Preclinical Atopic Dermatitis Skin in Infants: An Emerging Research Area.

Whereas clinically apparent atopic dermatitis (AD) can be confirmed by validated diagnostic criteria, the preclinical phenotype of infants who eventually develop AD is less well-characterized. Analogous to unaffected or nonlesional skin in established AD, clinically normal-appearing skin in infants who will develop clinical AD has distinct changes. Prospective studies have revealed insights into this preclinical AD phenotype. In this study, we review the structural, immunologic, and microbiome nature of the preclinical AD phenotype. Determination of markers that predict the development of AD will facilitate targeting of interventions to prevent the development or reduce the severity of AD in infants.

Adding Fuel to the Fire? The Skin Microbiome in Atopic Dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease characterized by epidermal barrier dysfunction, immune system dysregulation, and skin microbiome alterations. Skin microbiome studies in AD have demonstrated that disease flares are associated with microbial shifts, particularly Staphylococcus aureus predominance. AD-associated S. aureus strains differ from those in healthy individuals across various genomic loci, including virulence factors, adhesion proteins, and proinflammatory molecules-which may contribute to complex microbiome barrier-immune system interactions in AD. Different microbially based treatments for AD have been explored, and their future therapeutic successes will depend on a deeper understanding of the potential microbial contributions to the disease.

Staphylococcus aureus: The Bug Behind the Itch in Atopic Dermatitis.

Pruritus or itch is a defining symptom of atopic dermatitis (AD). The origins of itch are complex, and it is considered both a defense mechanism and a cause of disease that leads to inflammation and psychological stress. Considerable progress has been made in understanding the processes that trigger itch, particularly the pruritoceptive origins that are generated in the skin. This perspective review discusses the implications of a recent observation that the V8 protease expressed by Staphylococcus aureus can directly trigger sensory neurons in the skin through activation of protease-activated receptor 1. This may be a key to understanding why itch is so common in AD because S. aureus commonly overgrows in this disease owing to deficient antimicrobial defense from both the epidermis and the cutaneous microbiome. Increased understanding of the role of microbes in AD provides increased opportunities for safely improving the treatment of this disorder.

Progressive accumulation of hyperinflammatory NKG2Dlow NK cells in early childhood severe atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that often precedes the development of food allergy, asthma, and allergic rhinitis. The prevailing paradigm holds that a reduced frequency and function of natural killer (NK) cell contributes to AD pathogenesis, yet the underlying mechanisms and contributions of NK cells to allergic comorbidities remain ill-defined. Here, analysis of circulating NK cells in a longitudinal early life cohort of children with AD revealed a progressive accumulation of NK cells with low expression of the activating receptor NKG2D, which was linked to more severe AD and sensitivity to allergens. This was most notable in children co-sensitized to food and aeroallergens, a risk factor for development of asthma. Individual-level longitudinal analysis in a subset of children revealed coincident reduction of NKG2D on NK cells with acquired or persistent sensitization, and this was associated with impaired skin barrier function assessed by transepidermal water loss. Low expression of NKG2D on NK cells was paradoxically associated with depressed cytolytic function but exaggerated release of the proinflammatory cytokine tumor necrosis factor-α. These observations provide important insights into a potential mechanism underlying the development of allergic comorbidity in early life in children with AD, which involves altered NK cell functional responses, and define an endotype of severe AD.

Atopic Dermatitis Itch: Scratching for an Explanation.

Chronic pruritus is a cardinal symptom of atopic dermatitis (AD). The mechanisms underlying atopic itch involve intricate crosstalk among skin, immune components, and neural components. In this review, we explore these mechanisms, focusing on key players and interactions that induce and exacerbate itch. We discuss the similarities and differences between pruritus and pain in patients with AD as well as the relationship between pruritus and factors such as sweat and the skin microbiome. Furthermore, we explore novel targets that could provide significant itch relief in these patients as well as exciting future research directions to better understand atopic pruritus in darker skin types.

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.

