Asthma is a chronic disease affecting millions of children worldwide, and in severe cases requires hospitalization. The etiology of asthma is multifactorial, caused by both genetic and environmental factors. In recent years, the role of the early-life gut microbiome in relation to asthma has become apparent, supported by an increasing number of population studies, in vivo research, and intervention trials. Numerous early-life factors, which for decades have been associated with the risk of developing childhood asthma, are now being linked to the disease through alterations of the gut microbiome. These factors include cesarean birth, antibiotic use, breastfeeding, and having siblings or pets, among others. Association studies have highlighted several specific microbes that are altered in children developing asthma, but these can vary between studies and disease phenotype. This demonstrates the importance of the gut microbial ecosystem in asthma, and the necessity of well-designed studies to validate the underlying mechanisms and guide future clinical applications. In this review, we examine the current literature on the role of the gut microbiome in childhood asthma and identify research gaps to allow for future microbial-focused therapeutic applications in asthma.

Chronic hand eczema (CHE) is a prevalent dermatological condition characterized by significant morbidity and impaired quality of life. Delgocitinib, a pan-JAK inhibitor, has emerged as a promising topical treatment for CHE, targeting key cytokine-mediated inflammatory pathways involved in the disease. Delgocitinib 20 mg/g (2%) cream was approved by the European Medicines Agency (EMA) in 2024 for moderate-to-severe CHE, and its U.S. Food and Drug Administration (FDA) review is currently in progress.

PubMed, Medline and ClinicalTrials.gov were searched up to January 21, 2025, using specific search terms related to delgocitinib and chronic hand eczema.

Clinical trials have demonstrated its effectiveness in improving disease severity, including eczema signs and symptoms such as pain and itching, and enhancing patient-reported outcomes compared to vehicle. Topical delgocitinib has shown a favorable safety profile, with most adverse events being mild and unrelated to treatment. Serious adverse events were rare, and treatment discontinuation due to adverse events was minimal. This narrative review synthesizes current evidence on topical delgocitinib's clinical utility and safety in CHE, positioning it as a valuable therapeutic option. Further comparative studies are needed to evaluate its efficacy against oral JAK inhibitors and other topical immunosuppressants, providing insight into optimizing treatment strategies for this chronic condition.

Hyper-IgE Syndrome, also known as Job's syndrome, is a rare primary immunodeficiency disorder characterized by recurrent infections and elevated levels of immunoglobulin E. While respiratory and systemic manifestations have been more emphasized, dermatological manifestations in Hyper-IgE Syndrome also play a significant role in disease presentation.

This narrative review explores the dermatologic presentations of Hyper-IgE Syndrome in pediatric populations, including descriptions, associated symptoms/findings, and available treatment options.

Neonatal rash, mucocutaneous candidiasis, noma neonatorum, psoriasis, cold staphylococcal abscesses, and candida onychomycosis are among the dermatological manifestations of Hyper-IgE Syndrome. Each manifestation has unique characteristics and treatment considerations, necessitating accurate recognition and diagnosis for effective management. Optimal treatment strategies involve a combination of supportive care, topical/systemic therapies, antifungal medications, and surgical interventions when necessary. Further research is needed to enhance our understanding of these manifestations and evaluate treatment modalities for individuals affected by Hyper-IgE Syndrome.

Emerging evidence reveals significant epidemiologic, genetic, and immunologic connections between atopic dermatitis, vitiligo, and alopecia areata, challenging previously established notions of their distinct pathogenic and molecular signatures. Exploring these commonalities not only enhances our understanding of each disease's pathogenesis, but also supports the development of unified treatment strategies for these frequently co-occurring disorders. This review examines key immune players shared across the 3 conditions, including cytokines, immune cells, and signaling pathways. Building on these insights, we also evaluate a range of therapeutic options-ranging from treatments approved by the Food and Drug Administration to those currently in clinical trials-alongside proposed future therapeutic targets. This comprehensive approach aims to advance our management of these interconnected autoimmune and inflammatory disorders with greater precision.

Keratinocytes, the predominant cell type in the epidermis, are indispensable for maintaining skin barrier integrity, mediating host defense, and orchestrating immune responses. Beyond these well-established functions, emerging evidence reveals their dynamic interactions with the nervous system and their capacity to retain inflammatory memory. These discoveries position keratinocytes as key drivers of the onset, progression, and relapse of inflammatory skin diseases. In this review, we delve into the mechanisms underlying keratinocyte crosstalk with immune and neural cells, the metabolic reprogramming, including lactate and other metabolites, that may drive inflammatory memory, and the broader implications for disease pathogenesis and recurrence. Finally, we discuss the challenges to, and therapeutic potential of, targeting keratinocytes for the treatment of chronic inflammatory skin conditions.

