atypical distribution. The expressive percentage of positive tests, especially of allergens in skincare products, indicates the constant need to review the proposed treatments. Therefore, we recommend a specific and expanded PT battery for pediatric AD patients, including a negative control, to increase sensitivity for diagnosing ACD.

Critical Role of TSLP Receptor on CD4 T Cells for Exacerbation of Skin Inflammation.

Thymic stromal lymphopoietin (TSLP) is a key cytokine that initiates and promotes allergic inflammation both in humans and mice. It is well known that TSLP is important in initial step of inflammation by stimulating dendritic cells to promote Th2 differentiation of naive T cells. However, TSLP is abundantly produced in the late phase of inflammation, as well; therefore, we focused on the function of TSLP in chronic Th2-type inflammation. By establishing a novel (to our knowledge) chronic allergic skin inflammation mouse model with repetitive challenges of hapten after sensitization, we demonstrated that CD4 T cell-specific deletion of TSLP receptor (TSLPR) resulted in near-complete ablation of ear swelling and infiltration of CD4 T cells and eosinophils, but after second challenge. Of note, TSLPR deletion on CD4 T cells did not affect acute inflammation. As expected, transfer of Ag-sensitized wild-type CD4T cells, but not of TSLPR-deficient CD4T cells, increased skin inflammation in the model upon challenge. Furthermore, production of IL-4 from TSLPR-deficient CD4T cells in inflamed ear lesions was markedly diminished, demonstrating that TSLP-dependent IL-4 production from CD4T cells was critical for the exacerbation of skin inflammation. Similar results were obtained in Th2-type allergic skin inflammation model using MC903. Collectively, these results indicate that TSLP acts directly on CD4 T cells to elicit pathogenesis of Th2 cells, thereby having a critical role in exacerbation of skin inflammation in the chronic phase.

Enzymes and sensitization via skin exposure: A critical analysis.

Some proteins, including enzymes, can induce allergic sensitization of various types, including allergic sensitization of the respiratory tract. There is now an increased understanding of the role that the skin plays in the development of IgE-mediated allergy and this prompts the question whether topical exposure to enzymes used widely in consumer cleaning products could result in allergic sensitization. Here, the evidence that proteins can interact with the skin immune system and the way they do so is reviewed, together with a consideration of the experience gained over decades of the use of enzymes in laundry and cleaning products. The conclusion drawn is that although transcutaneous sensitization to proteins can occur (typically through compromised skin) resulting in IgE antibody-mediated allergy, in practice such skin contact with enzymes used in laundry and cleaning products does not appear to pose a significant risk of allergic disease. Further, the evidence summarized in this publication support the view that proteins do not pose a risk of allergic contact dermatitis.

Regulation of the immune response to contact sensitizers by Nrf2.

The skin is frequently exposed to chemical stress by organic chemicals or metal ions that can directly or indirectly challenge its immune components and may lead to T-cell-mediated delayed-type hypersensitivity reactions. The disruption of the skin's homeostasis by exposure to contact sensitizers (CSs) can trigger an inflammatory immune response that results in eczema and allergic contact dermatitis. The recognition of these chemicals depends on the expression of pattern recognition receptors on sentinel skin cells, mainly the innate resident immune cells orchestrating the skin's immune response and involving both oxidative and inflammatory pathways. The main driver of these both pathways is the Nrf2/Keap1 pathway, a major ubiquitous regulator of cellular oxidative and electrophilic stress, activated in various innate immune cells of the skin, including keratinocytes and epidermal Langerhans cells in the epidermis and dermal dendritic cells in the dermis. Nrf2 also shows a strong protective capacity by downregulating inflammatory pathways. In this review, the important role of Nrf2 in the regulation of the immune response to CSs will be discussed and highlighted.

IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation.

Chronic inflammation's tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33's direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33-Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.

MRGPRX2 sensing of cationic compounds-A bridge between nociception and skin diseases?

Mast cells are innate immune cells located at many barrier sites in the body and known to protect the host against environmental threats and to be involved in allergic diseases. More recently, new studies have investigated their roles in the regulation of skin inflammation and transmission of pain and itch sensations. Mast cell signalling through the Mas-related G protein-coupled receptor (MRGPR) X2 or its mouse orthologue MRGPRB2 has been reported to be one of the major mechanism by which mast cell can regulate such processes. MRGPRX2 and MRGPRB2 can induce mast cell degranulation upon binding to a broad panel of cationic molecules such as neuropeptides, bacteria-derived quorum sensing molecules, venom peptides, host defense peptides and, unfortunately, various FDA-approved drugs. Upon activation, mast cells release granule-associated proteases, lipids and multiple cytokines that can modulate vascular permeability, immune cells recruitment and activation status of tissue-projecting nociceptive sensory neurons (ie nociceptors). Here, we discuss the modality of MRGPRX2-dependent mast cell activation and its different consequences on the patterns of skin inflammation and associated diseases. We notably emphasize how MRGPRX2-dependent skin mast cell activation might trigger various pathological traits such as pruritus, pain and inflammation and therefore become a potential therapeutic target for inflammatory pain, itch, atopic dermatitis and drugs-induced injection site reactions.