Antioxidant defense of children and adolescents with atopic dermatitis: Association with disease severity

Background: Atopic dermatitis (AD) is a relapsing, chronic cutaneous inflammatory disease with onset, in general, in early childhood. Chronic skin inflammation is associated with overproduction of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Oxidative stress, an imbalance between the production of free radicals and antioxidant defense, results in tissue inflammation due to the upregulation of genes that encode inflammatory cytokines. This condition plays an important role in the pathogenesis of AD. Objective: To compare the antioxidant defense in children and adolescents with AD with that of healthy individuals and to verify the association of antioxidant defense with disease severity and nutritional status. Methods: Cross-sectional study that evaluated 48 children and adolescents with AD and 25 controls for nutritional assessment (body mass index z score [BMIZ] and height for age z score [HAZ]) and levels of vitamins A, C, E, and D, zinc (Zn), copper (Cu), antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx]), high-sensitivity C-reactive protein (CRP) and interleukin 33 (IL-33). Results: There was no significant difference in the comparison between AD and control groups for serum levels of vitamins (A, D, C, and E), copper, and antioxidant enzymes. Serum zinc levels were higher in the AD group (β = 24.20; 95% CI 13.95–34.91; P < 0.001) even after adjusting the BMIZ, HAZ, gender, IL-33, and CRP. Children and adolescents with moderate or severe AD compared to mild AD (SCORAD – 36.7±17.4 vs 11.8 ± 3.9; P < 0.001) had lower values of the vitamin E/total lipid ratio (3.68 [0.29;12.63] vs 5.92 [3.27;17.37]; P = 0.013) (AU)

Sensory neurons promote immune homeostasis in the lung.

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

Potential Role of IL-37 in Atopic Dermatitis.

Interleukin 37 (IL-37) is a recently discovered member of the IL-1 cytokine family that appears to have anti-inflammatory and immunosuppressive effects in various diseases. IL-37 acts as a dual-function cytokine, exerting its effect extracellularly by forming a complex with the receptors IL-18 α (IL-18Rα) and IL-1R8 and transmitting anti-inflammatory signals, as well as intracellularly by interacting with Smad3, entering the nucleus, and inhibiting the transcription of pro-inflammatory genes. Consequently, IL-37 is linked to IL-18, which plays a role in the pathogenesis of atopic dermatitis (AD), consistent with our studies. Some isoforms of IL-37 are expressed by keratinocytes, monocytes, and other skin immune cells. IL-37 has been found to modulate the skewed T helper 2 (Th2) inflammation that is fundamental to the pathogenesis of AD. This review provides an up-to-date summary of the function of IL-37 in modulating the immune system and analyses its potential role in the pathogenesis of AD. Moreover, it speculates on IL-37's hypothetical value as a therapeutic target in the treatment of AD.

Neutrophil recruitment by CD4 tissue-resident memory T cells induces chronic recurrent inflammation in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that continues to impose significant physical, mental, and economic burdens on patients. Recent research has suggested the significant role of tissue-resident memory (TRM) cells in AD. However, the precise role and mechanisms of action of TRM cells in AD remain unclear. A deeper understanding of the involvement of TRM cells in AD will unveil promising pathways for future innovative therapeutic strategies. METHODS: To investigate the involvement of TRM cells in AD, we used diverse mouse models and employed experimental techniques to manipulate cell formation and depletion. We assessed the inflammatory response by analyzing mouse ear phenotype, measuring ear thickness, and performing hematoxylin and eosin staining. Flow cytometry and immunofluorescence staining were used to identify different cell types and evaluate changes in cell quantity. Additionally, we used qPCR to analyze gene expression of relevant chemokines and cytokines. RESULTS: Our study revealed the presence of TRM cells in the skin after exposure to calcipotriol. After a 24-h re-challenge, we observed substantial neutrophil infiltration into the previously irritated skin. Neutrophil depletion prior to re-challenge effectively prevented early flare-up responses during AD recurrence. Furthermore, we demonstrate that CD4+TRM cells upregulate expression of cytokines INF-γ and TNF-α, which may induce the expression of CXCL1, thereby recruiting neutrophils and contributing to the chronic recurrent inflammation observed in AD. CONCLUSIONS: We have established a novel, chronic recurrent mouse model for investigating TRM cells in AD. Our findings demonstrate that CD4+TRM cells in the skin mediate early flare-up response during AD recurrence and influence the chronic recurrent inflammation of AD by recruiting neutrophils. Targeting CD4+TRM cells may represent a promising approach for the treatment of chronic recurrent inflammation in AD.