Allergic Eczema (AE) is a chronic, relapsing skin condition that significantly affects the quality of life of the AE patients and their caretakers. Decades of scientific and clinical research has helped understand the highly complex underpinnings of AE presentation wherein a multitude of variables, including the conspicuous variables such as environmental allergens, immunological triggers, genetic predisposition of individuals, to more nuanced socio-economic status, play an important part. Given the complexity of the disease, it is imperative to develop biomarkers enabling early and reliable clinical identifications and help in the active management of the disease, thereby minimizing the impact and burden of the disease on the patients. In this mini review, we provide a brief overview of AE, affected demographics, variables that trigger its onset, and summarize the discovery of various clinical biomarkers such as total and specific serum IgE levels, Th2 cytokine levels, filaggrin (FLG) mutations, periostin levels in skin, etc. that have been developed over the years to further improve the state of clinical monitoring of AE presentation and progression. Lastly, we also provide an overview of the clinical interventions and therapies, such as topical agents, phototherapy, and biologics, that are available to the patients to manage AE-related complications. While we have vastly improved the standard of care and diagnosis for the AE patients, there are still many unmet needs such as developing non-invasive, effective, and reliable clinical predictors and biomarkers which can usher better personalized treatments and provide a better quality of life to affected demographics.

Risk factors and the temporal relationship between atopic dermatitis (AD) and atopic march remain understudied.

Determine risk factors for atopic march in early-onset AD patients and the temporality between AD and atopic march.

We used the MarketScan Research Database for our retrospective cohort analysis from 2010 to 2018, comparing infants diagnosed with AD before age 1 with controls without early-onset AD. Primary outcomes were hazard ratios (HRs) for the development of asthma, allergic rhinitis, and food allergy.

Compared to 55,174 controls, higher proportions of the 27,228 AD patients developed asthma (19.21% vs 8.65%, P < .001), allergic rhinitis (28.27% vs 12.62%, P < .001), food allergy (16.00% vs 2.27%, P < .001), and all atopic triad conditions (10.69% vs 0.71%, P < .001). Among AD patients, higher proportions developed the atopic triad if they were male (HR 1.66, 95% confidence interval [1.45-1.90]), had severe disease (HR 3.16, [2.77-3.60]), or had family atopy history (HR > 3.40, P < .001 for all comparisons). Among AD patients, 20.1% developed allergic rhinitis.

Our study was based on health care claims data.

Early-onset AD is associated with higher rates of developing atopic march conditions compared to controls. Particular attention should be paid toward risk factors and atopic march screening in early-onset AD patients.

Atopic dermatitis is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to atopic dermatitis genetic association studies are poised to boost power to detect genetic signal and identify loci contributing to atopic dermatitis risk. Here, we present a multi-ancestry GWAS meta-analysis of twelve atopic dermatitis cohorts from five ancestral populations totaling 56,146 cases and 602,280 controls. We report 101 genomic loci associated with atopic dermatitis, including 16 loci that have not been previously associated with atopic dermatitis or eczema. Fine-mapping, QTL colocalization, and cell-type enrichment analyses identified genes and cell types implicated in atopic dermatitis pathophysiology. Functional analyses in keratinocytes provide evidence for genes that could play a role in atopic dermatitis through epidermal barrier function. Our study provides insights into the etiology of atopic dermatitis by harnessing multiple genetic and functional approaches to unveil the mechanisms by which atopic dermatitis-associated variants impact genes and cell types.

Immune responses are influenced by not only immune cells but also the tissue microenvironment where these cells reside. Recent advancements in understanding the underlying molecular mechanisms and structures of the epidermal tight junctions (TJs) and stratum corneum (SC) have significantly enhanced our knowledge of skin barrier functions. TJs, located in the granular layer of the epidermis, are crucial boundary elements in the differentiation process, particularly in the transition from living cells to dead cells. The SC forms from dead keratinocytes via corneoptosis and features three distinct pH zones critical for barrier function and homeostasis. Additionally, the SC-skin microbiota interactions are crucial for modulating immune responses and protecting against pathogens. In this review, we explore how these components contribute both to healthy and disease states. By targeting the skin barrier in therapeutic strategies, we can enhance its integrity, modulate immune responses, and ultimately improve outcomes for patients with inflammatory skin conditions.

Type 2 inflammation has a major role in barrier tissues such as the skin and airways and underlies common conditions including atopic dermatitis (AD) and asthma. Cytokines including interleukin 4 (IL-4), IL-5, and IL-13 are key immune signatures of type 2 inflammation and are the targets of multiple specific therapeutics for allergic diseases. Despite shared core immune mechanisms, the distinct structures and functions of the skin and airways lead to unique therapeutic responses. It is increasingly recognized that the nervous system has a major role in sensing and directing inflammatory processes. Indeed, crosstalk between type 2 immune activation and somatosensory functions mediates tissue-specific signatures such as itching in the skin. However, neuroimmune interactions are shaped by distinct neuronal and immune landscapes, and differ between the skin and airways. In the skin, dorsal root ganglia-derived neurons mediate pruritus via type 2 cytokines and neurogenic inflammation by mast cell or basophil activation. Conversely, vagal ganglia-derived neurons regulate airway immune responses by releasing neuropeptides/neurotransmitters such as calcitonin gene-related peptides, neuromedin U, acetylcholine, and noradrenaline. Sensory neuron-derived vasoactive intestinal peptide forms a feedback loop with IL-5, amplifying eosinophilic inflammation in the airways, a mechanism that is absent in the skin. These differences influence the efficacy of cytokine-targeted therapies. For instance, IL-4/IL-13-targeted therapies like dupilumab demonstrate efficacy in AD and allergic airway diseases, whereas IL-5-targeted therapies are effective in eosinophilic asthma but not AD. Understanding these neuroimmune interactions underscores the need for tailored therapeutic approaches to address allergic diseases where barrier tissues are involved.