Management of Allergic Diseases During COVID-19 Outbreak.

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) has challenged healthcare system capacities and safety for health care workers, reshaping doctor-patient interaction favoring e-Health or telemedicine. The pandemic situation may make difficult to prioritize patients with allergies diseases (AD), face-to-face evaluation, and moreover concern about the possible COVID-19 diagnosis, since COVID-19 shared many symptoms in common with AD. Being COVID-19 a novel disease, everyone is susceptible; there are some advances on vaccine and specific treatment. We evaluate existing literature on allergic diseases (AD): allergic rhinitis, asthma, food allergy, drug allergy, and skin allergy, and potential underlying mechanisms for any interrelationship between AD and COVID-19. RECENT FINDINGS: There is inconclusive and controversial evidence of the association between AD and the risk of adverse clinical outcomes of COVID-19. AD patients should minimize hospital and face-to-face visits, and those who have used biologics and allergen immunotherapy should continue the treatment. It is essential to wear personal protective equipment for the protection of health care workers. Social distancing, rational use of facemasks, eye protection, and hand disinfection for health care workers and patients deserve further attention and promotion. Teleconsultation during COVID-19 times for AD patients is very encouraging and telemedicine platform can provide a reliable service in patient care.

Pediatric allergic contact dermatitis. Part I: Clinical features and common contact allergens in children.

Allergic contact dermatitis (ACD), a delayed hypersensitivity skin reaction to environmental allergens, has a prevalence that is similar in children and adults. However, diagnostic testing for ACD in pediatric populations accounts for less than one tenth of all patch tests. The relative infrequency of pediatric patch testing may be attributed to the difficulty in testing in this population, which includes a smaller surface area for patch test placement and maintaining cooperation during patch testing, especially in younger children. Diagnosis can be difficult in children because the appearance of ACD can mimic other common pediatric skin conditions, particularly atopic dermatitis and irritant contact dermatitis. Comprehensive history taking, guided by patient presentation, age group, and location of dermatitis, helps build clinical suspicion. Such clinical suspicion is one of the major reasons behind patch testing, with additional indications being recalcitrant dermatitis and dermatitis with atypical distribution. US pediatric data have shown the top allergens to be metals, fragrances, topical antibiotics, preservatives, and emollients. These trends are important to recognize to guide management and accurate diagnosis, because ACD tends to persist if the allergen is not identified and can affect patients' quality of life.

Pediatric allergic contact dermatitis. Part 2: Patch testing series, procedure, and unique scenarios.

Patch testing is the criterion standard for diagnosing allergic contact dermatitis. Causative allergens differ between children and adults, necessitating the development of pediatric-specific patch test series. The Pediatric Baseline Series was developed in 2018 through expert consensus and includes relevant pediatric allergens that dermatologists can use in practice. Obstacles in patch testing, such as the need for multiple office visits, length of patch application, and avoidance of sweat and water on the testing area, are particularly challenging for the pediatric population, and several strategies are proposed. Aside from formal patch testing, alternatives like the repeat open application test and empiric allergen avoidance can be helpful in children. The key to management of allergic contact dermatitis is allergen avoidance, with emphasis on the need to properly identify causative allergens. Continued data collection through registries allows for a better understanding of the diagnosis and management of pediatric allergic contact dermatitis.

Memory T helper cells identify patients with nickel, cobalt, and chromium metal allergy.

BACKGROUND: Patch testing is the gold standard for identifying culprit allergens in allergic contact dermatitis; however, it is laborious and positive reactions are difficult to quantitate. Development of complementary in vitro tests is, therefore, of great importance. OBJECTIVES: This study aimed to improve the in vitro lymphocyte proliferation test (LPT) to detect allergic responses to nickel (Ni), cobalt (Co), and chromium (Cr). METHODS: Twenty-one metal allergic patients with a positive patch test to Ni (n=16), Co (n=8), and Cr (n=3) and 13 controls were included. All were tested by a flow cytometric LPT. RESULTS: Metal-reactive cells were identified as T helper (Th) cells with high expression of the memory marker CD45RO. Skin-homing (cutaneous lymphocyte-associated antigen positive [CLA+]) Ni-reactive memory Th (Thmem hi ) cells identified individuals with a positive patch test for Ni with 100% sensitivity (95% confidence interval [CI] 81%-100%) and 92% specificity (95% CI 67%-100%). Moreover, Co-specific Thmem hi cells expressing CCR6 identified patients with a positive patch test for Co with 63% sensitivity (95% CI 31%-86%) and 100% specificity (95% CI 77%-100%). In Cr allergic individuals, Cr-reactive Thmem hi cells tended to increased CLA and CCR6 expression. CONCLUSION: Metal-reactive Th cells with high expression of CD45RO and coexpression of CLA and CCR6 improved the LPT, making it an attractive supplement to the patch test.