[Reunderstanding of atopic dermatitis in the elderly].

Atopic dermatitis (AD) is a highly heterogeneous skin disease. Many characteristics of AD in the elderly are different from those in other age groups, and AD in the elderly is prone to misdiagnosis or missed diagnosis, which has gradually gained recognition and attention in recent years. The onset of elderly AD is related to changes of aging related barrier and immune function. Elderly AD is more common in Th1 type of skin inflammation, and has certain "reverse" characteristics in clinical manifestations. The diagnosis of elderly AD should be based on exclusion diagnosis. In addition to the stepwise treatment, personalized treatment should also be made based on factors, such as skin characteristics and comorbidities of the elderly.

The prevalence of sensitization to food allergens in children with atopic dermatitis

Introduction: Atopic dermatitis (AD) has a complex pathophysiology. The course of the disease is affected by both environmental factors and allergen hypersensitivities. Food and aeroallergens have a significant role in the pathogenesis and disease control. Objective: In this study, it was aimed to determine the prevalence of food and aeroallergen sensitivity of children with AD. Methods: Children under 18 years with AD who applied to pediatric allergy and immunology outpatient clinics were evaluated. All patients had a skin prick test (SPT) within most common food and aeroallergens. Results: One hundred seventy three patients were studied. Most of the moderate and severe AD patients were boys (boys 64% vs. girls 47%). Symptoms started earlier and positive results in SPTs with food allergens were more common in patients with SCORAD (SCORing Atopic Dermatitis) >25 (p < 0.0001). Egg white (39%), egg yolk (31%), cow’s milk (13%) and wheat flour (5%), were the most common allergens, respectively. The SCORAD scores were higher in multiple food sensitized patients’ groups (p < 0.001). Although, food sensitizations were prevalent in patients who had higher SCORAD scores (p = 0.001), there was no significant difference in sensitization with aeroallergens. (p = 0.392). Conclusion: Sensitizations to both food and aeroallergens are common in patients with AD. In addition, sensitization to these allergens and SCORAD severity in patients with AD have positive correlation (AU)

Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex. METHODS: We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed. RESULTS: In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation. CONCLUSIONS: In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).

Potential Anti-Allergy and Immunomodulatory Properties of Lactococcus lactis LB 1022 Observed In Vitro and in an Atopic Dermatitis Mouse Model.

Lactococcus lactis is a lactic acid bacterium and used in the dairy food industry. The ameliorating effects of Lactobacillus species on atopic dermatitis (AD) have been extensively studied, but the specific effect of L. lactis strains has not yet been investigated. In this study, the efficacy of L. lactis LB 1022, isolated from natural cheese, was evaluated using RAW 264.7, HMC-1 and HaCaT cell lines and an ovalbumin-sensitized AD mouse model. L. lactis LB 1022 exhibited nitric oxide suppression and anti-allergy and anti-inflammatory activity in vitro. Oral administration of L. lactis LB 1022 to AD mice significantly reduced the levels of IgE, mast cells, and eosinophils, and a range of T cell-mediated T helper Th1, Th2, and Th17-type cytokines under interleukin (IL)-10, transforming growth factor-ß (TGF-ß), thymus and activation-regulated chemokine (TARC), and thymic stromal lymphopoietin (TSLP). In addition, L. lactis LB 1022 treatment increased the concentration of short-chain fatty acids. Overall, L. lactis LB 1022 significantly modulated AD-like symptoms by altering metabolites and the immune response, illustrating its potential as candidate for use in functional food supplements to alleviate AD.