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin condition that imposes significant psychological and economic burdens on patients due to its recurring nature. Its etiology is multifactorial, involving interactions between genetic predispositions and environmental factors. The skin barrier serves as both a mechanical and immunological defense, and its structural damage and functional impairments significantly contribute to the pathogenesis of AD. This study aims to explore the future prospects and developmental trends of the skin barrier in the context of AD through a bibliometric analysis.

To analyze the research status, hot spots and development trend of skin barrier in AD.

Relevant studies were extracted from the Web of Science database and screened by researchers, with bibliometric analysis conducted using VOSviewer, CiteSpace, and other tools.

A total of 4,227 publications were identified over a 24-year research period. The United States is the leading contributor, with 1,263 publications, and demonstrates extensive collaboration with numerous countries. The journal with the highest number of publications is the Journal of Allergy and Clinical Immunology. The most prolific institutions is the University of California, San Francisco. Recent years have seen high citation intensity for keywords such as "dupilumab," "barrier dysfunction," and "gut microbiota".

The mechanism of the skin barrier in AD remains an area requiring ongoing research and analysis. Although significant progress has been achieved, future research will benefit from advancements in technology.

Atopic dermatitis (AD) is a chronic inflammatory skin condition with a multifactorial etiology. Herein, we report a case of a patient with AD undergoing long-term topical treatments who developed a dermatophyte infection following the administration of dupilumab. Dupilumab is known to enhance skin barrier function and induce changes in the skin microbiome. Notably, head and neck dermatitis caused by the overgrowth of Malassezia species due to dupilumab has been widely discussed. This phenomenon is thought to result from the suppression of T helper (Th)2 cytokines by dupilumab, leading to a decrease in the proportion of Staphylococcus aureus and a relative increase in fungal populations. Additionally, feedback activation of Th17 cytokines may trigger excessive inflammation against fungi, contributing to fungal infections. IL-13 plays critical roles in fungal colony formation, and tralokinumab, an IL-13 inhibitor, has shown potential efficacy in treating this head and neck dermatitis. While the relationship between microbiome changes and biologics like lebrikizumab and nemolizumab remains unexplored, investigating the differential effects of these therapies on the cutaneous microbiome could provide deeper insights into not only the unique characteristics of each biologic agent but also the roles of Th2 cytokines such as IL-4, IL-13, and IL-31 in the pathophysiology of AD. The present case underscores the importance of the comprehensive therapeutic approach for AD that accounts for microbiome dynamics and adapts to evolving skin changes throughout the course of treatment.

The present paper aimed to conduct an updated systematic review and meta-analysis to evaluate the safety and efficacy of crisaborole, delgocitinib, and ruxolitinib in treating mild-to-moderate atopic dermatitis (AD).

MEDLINE and Google Scholar databases were utilized to search articles published during the years 2015-2024. The review was limited to randomized controlled studies that measured specific outcomes for safety and efficacy aspects, including adverse events (AEs) or treatment-emergent adverse events (TEAEs) to evaluate safety and Investigator's static global assessment (ISGA) or improvement of at least 75% of Eczema Area and Severity Index (EASI-75) to evaluate efficacy.

The review included 17 articles in the analysis. The safety odds ratios (ORs) among participants using crisaborole, delgocitinib, and ruxolitinib were 1.14, 95% CI [0.97-1.36], 1.18, 95% CI [0.84-1.67], and 0.72, 95% CI [0.55-0.94], respectively, when compared to control groups. The three studied topical AD treatments were found to be significantly more effective compared to control groups (crisaborole, OR = 1.78, 95% CI [1.51-2.10], delgocitinib, OR = 6.34, 95% CI [3.57-11.27], and ruxolitinib, OR = 7.30, 95% CI [5.10-10.44]).

Delgocitinib and ruxolitinib demonstrated favorable safety and effectiveness profiles across various age cohorts, whereas crisaborole raised concerns over its safety and efficacy, particularly in children.

Atopic dermatitis (AD) is a chronic, inflammatory skin disease that can significantly affect quality of life. Presence, severity, and therapeutic response of AD are traditionally reported through clinical assessments including the Eczema Area and Severity Index or Investigator's Global Assessment. These clinical rating scales are visual assessments used in clinical trials to denotate AD severity. Alternatively, biomarkers open the potential to further enhance diagnosis of AD, assess disease status and severity, and potentially enable tailored treatment options for patients. Biomarkers can be classified according to their clinical use, clinical presentation, and underlying/endogenous molecular mechanisms. Specifically, interleukin (IL)-13, which has been shown to be a key biomarker in AD pathogenesis, can be used for prediction of AD development and to monitor clinical severity/response to treatment. Treatment with tralokinumab, a human monoclonal antibody that binds directly to-and subsequently blocks signaling of-IL-13, has been shown to reduce inflammation, re-balance the skin microbiome, and improve the skin barrier in patients with AD. In this review, key AD-related biomarkers, the role of IL-13 in driving AD pathogenesis, and the impact of IL-13 inhibition by tralokinumab on other AD-related biomarkers are discussed.