Allergic contact dermatitis due to the liquid skin adhesive Dermabond® predominantly occurs after the first exposure.

BACKGROUND: The clinical characteristics of patients with allergic contact dermatitis (ACD) due to a skin adhesive containing 2-octyl cyanoacrylate, Dermabond®, have not yet been elucidated. OBJECTIVE: To investigate the clinical characteristics of patients with ACD caused by Dermabond® application. METHODS: In this retrospective study, 577 patch tested patients were included. We identified patients with positive patch test results for Dermabond® and evaluated their results concerning (meth)acrylates and ethyl cyanoacrylate adhesive. RESULTS: Nine patients had positive patch test results to Dermabond®; six had developed secondary generalization.The mean time between Dermabond® application and ACD onset was 34 days (range, 27-44) in six patients with ACD after the first use, whereas, in the other three patients, it was 5.6 days (range, 4-8) after the second use. The time was significantly different between the two groups (P < .01). Positive reactions to ethyl cyanoacrylate adhesive (Aron Alpha) occurred in seven of nine patients, to ethyl cyanoacrylate 10% pet. in four of eight patients tested, and to 2-hydroxyethyl methacrylate in one of eight patients tested. CONCLUSIONS: Dermabond®-induced ACD is apparently characterized by a high prevalence of primary sensitization at first exposure to Dermabond®, secondary generalization is frequent, and most patients show cross-reactivity to ethyl cyanoacrylate.

Application of the adverse outcome pathway framework for investigating skin sensitization potential of nanomaterials using new approach methods.

BACKGROUND: Currently, considerable efforts to standardize methods for accurate assessment of properties and safety aspects of nanomaterials are being made. However, immunomodulation effects upon skin exposure to nanomaterial have not been explored. OBJECTIVES: To investigate the immunotoxicity of single-wall carbon nanotubes, titanium dioxide, and fullerene using the current mechanistic understanding of skin sensitization by applying the concept of adverse outcome pathway (AOP). METHODS: Investigation of the ability of nanomaterials to interact with skin proteins using the micro-direct peptide reactivity assay; the expression of CD86 cell surface marker using the U937 cell activation test (OECD No. 442E/2018); and the effects of nanomaterials on modulating inflammatory response through inflammatory cytokine release by U937 cells. RESULTS: The nanomaterials easily internalized into keratinocytes cells, interacted with skin proteins, and triggered activation of U937 cells by increasing CD86 expression and modulating inflammatory cytokine production. Consequently, these nanomaterials were classified as skin sensitizers in vitro. CONCLUSIONS: Our study suggests the potential immunotoxicity of nanomaterials and highlights the importance of studying the immunotoxicity and skin sensitization potential of nanomaterials to anticipate possible human health risks using standardized mechanistic nonanimal methods with high predictive accuracy. Therefore, it contributes toward the applicability of existing OECD (Organisation for Economic Co-operation and Development) testing guidelines for accurate assessment of nanomaterial skin sensitization potential.

The role of interleukin-1ß in the immune response to contact allergens.

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

Diet-induced obesity aggravates NK cell-mediated contact hypersensitivity reaction in Rag1-/- mice.

BACKGROUND: Previous studies showed that natural killer (NK) cells mediate contact hypersensitivity (CHS) reaction. Many reports are showing that obesity promotes several inflammatory diseases. It was shown that diet-induced obesity (DIO) aggravates classical T cell-mediated CHS in mice. OBJECTIVES: To determine whether the high-fat diet (HFD)-induced obesity modulates antigen-specific NK cell-mediated response. METHODS: We evaluated the effect of DIO on NK cell-mediated CHS reaction using a model of dinitrofluorobenzene (DNFB)-induced CHS in Rag1-/- mice. RESULTS: Rag1-/- mice fed HFD for 8 but not for 4 weeks developed aggravated CHS reaction determined by ear swelling measurement when compared to animals kept on normal diet (ND) prior to DNFB sensitization. The obese Rag1-/- mice presented the adipose tissue inflammation. Furthermore, in vitro analysis showed that feeding with HFD significantly increases interferon γ (IFN-γ) and interleukin (IL)-12p70 and decreases adiponectin concentration in liver mononuclear cell (LMNC) culture supernatants. The flow cytometry analysis of LMNC revealed that HFD treatment prior to DNFB sensitization increases the percentage of NK1.1+ IFN-γ+ cell population and affects the development and maturation of NK1.1+ cells. CONCLUSIONS: In summary, current results suggest that the DIO significantly modulates the local and systemic inflammatory response, contributing to exacerbation of the CHS response mediated by liver NK cells.