A new autoimmune disease: atopic dermatitis in children

Atopic dermatitis (AD) is mainly considered an allergy, exacerbated by allergic factors. Is there evidence to suggest the existence of autoimmune components in the pathophysiology of the illness? Studies in the literature that dealt with the occurrence of autoimmunity in children with AD were analyzed. We followed the studies published in PubMed for 10 years, from 2001 to 2021. Clinical signs and symptoms were similar to other autoimmune diseases, having periods of remission and relapses. Other correlations between AD and autoimmune diseases have been described, and patients with AD can also present with a wide range of autoimmune comorbidities. Three major factors contribute to the pathogenesis of AD: damage of the skin barrier, disorders of the immune response, and imbalances of the skin microbiome—all based on genetic changes and influenced by environmental factors. Predominant activation of Th 2 cells, with the increase of Th 1, Th 17, and Th 22 subsets, promotes skin inflammation. All this evidence suggests that AD might be classified as an autoimmune disease, not just as an allergic reaction (AU)

Purpurin suppresses atopic dermatitis via TNF-α/IFN-γ-induced inflammation in HaCaT cells.

OBJECTIVE: We investigated whether purpurin inhibits various pathways of inflammation leading to atopic dermatitis. INTRODUCTION: 1,2,4-Trihydroxyanthraquinone, commonly called purpurin, is an anthraquinone that is a naturally occurring red/yellow dye. Purpurin is a highly antioxidative anthraquinone and previous studies have reported antibacterial, anti-tumor, and anti-oxidation activities in cells and animals. However, the skin inflammatory inhibition activity mechanism study of purpurin has not been elucidated in vitro. METHODS: In this study, we investigated the anti-inflammatory activity of purpurin in HaCaT (human keratinocyte) cell lines stimulated with a mixture of tumor necrosis factor-alpha (TNF-α)/Interferon-gamma (IFN-γ). The inhibitory effect of Purpurin on cytokines (IL-6, IL-8, and IL-1ß) and chemokine (TARC, MDC, and RANTES) was confirmed by ELISA and RT-qPCR. We investigated each signaling pathway and the action of inhibitors through western blots. RESULTS: The expression levels of cytokines and chemokines were dose-dependently suppressed by purpurin treatment in TNF-α/IFN-γ-induced HaCaT cells from ELISA and real-time PCR. Purpurin also inhibited protein kinase B (AKT), mitogen-activated protein kinase (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) activation in TNF-α/IFN-γ-stimulated HaCaT cells. Additionally, there was a synergistic effect when purpurin and inhibitor were applied together, and inflammation was dramatically reduced. CONCLUSION: Therefore, these results demonstrate that purpurin exhibits anti-inflammatory and anti-atopic dermatitis activity in HaCaT cells.

Topical Melatonin Exerts Immunomodulatory Effect and Improves Dermatitis Severity in a Mouse Model of Atopic Dermatitis.

Oral melatonin supplement has been shown to improve dermatitis severity in children with AD, but the mechanism of the effect is unclear, and it is uncertain whether melatonin has a direct immunomodulatory effect on the dermatitis. Topical melatonin treatment was applied to DNCB-stimulated Balb/c mice, and gross and pathological skin findings, serum IgE, and cytokine levels in superficial lymph nodes were analyzed. Secretion of chemokines and cell proliferative response after melatonin treatment in human keratinocyte HaCaT cells were also studied. We found that in DNCB-stimulated Balb/c mice, topical melatonin treatment improved gross dermatitis severity, reduced epidermal hyperplasia and lymphocyte infiltration in the skin, and decreased IP-10, CCL27, IL-4, and IL-17 levels in superficial skin-draining lymph nodes. Melatonin also reduced cytokine-induced secretion of AD-related chemokines IP-10 and MCP-1 and decreased IL-4-induced cell proliferation in HaCaT cells. Melatonin seems to have an immunomodulatory effect on AD, with IP-10 as a possible target, and topical melatonin treatment is a potentially useful treatment for patients with AD.