The skin is the body's largest organ and performs several vital functions, such as controlling the movement of essential substances while protecting against external threats. Although mainly composed of keratinocytes (KCs), the skin also contains a complex network of immune cells that play a critical role in host defense and maintaining skin homeostasis. KCs proliferate in the basal layer of the epidermis and undergo differentiation, altering their functional and phenotypic characteristics. These differentiation steps are crucial for the stratification of the epidermis and the formation of the stratum corneum, ensuring the skin barrier's functions. Exposure to UV, environmental pollutants, or chemicals can lead to an overproduction of reactive species of oxygen (ROS), leading to oxidative stress. To ensure redox homeostasis and prevent damage resulting from the formation of ROS, the skin has an extensive network of antioxidant defense systems, mainly orchestrated by the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. Indeed, Nrf2 induces the expression of detoxification and antioxidant enzymes and suppresses inductions of pro-inflammatory cytokine genes. In this context, Nrf2 is critical in preserving skin functions such as epidermal differentiation, regulating skin immunity, and managing environmental stresses. Besides, this pathway plays an important role in the pathogenesis of common inflammatory skin diseases such as allergic contact dermatitis, atopic dermatitis, and psoriasis. Therefore, the present review highlights the crucial role of Nrf2 in KCs for maintaining skin homeostasis and regulating skin immunity, as well as its contribution to the pathophysiology of inflammatory skin diseases. Finally, a particular emphasis will be placed on the therapeutic potential of targeting the Nrf2 pathway to alleviate symptoms of these inflammatory skin disorders.

Phasing, the process of determining which alleles at different loci on homologous chromosomes belong together on the same chromosome, is crucial in the diagnosis and management of autosomal recessive diseases. Advances in long-read sequencing technologies have significantly enhanced our ability to accurately determine haplotypes. This review discusses the application of low-coverage long-read sequencing, nanopore Cas9-guided long-read sequencing, and adaptive sampling in phasing, highlighting their utility in complex clinical scenarios. Through clinical vignettes, we explore the importance of phasing in gene therapy design for recessive dystrophic epidermolysis bullosa and the role of revertant mosaicism in therapeutic epidermal autografts. Despite its promise, phasing with long-read sequencing faces challenges, including low efficiency in enriching target regions and the inherent error rate of nanopore sequencing. Future developments in long-read sequencing technologies will be critical in overcoming these limitations and expanding the applicability of phasing across various clinical settings.

Atopic dermatitis (AD) is prone to exacerbations in response to various triggering factors and flare-ups after remission. We searched for molecules associated with relapse/exacerbation of AD among molecules with altered gene expression in the skin of patients with AD. Microarray analyses were performed on lesional and nonlesional skin of adolescent or adult patients with recalcitrant AD and healthy controls. Five chaperones involved in intracellular stress responses, namely heat shock protein family A (Hsp70) member 9 (HSPA9), heat shock protein 90 beta family member 1 (HSP90B1), calnexin (CANX), malectin (MLEC; endoplasmic reticulum-associated degradation), and heat shock protein family D (Hsp60) member 1 (HSPD1), were consistently upregulated in involved and uninvolved skin of patients with AD. Damage-associated molecular patterns were upregulated in involved skin. KLF transcription factor 2 (KLF2) was decreased in involved skin and exhibited a decreasing trend in uninvolved skin of patients with AD. CD4(+)/CD8(+) double-positive cells (1.4% of T cells) were detected in lesions with declined KLF2 levels. WNT inhibitory factor 1 (WIF1) was downregulated in involved skin. Prolactin-induced protein was upregulated in only uninvolved skin of patients with AD. We found increased intracellular stress responses and decreased expression of KLF2 in the skin of patients with AD. Multifactorial genetic diseases, such as asthma, inflammatory bowel disease, type 2 diabetes, and rheumatoid arthritis, are associated with intracellular stress. Intracellular abnormalities may also be responsible for AD. Further research on AD may incorporate enhanced intracellular stress response and the decreased expression of KLF2 into the mechanism underlying AD.

Chronic spontaneous urticaria (CSU), atopic dermatitis (AD), psoriasis and rosacea are highly prevalent inflammatory skin conditions which impose a significant burden on patients' quality of life. Their pathophysiology is likely multifactorial, involving genetic, immune and environmental factors. Recent advancements in the field have demonstrated the key role of mast cells (MC) in the pathophysiology of these conditions. The Mas-related G protein-coupled receptor X2 (MRGPRX2) has emerged as a promising non-IgE-mediated MC activation receptor. MRGPRX2 is predominately expressed on MC and activated by endogenous and exogenous ligands, leading to MC degranulation and release of various pro-inflammatory mediators. Mounting evidence on the presence of endogenous MRGPRX2 agonists (substance P, cortistatin-14, LL37, PAMP-12 and VIP) and its high expression among patients with CSU, AD, rosacea, psoriasis and chronic pruritus emphasizes the pathogenic role of MRGPRX2 in these conditions. Despite the currently available treatments, there remains a pressing need for novel drug targets and treatment options for these chronic inflammatory skin conditions. Here, we reviewed the pathogenic role of MRGPRX2 and its potential as a novel therapeutic target and provided an update on future research directions.

Our objectives were to explore epidermal barrier defects in dogs with atopic dermatitis and to determine whether the defects are genetically determined or secondary to skin inflammation. First, the expression of filaggrin, corneodesmosin, and claudin1, analyzed using indirect immunofluorescence in skin biopsies collected from 32 healthy and 32 dogs with atopic dermatitis, was weaker in the atopic skin (P = .003). Second, primary keratinocytes of atopic dogs and healthy dogs were used to produce 3-dimensional reconstructed canine epidermis. The expression of the same proteins was analyzed using indirect immunofluorescence, immunoblotting, and RT-qPCR, whereas reconstructed canine epidermis morphology was investigated by transmission electron microscopy, and the barrier was investigated by functional assays. Next, inflammatory cytokines (IL-4, IL-13, IL-31, and TNFα) were added to the culture medium. The morphology, protein expression, and barrier function of the reconstructed canine epidermis were similar whether produced with keratinocytes from healthy dogs or dogs with atopy. Addition of inflammatory cytokines impaired the protein expression and epidermal barrier of the 2 types of reconstructed canine epidermis equally. To conclude, the reduced expression of epidermal barrier proteins observed in vivo was not reproduced in vitro unless cytokines were used, suggesting that it is induced by the inflammatory milieu.

Vitiligo is a cutaneous autoimmune disorder characterized by progressive depigmentation due to melanocyte destruction by cytotoxic T cells. Genetic factors predispose patients to the disease and are supported by environmental factors that often initiate new disease episodes. We investigated whether disease outcomes were partially defined by pathogenic microbes that drive nutrient deficiency and inflammation. Our study presents the results of research on the diet and gut microbiome composition of patients with vitiligo and healthy controls from Kazakhstan and the United States. Dietary nutrient intake was assessed using the National Institutes of Health-generated Diet History Questionnaire. Patients with active vitiligo exhibit a limited intake of specific fatty acids, amino acids, fiber, and zinc. Disease activity was further characterized by the abundance of Odoribacter and Escherichia in the gut. Metabolic pathway analysis supported the role of the Escherichia genus in disease activity by limiting energy metabolism and amino acid biosynthetic pathways. Disease activity also aligned with elevated circulating pro-inflammatory cytokines. These findings suggest that nutritional limitations are not compensated by metabolites from the gut microbiome in active disease, potentially leaving room for inflammation and exacerbating vitiligo. The intricate relationship among diet, gut microbiome composition, and disease progression in vitiligo highlights potential avenues for targeted interventions to reduce autoimmune activity and improve patient outcomes.

Atopic dermatitis and psoriasis have traditionally been considered distinct inflammatory skin diseases with unique pathogenic mechanisms. However, accumulating evidence suggests significant overlap in their immunological pathways, metabolic features, and microbiome characteristics, challenging this conventional dichotomy. This review comprehensively examines the complex relationship between psoriasis and atopic dermatitis, with particular emphasis on their shared and distinct pathogenic mechanisms. We analyze the immunological networks, metabolic pathways, and microbial factors contributing to their development and progression. The review expands upon the disease spectrum hypothesis and discusses the nomenclature for conditions exhibiting features of both diseases. We critically evaluate the clinical and histopathological characteristics of concomitant psoriasis and atopic dermatitis, highlighting recent advances in molecular diagnostics for accurate disease differentiation. Importantly, we propose standardized diagnostic criteria for psoriasis dermatitis and examine current therapeutic strategies for managing overlapping conditions. Recent developments in targeted therapies and their implications for treatment selection are thoroughly discussed. By synthesizing current evidence and identifying knowledge gaps, this review provides insights into the complex interplay between psoriasis and atopic dermatitis, aiming to guide clinical decision-making and future research directions in this evolving field.

FLG and FLG2 proteins are expressed in the outer layers of the epidermis, where they are vital in epidermal differentiation and skin barrier formation. Filaggrinopathies involving dysfunctions in these proteins are associated with a spectrum of phenotypic presentations, from monogenic to multifactorial conditions. This review examines biosynthesis and function of FLG and FLG2 proteins and evaluates their molecular pathogenesis in filaggrinopathies. Moreover, genotype-phenotype correlations are assessed, emphasizing genetic diagnosis complexities and diverse immune dysregulation patterns. Finally, it examines ongoing immunotherapeutic approaches by targeting different cytokines as promising treatment options for filaggrinopathies management.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease worldwide. AD is a highly complex disease with different subtypes. Many elements of AD pathophysiology have been described, but if/how they interact with each other or which mechanisms are important in which patients is still unclear. Langerhans cells (LCs) are antigen-presenting cells (APCs) in the epidermis. Depending on the context, they can act either pro- or anti-inflammatory. Many different studies have investigated LCs in the context of AD and found them to be connected to all major mechanisms of AD pathophysiology. As APCs, LCs recruit other immune cells and shape the immune response, especially adaptive immunity via polarization of T cells. As sentinel cells, LCs are primary sensors of the skin microbiome and are important for the decision of immunity versus tolerance. LCs are also involved with the integrity of the skin barrier by influencing tight junctions. Finally, LCs are important cells in the neuro-immune crosstalk in the skin. In this review, we provide an overview about the many different roles of LCs in AD. Understanding LCs might bring us closer to a more complete understanding of this highly complex disease. Potentially, modulating LCs might offer new options for targeted therapies for AD patients.

Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood.

We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity.

We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases-funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures.

S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21.

CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.

The skin is a large and sophisticated organ populated by innate and adaptive immune effector cells. These immune cells provide a critical first line of defense against pathogens, but genetic and environmental factors can lead to inappropriate signaling that may manifest as hypersensitivity. The most common cutaneous allergic disorders in children include atopic dermatitis, urticaria/angioedema, and contact dermatitis. In this review, we will briefly review these conditions, with a focus on recent developments in our understanding of the diagnosis and management of these disorders.

Information on skin barrier in horses is limited. A study on the epidermal ultrastructure of normal and allergic horses documented disorganized amorphous intercellular lipids in the stratum corneum of allergic samples. These findings are similar to atopic canine and human skin. Currently, there is no published study comparing skin barrier function parameters between normal and allergic horses; thus, the functional implications of the ultrastructural changes are unknown. In normal horses, body location, gender, breed, and ambient conditions affect skin barrier parameters, such as Transepidermal Water Loss. Skin microbiome studies on normal horses have highlighted the importance of season and environmental conditions, since horses housed together share similar microbiomes. Skin dysbiosis and predominance of staphylococcus have been described in horses with pastern dermatitis. Transcriptomic studies of the epidermis of normal and allergic horses have found that lesional allergic skin has substantial transcriptomic differences when compared with healthy skin, namely downregulation of genes of tight junctions, keratins, and upregulation of serine proteases and IL-13. Keratinocytes harvested from horses with insect bite hypersensitivity show upregulation of IL-31 gene expression under stimulation. While more research is clearly needed, preliminary results seem to support skin barrier differences between normal and allergic horses.

Earthworm (Pheretima communisima) is used as a traditional medicine for the management of allergic airway inflammation. Atopic dermatitis (AD) is a persistent, recurrent disorder marked by allergic inflammation and skin barrier dysfunction. However, the pharmaceutical effects of earthworms on AD have not been defined. Our study examined the anti-allergic and anti-inflammatory actions of earthworm ethanolic extract (EWE) on allergic skin inflammation in a Dermatophagoides farinae mite antigen-induced AD mice model, TNF-α/IFN-γ-treated human keratinocytes, and compound 48/80-treated mouse mast cells. Oral administration of EWE in AD mouse reduced inflammatory cell accumulation, epidermal hyperplasia, and dermatitis severity in AD skin lesions and thymic stromal lymphopoietin (TSLP) and immunoglobulin (Ig) E concentrations in serum. EWE administration in AD mice also reduced secretion of Interleukin (IL)-4, IL-13, IL-5, and IFN-γ in cultures of isolated splenic cells. Immunohistofluorescence staining of skin lesions from AD mice revealed that EWE induced expression of claudin-1, filaggrin, and SIRT1. In HaCaT keratinocytes cotreated with IFN-γ and TNF-α, EWE inhibited secretion of the chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) in a dose-dependent manner. In addition, EWE inhibited histamine release in activated MC/9 mast cells. These results show that EWE might be therapeutics for the management of AD.

Atopic dermatitis (AD) is a chronic and inflammatory skin disorder characterized by impaired barrier function and imbalanced immunity. Recent advances have revealed that dysbiosis of skin microbiota plays important roles in the pathogenesis and development of AD. Meanwhile, endogenous and external factors contribute to the dysbiosis of skin microbiota in AD. Additionally, various treatments, including topical treatments, phototherapy, and systemic biologics, have demonstrated positive impacts on the clinical outcomes, alongside with the modulations of cutaneous microbiota in AD patients. Importantly, therapeutics or products regulating skin microbiota homeostasis have demonstrated potential for AD treatment in early clinical studies. In this review, we underline changes of the skin microbiota correlated with AD. Meanwhile, we provide an overview of the skin microbiota regarding its roles in the pathogenesis and development of AD. Finally, we summarize therapeutic strategies restoring the skin microbial homeostasis in AD management.

Resveratrol is a polyphenolic compound showing anti-inflammatory activity by inhibition of high mobility group box 1 cytokine responsible for the activation of nuclear factor-κB pathway in atopic dermatitis. To evaluate the efficacy of resveratrol through topical route we have developed resveratrol-loaded nanoemulgel for the effective management of atopic dermatitis in mice model. The resveratrol-loaded nanoemulsion (0.5%, 0.75% and 1% w/w) was optimized by spontaneous nano-emulsification. The optimized resveratrol-loaded nanoemulsions showed average globule size in the 180-230 nm range and found to be monodispersed. The resveratrol nanoemulgel was prepared with a SEPINEO™ P 600 gel base and propylene glycol. Ex vivo permeation and retention study resulted in significantly higher skin retention of resveratrol from resveratrol-loaded nanoemulgel than free resveratrol-loaded gel. Preclinical efficacy of resveratrol nanoemulgel displayed promising therapeutic outcomes where, western blotting of skin tissues disclosed a significant reduction in the relative expression of high mobility group box 1, the receptor for advanced glycation end products, toll-like receptor-4 and phosphorylated nuclear factor-κB. Further, real-time polymerase chain reaction also disclosed a significant reduction in pro-inflammatory cytokines such as thymic stromal lymphopoietin, interleukin-4, interleukin-13, interleukin-31, tumor necrosis factor-α and interleukin-6. The histopathological examination of skin sections showed improvement in the skin condition. Collectively, the findings from our study showcased the significant improvement in the atopic dermatitis skin condition in mice model after topical application of resveratrol loaded nanoemulgel.

FLG is a well-known biomarker of atopic dermatitis and skin dryness. Its full proteolysis (or filaggrinolysis) produces the major constituents of the natural moisturizing factor. Some proteases/peptidases remain to be identified in this multistep process. Mining 16 omics analyses, we identified prolyl endopeptidase (PREP) as a candidate peptidase. Indirect immunofluorescence and confocal analysis demonstrated its localization in the granular and deep cornified layers, where it colocalized with FLG. Tandem mass spectroscopy and fluorescent quenching activity assays showed that PREP cleaved several synthetic peptides derived from the FLG sequence, at the carboxyl side of an internal proline. Deimination of these peptides increased PREP enzymatic efficiency. Specific inhibition of PREP in reconstructed human epidermis using benzyloxycarbonyl-pro-prolinal induced the accumulation of FLG monomers. Downregulation of PREP expression in reconstructed human epidermis using RNA interference confirmed the impact of PREP on FLG metabolism and highlighted a more general role of PREP in keratinocyte differentiation. Indeed, quantitative global proteomic, western blotting, and RT-qPCR analyses showed a strong reduction in the expression of bleomycin hydrolase, known to be involved in filaggrinolysis, and of several other actors of cornification such as loricrin. Consequently, at the functional level, the transepidermal electric resistance was drastically reduced.

The onset of atopic dermatitis (AD) is complex, and its specific pathological mechanisms have not yet been fully elucidated.

Using circulating multi-omics as the exposure factors and AD as the outcome, we conducted univariable MR analysis. The circulating multi-omics data included immunomics (731 immune cell types), proteomics (4907 plasma proteins), metabolomics (1400 metabolites and 486 additional metabolites), and 91 inflammatory factors. MR analysis was conducted using IVW, WM, Simple Mode, Weighted Mode, and MR-Egger methods, with IVW as the primary analysis tool. To address horizontal pleiotropy, we utilized MR-Egger intercept tests and MR-PRESSO for correction, alongside the Cochrane Q statistic for heterogeneity assessment. Sensitivity analysis was performed using a leave-one-out strategy. To control for false positives due to multiple testing, we set a standard of a 5% false discovery rate. Additionally, we conducted F-statistics on the included SNPs to eliminate the impact of weak instrumental variables.

IL-18R1 on AD (OR = 1.12, 95% CI: 1.08-1.17, P FDR < 0.01). Mannonate levels on AD (OR = 0.88, 95% CI: 0.83-0.94, P FDR = 0.03). Retinol (Vitamin A) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) on AD (OR = 1.12, 95% CI: 1.06-1.18, PFDR = 0.03). HVEM on CM CD4+ cells on AD (OR = 0.81, 95% CI: 0.75-0.88, P FDR < 0.01). CR2 on AD (OR = 0.81, 95% CI: 0.72-0.90, P FDR = 0.04). MANSC1 on AD (OR = 0.87, 95% CI: 0.81-0.93, P FDR = 0.04). IL18R1 (4097 inflammatory markers) on AD (OR = 1.11, 95% CI: 1.06-1.17, P FDR = 0.01). HNRNPAB on AD (OR = 1.44, 95% CI: 1.23-1.70, P FDR < 0.01).

This study further explored the correlations between multi-omics data and AD. We identified seven previously unreported circulating substances with causal relationships to AD, filling a current theoretical gap.

The root bark of Dictamus dasycarpus Turcz. has been traditionally used for the topical treatment of skin disorders like pruritus. This study was designed to investigate the inflammatory and skin barrier protective effects of D. dasycarpus in mice with calcipotriol (MC903)-induced atopic dermatitis (AD). Topical skin lesions on male Balb/c mice (8 weeks old) were treated topically with an ethanolic extract of D. dasycarpus (EEDD), and skin water content, water holding capacity (WHC), histopathological abnormalities, and inflammatory cytokine and chemokine levels were investigated. Topical application of EEDD effectively alleviated skin lesion severity, improved skin water content and WHC, and ameliorated histopathological abnormalities, including hyperkeratosis, blood vessel numbers near the epidermis, spongiotic changes, and immune cell infiltration in skin tissues. EEDD also suppressed inflammatory cytokines and chemokines, such as tumor necrosis factor (TNF)-α, thymic stromal lymphopoietin (TSLP), interleukin (IL)-1β, IL-4, IL-8, and monocyte chemotactic protein (MCP)-1. In RAW264.7 cells, EEDD reduced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) expression and suppressed the phosphorylations of extracellular signal-regulated kinase (ERK) and p38. These results suggest that the root bark of D. dasycarpus has therapeutic potential due to its anti-dermatitis and skin barrier protective effects in AD and that it could be used as an ingredient in skincare products.

Previous observational studies focused on the association of tea intake and allergic diseases. However, it is not known whether these associations are causal. We used a bidirectional Mendelian randomization (MR) study to assess the causal relationship of tea intake with the risk of allergic diseases, such as atopic dermatitis (AD), allergic rhinitis (AR), and allergic asthma (AA). Single-nucleotide polymorphisms (SNPs) which had genetic statistical significance with tea intake were used as instrumental variables (IVs). We employed heritable IVs of tea intake from the UK Biobank, which included 447,485 samples. Sensitivity analyses were further performed using MR Egger and MR-PRESSO. Inverse variance weighted (IVW) method was used as the main approach. In this MR study, 40 independent SNPs were selected for tea intake. The MR analysis revealed that an increase in genetically predicted tea intake was associated with a lower risk of AD (OR = 0.709, 95% CI = 0.546-0.919, p = 0.009). Furthermore, we observed a causal effect of genetically predicted tea intake on the risk of AA (OR = 0.498, 95% CI = 0.320-0.776, p = 0.002). However, no significant causal relationship was found between genetically predicted tea intake and AR (OR = 1.008, 95% CI = 0.998-1.017, p = 0.115). Our MR analysis suggested that increased tea intake may reduce the risk of AD and AA in European population. This suggests that tea intake is likely a trigger or a prevention strategy for AD and AA.

The prevalence of many chronic noncommunicable diseases has been steadily rising over the past six decades. During this time, over 350,000 new chemical substances have been introduced to the lives of humans. In recent years, the epithelial barrier theory came to light explaining the growing prevalence and exacerbations of these diseases worldwide. It attributes their onset to a functionally impaired epithelial barrier triggered by the toxicity of the exposed substances, associated with microbial dysbiosis, immune system activation, and inflammation. Diseases encompassed by the epithelial barrier theory share common features such as an increased prevalence after the 1960s or 2000s that cannot (solely) be accounted for by the emergence of improved diagnostic methods. Other common traits include epithelial barrier defects, microbial dysbiosis with loss of commensals and colonization of opportunistic pathogens, and circulating inflammatory cells and cytokines. In addition, practically unrelated diseases that fulfill these criteria have started to emerge as multimorbidities during the last decades. Here, we provide a comprehensive overview of diseases encompassed by the epithelial barrier theory and discuss evidence and similarities for their epidemiology, genetic susceptibility, epithelial barrier dysfunction, microbial dysbiosis, and tissue inflammation.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases. AD pathogenesis is associated with increased oxidative stress, impairment of the skin barrier, and activation of the immune response. Rosmarinic acid (RA), a caffeic acid ester, is known for its anti-inflammatory and antioxidant properties. However, the effects of RA on Dermatophagoides farinae extract (DfE)-induced AD-like skin inflammation, as well as its ability to regulate oxidative stress through the Nrf2/HO-1 pathway in TNF-α/IFN-γ-treated keratinocytes, remain unclear. We investigated RA activity in a DfE-induced AD-like skin inflammation mouse model and IFN-γ/TNF-α-stimulated keratinocytes. We found that RA attenuates DfE-induced inflammation by decreasing dermatitis scores and serum inflammatory marker levels and mast cell infiltration. Additionally, RA significantly suppressed IFN-γ/TNF-α-induced chemokine production in keratinocytes and reduced Th cytokine levels in concanavalin A-stimulated splenocytes. Importantly, RA also increased Nrf2/HO-1 expression in TNF-α/IFN-γ-treated keratinocytes. In conclusion, this study demonstrated that RA effectively alleviates DfE-induced AD-like skin lesions by reducing the levels of inflammatory cytokines and chemokines. Furthermore, RA promotes Nrf2/HO-1 signaling in keratinocytes, which may help mitigate DfE-induced oxidative stress, thereby alleviating AD-like skin inflammation. These findings highlight the potential of RA as a therapeutic agent for treating AD and other skin inflammation.

Acne vulgaris (AV) is the eighth most common nonfatal disease globally. Previous work identified an association between AV and increased filaggrin (FLG) protein expression in the follicular epidermis, but further work did not find a clear link between loss-of-function (LoF) FLG gene mutations and protection from AV.

To explore any association between AV and FLG LoF mutations in a cohort of genotyped patients of Bangladeshi ancestry with atopic eczema (AE) in East London.

A retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone -clinical assessment. A χ2-test or Fisher's exact test was used to determine differences in AV history between FLG LoF genotype groups.

We found a significant reduction in history of AV in patients with AE with FLG LoF mutations (19 of 82) relative to those without FLG mutations (47 of 129) (23% vs. 36.4%; P = 0.02). We showed a nonsignificant reduction in AV diagnosis in patients with impaired barrier function (measured by transepidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (P = 0.02).

In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV.