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Background: Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α‐subunit of interleukin (IL)‐4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored. Methods: We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non‐lesional skin of adults and adolescents with moderate‐to‐severe AD over the course of 16‐week treatment with dupilumab and compared those values with that of matched healthy volunteers. Results: Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL‐4/IL‐13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non‐hydroxy fatty acids and C18‐sphingosine and increased the level of esterified omega‐hydroxy fatty acid‐containing ceramides) and increased ceramide chain length in lesional as well as non‐lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment. Conclusions: Inhibition of IL‐4/IL‐13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]

Allergic diseases are allergen‐induced immunological disorders characterized by the development of type 2 immunity and IgE responses. The prevalence of allergic diseases has been on the rise alike cardiovascular disease (CVD), which affects arteries of different organs such as the heart, the kidney and the brain. The underlying cause of CVD is often atherosclerosis, a disease distinguished by endothelial dysfunction, fibrofatty material accumulation in the intima of the artery wall, smooth muscle cell proliferation, and Th1 inflammation. The opposed T‐cell identity of allergy and atherosclerosis implies an atheroprotective role for Th2 cells by counteracting Th1 responses. Yet, the clinical association between allergic disease and CVD argues against it. Within, we review different phases of allergic pathology, basic immunological mechanisms of atherosclerosis and the clinical association between allergic diseases (particularly asthma, atopic dermatitis, allergic rhinitis and food allergy) and CVD. Then, we discuss putative atherogenic mechanisms of type 2 immunity and allergic inflammation including acute allergic reactions (IgE, IgG1, mast cells, macrophages and allergic mediators such as vasoactive components, growth factors and those derived from the complement, contact and coagulation systems) and late phase inflammation (Th2 cells, eosinophils, type 2 innate‐like lymphoid cells, alarmins, IL‐4, IL‐5, IL‐9, IL‐13 and IL‐17). [ABSTRACT FROM AUTHOR]

Microbial metabolism of specific dietary components, such as fiber, contributes to the sophisticated inter‐kingdom dialogue in the gut that maintains a stable environment with important beneficial physiological, metabolic, and immunological effects on the host. Historical changes in fiber intake may be contributing to the increase of allergic and hypersensitivity disorders as fiber‐derived metabolites are evolutionarily hardwired into the molecular circuitry governing immune cell decision‐making processes. In this review, we highlight the importance of fiber as a dietary ingredient, its effects on the microbiome, its effects on immune regulation, the importance of appropriate timing of intervention to target any potential window of opportunity, and potential mechanisms for dietary fibers in the prevention and management of allergic diseases. In addition, we review the human studies examining fiber or prebiotic interventions on asthma and respiratory outcomes, allergic rhinitis, atopic dermatitis, and overall risk of atopic disorders. While exposures, interventions, and outcomes were too heterogeneous for meta‐analysis, there is significant potential for using fiber in targeted manipulations of the gut microbiome and its metabolic functions in promoting immune health. [ABSTRACT FROM AUTHOR]

In the Th2 high group, in contrast to the Th2 low, the IL-13 response by SEB CLA SP + sp T cells directly correlated with EASI score and plasma levels of CCL17 and sIL-2R (Figure 2A-C). I Staphylococcus aureus i , memory skin-homing cutaneous lymphocyte-associated antigen (CLA) SP + sp T cells and IL-13 constitute relevant players in atopic dermatitis (AD) pathogenesis.1 Since circulating CLA SP + sp T cells reflect cutaneous abnormalities present in human inflammatory skin diseases,2 an I ex vivo i coculture model made of purified circulating CLA SP +/- sp effector and central memory T cells and autologous lesional epidermal cells was established. SEB-induced IL-13 production in CLA+ memory T cells defines Th2 high and Th2 low responders in atopic dermatitis. [Extracted from the article]

BackgroundThere are sparse and conflicting data regarding the long-term clinical course of atopic dermatitis (AD). Although often described as a childhood disease, newer population-based estimates suggest the prevalence of pediatric and adult disease may be similar.MethodsOur objective was to determine whether there is a decline in the prevalence of AD in population-based cohorts of patients followed longitudinally beyond childhood. We conducted a systematic review and meta-analysis including studies assessing AD prevalence across 3 or more points in time. The primary outcome was weighted overall risk difference (percentage decrease in AD prevalence).ResultsOf 2080 references reviewed, 7 studies with 13 515 participants were included. Participants were assessed at 3-6 time points, ranging from age 3 months to 26 years. The percentage decrease in prevalence after age 12 was 1%, which was not significantly different from zero (95% confidence interval -2%-5%). Similar results were found with other age cut-offs.ConclusionThe prevalence of AD in longitudinal birth cohort studies is similar in childhood and adolescence/early adulthood.

Thus, the S3 guideline for allergy prevention for German-speaking countries recommended early peanut introduction only for high-risk (Atopic eczema) children of families that regularly eat peanuts, if a peanut allergy is excluded via testing. Basophil activation test shows high accuracy in the diagnosis of peanut and tree nut allergy: the Markers of Nut Allergy Study. The LEAP study[1] elegantly supplied evidence that early and regular peanut introduction into the diet of infants with severe atopic eczema or egg allergy, or both (at-risk population) as early as by age 4-10 months dramatically reduces the prevalence of peanut allergy by the age of 5 years by 81%. [Extracted from the article]

Background: Atopic dermatitis (AD) and psoriasis represent two of the most common inflammatory skin diseases in developed countries. A hallmark of both diseases is T‐cell infiltration into the skin. However, it is still not clarified to what extent these infiltrating T cells are antigen‐specific skin‐homing T cells or unspecific heterogeneous bystander cells. Methods: To elucidate this, T cells from lesional skin and from blood of 9 AD and 10 psoriasis patients were compared by receptor (TCR) sequencing. Therefore, peripheral blood mononuclear cells (PBMC) were cell‐sorted according to expression of the cutaneous leukocyte antigen (CLA) into skin‐homing (CLA+) and non‐skin‐homing (CLA−) subfractions. Aeroallergen‐specific T‐cell lines were grown from AD patients' PBMC in parallel. Results: Intra‐individual comparison of TCRB CDR3 regions revealed that clonally expanded T cells in skin lesions of both AD and psoriasis patients corresponded to skin‐homing circulating T cells. However, in psoriasis patients, these T‐cell clones were also detectable to a larger extent among CLA− circulating T cells. Up to 28% of infiltrating cells in AD skin were identified as allergen‐specific by overlapping TCR sequences. Conclusions: Our data show that in line with the systemic nature of psoriasis, T‐cell clones that infiltrate psoriatic skin lesions do not exclusively possess skin‐homing ability and are therefore most probably specific to antigens that are not exclusively expressed or located in the skin. T cells driving AD skin inflammation appear to home nearly exclusively to the skin and are, to a certain extent, specific to aeroallergens. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting in decreased quality of life. Histamine and specifically the H 4 receptor play a key role in the inflammatory process in AD and serve as targets for novel therapeutic approaches., Objective: In the present study we aimed to elucidate the immunopathological mechanisms with which the H 4 receptor impacts TH2 cells and contributes to AD pathophysiology., Methods: Total CD4 + T cells obtained from healthy or AD individuals and in vitro differentiated TH2 cells were cultured under different conditions and the mRNA expression or protein production of target molecules were determined using quantitative real-time PCR and ELISA., Results: H 4 receptor mRNA expression was upregulated concentration dependent upon IL-4 stimulation in in vitro differentiated TH2 cells progressively during the differentiation. Transcriptomic analysis of in vitro differentiated TH2 versus TH1 cells revealed that the H 4 receptor among other genes represents one of the highly upregulated genes in TH2 cells. Most importantly, increased amounts of IL-5 and IL-13 mRNA expression were detected in in vitro differentiated TH2 cells as well as protein secretion in the presence of histamine or of the H 4 receptor-selective-agonist when compared to the untreated control., Conclusion: We show for the first time an H 4 receptor dependent upregulation of the pro-inflammatory cytokines IL-5 and IL-13 in human TH2 cells by histamine. This suggests that the blockade of the H 4 receptor may lead to downregulation of these cytokines and amelioration of AD symptoms as reported in first clinical studies., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Several studies have evaluated prophylactic emollients as a preventive strategy against atopic dermatitis (AD) and food allergy (FA). We aimed to synthesize the evidence on efficacy and safety of prophylactic emollients started during the first 6 weeks of infancy for prevention of AD and FA. Methods: MEDLINE, Embase, CINAHL, BIOSIS, and the Cochrane Library databases were searched systematically for randomized controlled trials published between January 2000 and July 2020, which assessed the effects of prophylactic emollients initiated within the first 6 weeks of life on the development of AD within 24 months of age, compared to no treatment. Risk of bias and certainty of evidence were assessed using the Cochrane Collaboration's tool and GRADE process, respectively. Results: Of the 1486 articles identified, 10 studies fulfilled inclusion criteria. In infants given emollients, there was no significant reduction on the development of AD (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.64, 1.10) compared to the control group. However, there was significant benefit of prophylactic emollients (RR 0.75, 95% CI 0.62–1.11) in the high‐risk population (n = 8 studies). There was also significant benefit (RR 0.59, 95% CI 0.43, 0.81) in studies (n = 6) where emollients were used continuously to the point of AD assessment; but not when treatment was ceased for an interval before AD assessment. There were no protective effects on FA found. Conclusion: The prophylactic application of emollients initiated in early infancy may prevent AD, especially in high‐risk populations and when used continuously. We hypothesize that emollients may delay rather than prevent AD. [ABSTRACT FROM AUTHOR]

The epithelial barrier is the first line of defense that forms a protective barrier against pathogens, pollutants, and allergens. Epithelial barrier dysfunction has been recently implicated in the development of allergic diseases such as asthma, atopic dermatitis, food allergy, and rhinitis. However, there is limited knowledge on epithelial barrier dysfunction in ocular allergy (OA). Since the ocular surface is directly exposed to the environment, it is important to understand the role of ocular epithelia and their dysfunction in OA. Impaired epithelial barrier enhances allergen uptake, which lead to activation of immune responses and development of chronic inflammation as seen in allergies. Abnormal expression of tight junction proteins that helps to maintain epithelial integrity has been reported in OA but sufficient data not available in chronic atopic (AKC) and vernal keratoconjunctivitis (VKC), the pathophysiology of which is not just complex, but also the current treatments are not completely effective. This review provides an overview of studies, which indicates the role of barrier dysfunction in OA, and highlights how ocular barrier dysfunction possibly contributes to the disease pathogenesis. The review also explores the potential of ocular epithelial barrier repair strategies as preventive and therapeutic approach. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is a frequent and heterogeneous inflammatory skin disease, for which personalized medicine remains a challenge. High‐throughput approaches have improved understanding of the complex pathophysiology of AD. However, a purely data‐driven AD classification is still lacking. Methods: To address this question, we applied an original unsupervised approach on the largest available transcriptome dataset of AD lesional (n = 82) and healthy (n = 213) skin biopsies. Results: Taking into account pathological and physiological state, a variance‐based filtering revealed 222 AD‐specific hyper‐variable genes that efficiently classified the AD samples into 4 clusters that turned out to be clinically and biologically distinct. Comparison of gene expressions between clusters identified 3 sets of upregulated genes used to derive metagenes (MGs): MG‐I (19 genes) was associated with IL‐1 family signaling (including IL‐36A and 36G) and skin remodeling, MG‐II (23 genes) with negative immune regulation (including IL‐34 and 37) and skin architecture, and MG‐III (17 genes) with B lymphocyte immunity. Sample clusters differed in terms of disease severity (p =.02) and S. aureus (SA) colonization (p =.02). Cluster 1 contained the most severe AD, highest SA colonization, and overexpressed MG‐I. Cluster 2 was characterized by less severe AD, low SA colonization, and high MG‐II expression. Cluster 3 included mild AD, mild SA colonization, and mild expression of all MGs. Cluster 4 had the same clinical features as cluster 3 but had hyper‐expression of MG‐III. Last, we successfully validated our method and results in an independent cohort. Conclusion: Our study revealed unrecognized AD endotypes with specific underlying biological pathways, highlighting novel pathophysiological mechanisms. These data could provide new insights into personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The cytokine profile of atopic dermatitis (AD) depends on age, ethnicity, and disease severity. This study examined biomarkers in children with AD collected by tape strips and skin biopsies, and examined whether the levels differed with filaggrin genotype, disease severity, and food allergy. Methods: Twenty‐five children aged 2–14 years with AD were clinically examined. Skin biopsies were collected from lesional skin and tape strips were collected from lesional and non‐lesional skin. We analyzed natural moisturizing factor (NMF) and 17 immune markers represented by mRNA levels in skin biopsies and protein levels in tape strips. Common filaggrin gene mutations were examined in all children. Results: The cytokine profile in lesional skin was dominated by a T helper (Th) 2 response in skin biopsies, and by a general increase in innate inflammation markers (interleukin (IL)‐1α, IL‐1β, IL‐8, IL‐18) along with TARC and CTACK in tape strips. The levels of TARC, CTACK, IL‐8, IL‐18 showed significant correlation with AD severity in both lesional and non‐lesional tape stripped skin, while no significant correlations were observed in skin biopsy data. In tape strips from lesional and non‐lesional skin, the levels of NMF and selected cytokines differed significantly between children with and without FLG mutations and food allergy. Conclusion: Sampling of the stratum corneum with non‐invasive tape strips can be used to identify biomarkers that are associated with disease severity, food allergy and FLG mutations. Skin biopsies showed robust Th2 signature but was inferior for association analysis regarding severity. [ABSTRACT FROM AUTHOR]

Background: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases worldwide and Staphylococcus aureus colonization and secondary infections occur in the majority of AD patients. Allergic sensitizations against microbial antigens have been discussed as possible trigger factors of AD. Recently, we reported IgE sensitization against fibronectin‐binding protein 1 (FBP1), an essential virulence component in S. aureus, in a subgroup of patients suffering from AD. To expand these findings by investigating delayed‐type immune reactions, the objective of this study was to detect and phenotypically characterize FBP1‐specific T cells as possible trigger factors in AD. Methods: Immunodominant T‐cell epitopes were mapped by proliferation testing of patient‐derived FBP1‐specific T‐cell lines after stimulation with single 15mer peptides, which were derived from different functional domains of the FBP1 sequence. Major histocompatibility complex class II tetramers carrying immunodominant epitopes successfully stained T helper cells in 8 out of 8 HLA‐matched, IgE‐sensitized AD patients. Results: Cytokine profiling of multimer‐sorted cells revealed that predominantly the type 2 cytokines IL‐13 and IL‐4 were secreted by these cells. In contrast, IL‐17, the marker cytokine for response to extracellular pathogens, was scarcely detectable. Conclusions: We demonstrate that FBP1 contains immunodominant peptides that induce a specific pro‐inflammatory T helper cell response with increased Th2 levels that can drive an allergic inflammation in sensitized AD patients. [ABSTRACT FROM AUTHOR]

Background: Early exposure to allergens through a defect skin barrier has been proposed as a mechanism for inducing sensitization and development of allergic diseases. We hypothesized that early‐onset, severe atopic dermatitis (AD) is associated with development of aeroallergen sensitization and allergic rhinitis. Methods: We included 368 children from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) at‐risk mother‐child cohort. AD was diagnosed prospectively based on Hanifin&Rajka's criteria and severity assessed using the Scoring Atopic Dermatitis (SCORAD) index. Early‐onset AD was defined as debut ≤1 year, late‐onset as debut from 1–6 years. Aeroallergen sensitization and allergic rhinitis were diagnosed at ages 6–7 and 12 years. Associations between early‐onset and late‐onset AD and allergy endpoints were calculated using general estimating equations (GEE) models to compute the overall odds ratios (OR) for both time points. Results: Early‐onset AD (yes/no) and severity (SCORAD) were associated with development of aeroallergen sensitization during childhood; GEE OR = 1.68 [1.08; 2.62], p =.02 and 1.08 [1.03; 1.12], p <.001, whereas late‐onset AD showed a borderline significant association and late‐onset severity showed no association; GEE OR = 1.65 [0.92; 2.94], p =.08 and 1.01 [0.97; 1.06], p =.55. The same trend was seen for allergic rhinitis with significant association between early‐onset AD and allergic rhinitis; GEE OR = 1.56 [1.01; 2.41], p =.04 and severity; GEE OR = 1.09 [1.05; 1.13], p <.001, whereas late‐onset AD showed no association. The effects on sensitization and rhinitis of early‐onset versus late‐onset AD severity were significantly different: p‐interactionsensitization =.03 and p‐interactionrhinitis <.01. Conclusion: Increasing severity of early‐onset AD, but not late‐onset AD, associates with aeroallergen sensitization and allergic rhinitis later in childhood. [ABSTRACT FROM AUTHOR]

Cameron S, Donnelly A, Broderick C, et al. Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis. Allergy. 2024;79:26‐36.The name of one of the co‐authors was misspelled in the published version.The incorrect author name wasJesper Elbeling.The correct author name should beJesper Elberling.The online version of the article has been corrected.We apologize for this error [Extracted from the article]

Background: Treatments for alopecia areata (AA) patients with extensive scalp hair loss are limited, and recent evidence supports a role for type 2 T‐cell (Th2)‐immune response in AA. Dupilumab, a monoclonal antibody inhibiting Th2 signaling, approved for type 2 diseases including atopic dermatitis, was evaluated in AA patients. Methods: Alopecia areata patients with and without concomitant atopic dermatitis were randomized 2:1 to receive weekly subcutaneous dupilumab (300 mg) or placebo for 24 weeks, followed by another 24‐week dupilumab open‐label phase. The primary outcome was change from baseline in the Severity of Alopecia Tool (SALT) score at week 24; secondary outcomes included a range of measures of hair regrowth. Results: Forty and 20 patients were assigned to the dupilumab and placebo arms, respectively. At week 24, disease worsening was documented in the placebo arm, with a least‐squares mean change in the SALT score of −6.5 (95% confidence‐interval [CI], −10.4 to −2.6), versus a change of 2.2 (95% CI, −0.6 to 4.94) in the dupilumab arm (p <.05). After 48 weeks of dupilumab treatment, 32.5%, 22.5% and 15% of patients achieved SALT30/SALT50/SALT75 improvement, respectively, while in patients with baseline IgE ≥ 200 IU/ml response rates increased to 53.8%, 46.2%, and 38.5%, respectively. Moreover, baseline IgE predicts treatment response with 83% accuracy. No new safety signals were detected. Conclusions: This hypothesis‐driven trial is the first to indicate the possible pathogenic role of the Th2 axis and Th2 targeting in AA patients. Patient selection based on baseline serum IgE levels may improve treatment results (Clinicaltrials.gov number, NCT03359356). [ABSTRACT FROM AUTHOR]

Allergic diseases like asthma, allergic rhinitis, food allergy, hymenoptera allergy, or atopic dermatitis are highly prevalent in women of childbearing age and may affect up to 30% of this age group. This review focuses on the management of allergic diseases during pregnancy. Furthermore, we discuss the challenges of counseling women with allergic diseases in the reproductive age, including considerations relevant to the ongoing SARS‐CoV‐2 pandemic. To create the optimal milieu for the unborn child, a multitude of immunological changes occur during pregnancy which may favor type 2 responses and aggravate disease phenotypes. In co‐occurrence with suboptimal preconception disease control, this elevated Th2 responses may aggravate allergic disease manifestations during pregnancy and pose a risk for mother and child. Due to limitations in conducting clinical trials in pregnant women, safety data on anti‐allergic drugs during pregnancy are limited. The lack of information and concerns among pregnant patients demands counseling on the benefits of anti‐allergic drugs and the potential and known risks. This includes information on the risk for mother and child of disease aggravation in the absence of treatment. By doing so, informed decisions and shared decision‐making can take place. [ABSTRACT FROM AUTHOR]

Background: Bacille Calmette‐Guérin (BCG) vaccine could play a role in counteracting the rising prevalence of atopic diseases, through its beneficial off‐target effects. We aimed to determine whether neonatal BCG vaccination reduces the incidence of eczema in infants. Methods: Randomized controlled trial with 1272 infants allocated to receive BCG‐Denmark or no BCG at birth. The primary outcome was the 12‐month incidence of eczema based on 3‐monthly questionnaires. Eczema was also assessed at a 12‐month clinic visit. ClinicalTrial.gov: NCT01906853. Results: The 12‐month eczema incidence was 32.2% in the BCG group compared with 36.6% in the control group (adjusted risk difference (aRD) −4.3%, 95% CI −9.9% to 1.3%, multiple imputation model). In addition, comparing infants in the BCG group with the control group, 15.7% vs. 19.2% had eczema lesions at the 12‐month visit (aRD −3.5%, 95% CI −8.0% to 1.0%); 35.7% vs. 39.0% reported using topical steroids (aRD −3.3, 95% CI −9.2 to 2.7); and 7.3% vs. 10.2% had severe eczema scores (aRD −3.0%, 95% CI −8.8% to 2.7%). In 344 high‐risk infants (two atopic parents), the 12‐month eczema incidence was 35.3% in the BCG group compared with 46.8% in the control group (aRD −11.5%, 95% CI −21.9% to −1.2%; number needed to treat 8.7, 95% CI 4.6 to 83.3). Conclusion: There is insufficient evidence to recommend neonatal BCG vaccination in all infants for the prevention of eczema in the first year of life; however, a modest beneficial effect was observed among high‐risk infants. A single dose of BCG‐Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents. [ABSTRACT FROM AUTHOR]

Background: Epicutaneous sensitization is an important route for the production of IgE, and skin inflammation‐induced IgE has recently been reported having features of natural antibody. Atopic dermatitis (AD) and psoriasis have differentially increased level of serum IgE; however, the production mechanism of IgE in these inflammatory skin diseases remains unknown. Objective: To explore the origin of IgE in AD and psoriasis by analyzing the B cell receptor repertoire. Methods: mRNA was prepared from peripheral blood mononuclear cells of AD and psoriasis patients that had elevated serum levels of IgE, and immunoglobulin heavy chain (IGH) repertoires were sequenced after reverse transcription. Clonal lineages of B cells containing members expressing IgE were identified, and somatic hypermutations in IGH inherited from common ancestors within the clonal lineage were used to infer the relationships between B cells. Results: The proportions of IGHE from AD and psoriasis were higher than that of normal control, which were positively correlated with the levels of serum total IgE. The somatic hypermutation value of IGHE variable region was lower than that of IGHG and IGHA, but higher than IGHM and IGHD, indicating a mixed natural and adaptive origins of IgE; and psoriasis demonstrated lower level of hypermutation than AD. The Shannon indexes of CDR3 in IGHE of AD and psoriasis were higher than that of normal control, also supporting the natural origin. The VH usage of IgE was weakly biased in AD and psoriasis patients with high level of house dust mite‐specific IgE. Comparison of the number of shared mutations in multi‐isotype lineages containing IgE showed that isotype‐switching from IgG‐expressing B cells might be the major source of IgE in AD and psoriasis. Conclusion: IgE has heterogeneous origin in AD and psoriasis, and skin inflammation may contribute to the increased production of natural IgE. [ABSTRACT FROM AUTHOR]

Background: In order to improve targeted therapeutic approaches for children with atopic dermatitis (AD), novel insights into the molecular mechanisms and environmental exposures that differentially contribute to disease phenotypes are required. We wished to identify AD immunological endotypes in South African children from rural and urban environments. Methods: We measured immunological, socio‐economic and environmental factors in healthy children (n = 74) and children with AD (n = 78), in rural and urban settings from the same ethno‐linguistic AmaXhosa background in South Africa. Results: Circulating eosinophils, monocytes, TARC, MCP‐4, IL‐16 and allergen‐specific IgE levels were elevated, while IL‐17A and IL‐23 levels were reduced, in children with AD regardless of their location. Independent of AD, children living in a rural environment had the highest levels of TNFα, TNFβ, IL‐1α, IL‐6, IL‐8, IL‐21, MCP‐1, MIP‐1α, MIP‐1β, MDC, sICAM1, sVCAM1, VEGFA, VEGFD and Tie2, suggesting a generalized microinflammation or a pattern of trained immunity without any specific TH polarization. In contrast, IL‐15, IL‐22, Flt1, PIGF and βFGF were highest in urban children. Rural healthy children had the lowest levels of food allergen‐specific IgG4. Early life nutritional factors, medications, animal exposures, indoor environment, sunlight exposure, household size, household income and parental education levels were associated with differences in circulating cytokine levels. Conclusions: This study highlights the immunological impact of environmental exposures and socio‐economic status in the manifestation of immune endotypes in children with AD living in urban and rural areas, which are important in selecting appropriately matched immunological therapies for treatment of AD. [ABSTRACT FROM AUTHOR]

Food allergy (FA) is now one of the most common chronic diseases of childhood often lasting throughout life and leading to significant worldwide healthcare burden. The precise mechanisms responsible for the development of this inflammatory condition are largely unknown; however, a multifactorial aetiology involving both environmental and genetic contributions is well accepted. A precise understanding of the pathogenesis of FA is an essential first step to developing comprehensive prevention strategies that could mitigate this epidemic. As it is frequently preceded by atopic dermatitis and can be prevented by early antigen introduction, the development of FA is likely facilitated by the improper initial presentation of antigen to the developing immune system. Primary oral exposure of antigens allowing for presentation via a well‐developed mucosal immune system, rather than through a disrupted skin epidermal barrier, is essential to prevent FA. In this review, we present the data supporting the necessity of (1) an intact epidermal barrier to prevent epicutaneous antigen presentation, (2) the presence of specific commensal bacteria to maintain an intact mucosal immune system and (3) maternal/infant diet diversity, including vitamins and minerals, and appropriately timed allergenic food introduction to prevent FA. [ABSTRACT FROM AUTHOR]

Background: Several biologics for atopic dermatitis (AD) have demonstrated good efficacy in clinical trials, but with a substantial proportion of patients being identified as poor responders. This study aims to understand the pathophysiological backgrounds of patient variability in drug response, especially for dupilumab, and to identify promising drug targets in dupilumab poor responders. Methods: We conducted model‐based meta‐analysis of recent clinical trials of AD biologics and developed a mathematical model that reproduces reported clinical efficacies for nine biological drugs (dupilumab, lebrikizumab, tralokinumab, secukinumab, fezakinumab, nemolizumab, tezepelumab, GBR 830, and recombinant interferon‐gamma) by describing system‐level AD pathogenesis. Using this model, we simulated the clinical efficacy of hypothetical therapies on virtual patients. Results: Our model reproduced reported time courses of %improved EASI and EASI‐75 of the nine drugs. The global sensitivity analysis and model simulation indicated the baseline level of IL‐13 could stratify dupilumab good responders. Model simulation on the efficacies of hypothetical therapies revealed that simultaneous inhibition of IL‐13 and IL‐22 was effective, whereas application of the nine biologic drugs was ineffective, for dupilumab poor responders (EASI‐75 at 24 weeks: 21.6% vs. max. 1.9%). Conclusion: Our model identified IL‐13 as a potential predictive biomarker to stratify dupilumab good responders, and simultaneous inhibition of IL‐13 and IL‐22 as a promising drug therapy for dupilumab poor responders. This model will serve as a computational platform for model‐informed drug development for precision medicine, as it allows evaluation of the effects of new potential drug targets and the mechanisms behind patient variability in drug response. [ABSTRACT FROM AUTHOR]

Background: A systematic review showed limited associations between pregnancy diet and offspring allergy. We developed a maternal diet index during pregnancy that was associated with offspring allergy outcomes. Methods: Data came from Healthy Start, a Colorado pre‐birth cohort of mother/offspring dyads. Food propensity questionnaires were completed during pregnancy. Offspring allergic rhinitis, atopic dermatitis, asthma, wheeze, and food allergy diagnosis up to age four were verified from electronic medical records. Data were randomized into test and replication sets. The index included the weighted combination of variables that best predicted a combined outcome of any allergy in the test set. Index utility was verified in the replication set. Separate adjusted and unadjusted logistic models estimated associations between the index and each offspring allergy diagnosis in the full sample. Results: The index included weighted measures of intake of vegetables, yogurt, fried potatoes, rice/grains, red meats, pure fruit juice, and cold cereals. Vegetables and yogurt were associated with the prevention of any allergy, while other components were associated with increased disease. In adjusted models, a one‐unit increase in the index was significantly associated with reduced odds of offspring allergic rhinitis (odds ratio (CI) 0.82 [0.72–0.94]), atopic dermatitis (0.77 [0.69–0.86]), asthma (0.84 [0.74–0.96]), and wheeze (0.80 [0.71–0.90]), but not food allergy (0.84 [0.66–1.08]). Conclusions: This is the first study that has shown associations between an index of maternal dietary intake during pregnancy and multiple offspring allergic diseases. The results give hope for prevention of allergic diseases in utero. [ABSTRACT FROM AUTHOR]

Collectively, these results indicates that the TT genotype of I DOCK8 i gene augments IL-31 production by promoting EPAS1 nuclear localization. 3 a Multiple logistic regression model: Dominant (major allele homozygotes vs. heterozygotes and minor allele homozygotes), Co-dominant 1 (heterozygotes vs. major allele homozygotes), Co-dominant 2 (minor allele homozygotes vs. major allele homozygotes), Recessive (minor allele homozygotes vs. major allele homozygotes and heterozygotes), Over-dominant (major and minor allele homozygotes vs. heterozygotes). [Extracted from the article]

In fact, lean mice with a T cell-specific loss of Pparg (Cd4 SP cre sp Pparg SP fl/fl sp ) showed augmented Th17-driven AD diseases.3 Therefore, PPAR could maintain a Th2 phenotype and prevent the amplification of a more pathological Th17-type inflammation. Rosiglitazone, a PPAR agonist, significantly reduced AD severity in obese mice, and sensitized them to anti-IL-4/anti-IL-13 therapy gl Thus, obesity worsens AD by exacerbating pathological Th17 responses, turning a therapy into an antitherapy. [Extracted from the article]

Median goblet cell density was 2.6 cells/mm (IQR 1.1-4.0) in patients compared to 4.1 cells/mm and 9.8 cells/mm in HCs (Table S1b). Conjunctival inflammation in dupilumab-treated atopic dermatitis comprises a multicellular infiltrate with elevated T1/T17 cytokines: A case series study Composite images derived from Imaging Mass Cytometry of conjunctival biopsy samples from AD patients developing conjunctivitis during dupilumab treatment. [Extracted from the article]

Keywords: allergy diagnosis; atopic dermatitis; food allergy EN allergy diagnosis atopic dermatitis food allergy 3845 3848 4 12/01/21 20211201 NES 211201 Atopic dermatitis (AD) typically develops in infancy and affects up to 20% of children in high-income countries.1 I Immediate i (IgE-mediated) food allergy (FA) affects around 3% of children.2 Children with AD are at higher risk of I immediate i - I type i FA.3,4 Up to a third of children with moderate to severe AD have FA.3 A Danish population-based study, evaluating children from birth to 6 years, showed that 15% of all children with AD had concomitant FA and almost all children with FA had concomitant AD.4 In a recent review, the likelihood of food sensitization was reported to be 6 times higher in patients with AD compared to healthy controls at 3 months of age.5 Furthermore, up to 15% of subjects with AD had a positive oral food challenge (OFC).5 A population-based study from Australia showed that one out of five infants with AD, mainly infants with early-onset AD (<3 months), were allergic to peanut, egg white, or sesame compared to one in 20 without AD,6 when evaluated by an oral food challenge at 12 months. Some of the guidance highlight increased risk factors for the development of FA, particularly AD, hence the importance of early diagnosis and management of AD and FA. As around 20% of children in the general population have AD and only around 3% of children have FA, an algorithm which directs the evaluation of infants and small children with AD for FA will prove useful for clinicians. [Extracted from the article]

Atopic eczema (AE) is an inflammatory skin disease with involvement of genetic, immunological and environmental factors. One hallmark of AE is a skin barrier disruption on multiple, highly interconnected levels: filaggrin mutations, increased skin pH and a microbiome dysbiosis towards Staphylococcus aureus overgrowth are observed in addition to an abnormal type 2 immune response. Extrinsic factors seem to play a major role in the development of AE. As AE is a first step in the atopic march, its prevention and appropriate treatment are essential. Although standard therapy remains topical treatment, powerful systemic treatment options emerged in the last years. However, thorough endotyping of the individual patients is still required for ideal precision medicine approaches in future. Therefore, novel microbial and immunological biomarkers were described recently for the prediction of disease development and treatment response. This review summarizes the current state of the art in AE research. [ABSTRACT FROM AUTHOR]

Microbiota composition and associated metabolic activities are essential for the education and development of a healthy immune system. Microbial dysbiosis, caused by risk factors such as diet, birth mode, or early infant antimicrobial therapy, is associated with the inception of allergic diseases. In turn, allergic diseases increase the risk for irrational use of antimicrobial therapy. Microbial therapies, such as probiotics, have been studied in the prevention and treatment of allergic diseases, but evidence remains limited due to studies with high heterogeneity, strain‐dependent effectiveness, and variable outcome measures. In this review, we sketch the relation of microbiota with allergic diseases, the overuse and rationale for the use of antimicrobial agents in allergic diseases, and current knowledge concerning the use of bacterial products in allergic diseases. We urgently recommend 1) limiting antibiotic therapy in pregnancy and early childhood as a method contributing to the reduction of the allergy epidemic in children and 2) restricting antibiotic therapy in exacerbations and chronic treatment of allergic diseases, mainly concerning asthma and atopic dermatitis. Future research should be aimed at antibiotic stewardship implementation strategies and biomarker‐guided therapy, discerning those patients that might benefit from antibiotic therapy. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common inflammatory skin disease associated with barrier disfunction and T SB H sb 2/T SB H sb 22 immune polarity.1,2 Patients with AD are often colonized or infected with I Staphylococcus aureus i ( I S. aureus i ).3 Recent large cohort studies and skin microbiome analyses have identified that AD is dominated by I S. aureus i .4 However, the interaction of cytokines and bacteria in AD skin remains unclear. Keywords: atopic dermatitis; dermatology; infections; inflammation; innate immunity; keratinocytes EN atopic dermatitis dermatology infections inflammation innate immunity keratinocytes 3534 3537 4 11/01/21 20211101 NES 211101 ACKNOWLEDGEMENTS KY was supported by Japan Society for the Promotion of Science (JSPS) overseas research fellowships from 2020 to 2022. TH2 cytokines and Staphylococcus aureus cooperatively induce atopic dermatitis-like transcriptomes. [Extracted from the article]

Preferential splicing to the presumed non-functional short IL-31RA isoform was identified in healthy skin, whereas during allergic inflammation transcription of both functional and non-functional IL-31RA was reduced and this preferential splicing was no longer evident. IL-31RA splice variant transcription was measured using qPCR assays targeting total IL-31RA transcription, long IL-31RA isoforms mRNA transcript variants X1-4, short IL-31RA isoform mRNA transcript variant X5, or the reference genes CG14980-PB and RPS19. Reduced IL-31 receptor alpha splice variant mRNA following allergen challenge in a canine model of atopic dermatitis. [Extracted from the article]

Background: Mucosal‐associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I‐related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined. Methods: Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1‐dependent immune surveillance in a MC903‐driven murine model of AD. Results: The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL‐4‐ and IL‐13‐producing cells. In addition, the therapeutic efficacy of phototherapy against MC903‐driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6‐formylpterin. Conclusion: We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands. [ABSTRACT FROM AUTHOR]

Background: The high susceptibility of AD patients to microbial skin infections has been attributed to a deficient antimicrobial peptide (AMP) expression, which is contradicted by a growing amount of recent studies clearly demonstrating that AMP expression is not impaired in lesional skin of AD patients. The reasons for the high susceptibility of AD patients to microbial infections are still unknown. Methods: The influence of self‐DNA on the antimicrobial activity of RNase 7, LL‐37, and hBD2 has been investigated using antibacterial and antiviral assays. The amount of self‐DNA on skin has been analyzed by skin rinsings and subsequent quantification using dsDNA assays. DNA source was identified by qPCR. Results: Complex formation of the AMPs with self‐DNA significantly impaired their antibacterial activity against Staphylococcus aureus and their antiviral activity against HSV‐1. The inhibition of the antibacterial activity was dependent on the DNA concentration but not on the length of the DNA molecules. Of note, we detected significant higher amounts of cell‐free self‐DNA in skin rinses taken from lesional AD skin compared to skin rinses from non‐lesional skin and from normal skin of healthy donors. Consequently, rinse solution from AD lesional skin prevented antibacterial activity of LL‐37. Conclusion: Our study indicates that extracellular self‐DNA is released in considerable amounts in AD skin lesions and AMP‐self‐DNA‐complex formation leads to a significant loss of antibacterial and antiviral activity in atopic dermatitis. Studies on strategies to reduce the amount of extracellular DNA in AD are needed to identify possible methods relevant in clinical settings. [ABSTRACT FROM AUTHOR]

However, the clinical phenotypes in AD with high serum RANKL or RANKL/OPG ratio might represent the characteristics of severe AD, since those AD subgroups showed high severity. The differences of serum RANKL levels (A, C) and RANKL/OPG ratio (B, D) were analyzed between the adults' subgroups: healthy controls, AD (EASI < 16), and AD (EASI >= 16). Serum receptor activator of nuclear factor kappa- ligand/osteoprotegerin ratio correlates with severity and suggests fracture's risk in older women with atopic dermatitis. [Extracted from the article]

Background: Parabens, widely used as preservatives in cosmetics, foods, and other consumer products, are suspected of contributing to allergy susceptibility. The detection of parabens in the placenta or amniotic fluid raised concerns about potential health consequences for the child. Recently, an increased asthma risk following prenatal exposure has been reported. Here, we investigated whether prenatal paraben exposure can influence the risk for atopic dermatitis (AD). Methods: 261 mother‐child pairs of the German mother‐child study LINA were included in this analysis. Eight paraben species were quantified in maternal urine obtained at gestational week 34. According to the parental report of physician‐diagnosed AD from age 1 to 8 years, disease onset, and persistence, childhood AD was classified into four different phenotypes. Results: 4.6% (n = 12) and 12.3% (n = 32) of the children were classified as having very early‐onset AD (until age two) either with or without remission, 11.9% (n = 31) as early‐onset (after age two), and 3.1% (n = 8) as childhood‐onset AD (after age six). Exposure to ethylparaben and n‐butylparaben was associated with an increased risk to develop very early‐onset AD without remission (EtP: adj.OR/95% CI:1.44/1.04–2.00,nBuP:adj.OR/95% CI:1.95/1.22–3.12). The effects of both parabens were predominant in children without a history of maternal AD and independent of children's sex. Conclusion: Prenatal EtP or nBuP exposure may increase children's susceptibility for persistent AD with disease onset at very early age. This association was particularly pronounced in children without a history of maternal AD, indicating that children without a genetic predisposition are more susceptible to paraben exposure. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases leading to pruritic skin lesions. A subset of AD patients exhibits a disseminated severe HSV infection called eczema herpeticum (EH) that can cause life‐threatening complications. This review gives an overview of the clinical picture, and characteristics of the patients as well as the diagnosis and therapy of EH. A special focus lies on the pathophysiological hallmarks identified so far that predispose for EH. This aspect covers genetic aberrations, immunological changes, and environmental influences displaying a complex multifactorial situation, which is not completely understood. Type 2 skewing of virus‐specific T cells in ADEH+ patients has been implicated in immune profile abnormalities, along with impaired functions of dendritic cells and natural killer cells. Furthermore, aberrations in interferon pathway‐related genes such as IFNG and IFNGR1 have been identified to increase the risk of EH. IL‐4, IL‐25, and thymic stromal lymphopoietin (TSLP) are overexpressed in EH, whereas antimicrobial peptides like human β‐defensins and LL‐37 are reduced. Concerning the epidermal barrier, single nucleotide polymorphisms (SNPs) in skin barrier proteins such as filaggrin were identified in ADEH+ patients. A dysbalance of the skin microbiome also contributes to EH due to an increase of Staphylococcus aureus, which provides a supporting role to the viral infection via secreted toxins such as α‐toxin. The risk of EH is reduced in AD patients treated with dupilumab. Further research is needed to identify and specifically target risk factors for EH in AD patients. [ABSTRACT FROM AUTHOR]

Background: Expression of the tight junction proteins Cldn1 and 4 is altered in skin diseases such as atopic dermatitis, and Cldn1 deficiency affects skin barrier formation. Impedance spectroscopy (IS) has been proven to allow detection of alterations in the skin barrier but is currently unable to separate effects on viable epidermis (VE) and stratum corneum (SC). Methods: Effects of siRNA‐mediated Cldn1 and 4 knockdown in reconstructed human epidermis (RHE) on VE and SC barrier function were investigated with Ussing chamber‐based IS. Barrier components were sequentially altered, employing iron oxide nanoparticles and EGTA, to identify their contribution to the impedance spectrum. Resistance changes due to apically applied hyperosmolar electrolyte were used to identify barrier defects non‐invasively. Results: IS of RHE yielded two relaxation frequencies, representing the barrier properties of the SC (~1000 Hz) and VE (~100 Hz). As proof of concept, it was shown that the Cldn1 knockdown‐induced resistance drop arises from the impairment of both SC and VE, indicated by a shift of both relaxation frequencies. Hyperosmolar electrolyte penetration allowed non‐invasive detection of Cldn1 knockdown via time‐dependent frequency shifts. The absence of Cldn4 knockdown‐induced changes revealed the weaknesses of transepithelial electrical resistance analysis. Conclusion: In conclusion, the present technique allows to separately measure the barrier properties of SC and VE and further evaluate the Cldn1 and 4 knockdown impact on the skin barrier. As the measurement with agarose‐embedded electrolyte allowed non‐invasive identification of the Cldn1 knockdown, this opens the way to detailed in vivo skin barrier assessment. [ABSTRACT FROM AUTHOR]

Background: In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk‐related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients. Methods: We used 18‐FDG PET‐CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD‐related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk. Results: We found significant correlations between vascular inflammation and Th2‐related products in skin and blood of AD patients as well as atherosclerosis‐related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET‐CT. Conclusion: Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis‐related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD. [ABSTRACT FROM AUTHOR]

Background: Allergic disorders such as atopic dermatitis (AD) are strongly associated with an impairment of the epithelial barrier, in which tight junctions and/or filaggrin expression can be defective. Skin barrier assessment shows potential to be clinically useful for prediction of disease development, improved and earlier diagnosis, lesion follow‐up, and therapy evaluation. This study aimed to establish a method to directly assess the in vivo status of epithelial barrier using electrical impedance spectroscopy (EIS). Methods: Thirty‐six patients with AD were followed during their 3‐week hospitalization and compared with 28 controls. EIS and transepidermal water loss (TEWL) were measured in lesional and non‐lesional skin. Targeted proteomics by proximity extension assay in serum and whole‐genome sequence were performed. Results: Electrical impedance spectroscopy was able to assess epithelial barrier integrity, differentiate between patients and controls without AD, and characterize lesional and non‐lesional skin of patients. It showed a significant negative correlation with TEWL, but a higher sensitivity to discriminate non‐lesional atopic skin from controls. During hospitalization, lesions reported a significant increase in EIS that correlated with healing, decreased SCORAD and itch scores. Additionally, EIS showed a significant inverse correlation with serum biomarkers associated with inflammatory pathways that may affect the epithelial barrier, particularly chemokines such as CCL13, CCL3, CCL7, and CXCL8 and other cytokines, such as IRAK1, IRAK4, and FG2, which were significantly high at admission. Furthermore, filaggrin copy numbers significantly correlated with EIS on non‐lesional skin of patients. Conclusions: Electrical impedance spectroscopy can be a useful tool to detect skin barrier dysfunction in vivo, valuable for the assessment of AD severity, progression, and therapy efficacy. [ABSTRACT FROM AUTHOR]

Background: Flow cytometry is a well‐accepted approach for immune profiling; however, its value is restricted by the limited number of markers that can be analyzed simultaneously. Mass cytometry/CyTOF offers broad‐scale immune characterization integrating large number of parameters. While partial blood phenotyping was reported in atopic dermatitis (AD), patients' comprehensive profiling, critical for leveraging new targeted treatments, is not available. IL‐21 may be involved in inflammatory skin diseases but its role in AD is not well established. Methods: We studied T‐cell polarization in the blood of 20 moderate‐to‐severe AD and 15 controls. Using CyTOF and an unsupervised analysis, we measured the frequencies and mean metal intensities of activated polar CD4+/CD8+ T‐cell subsets. Immunohistochemistry, immunofluorescence, and qRT‐PCR were used to analyze skin samples. Results: Examining 24 surface, intracellular markers, and transcription factors, we identified six CD4+ and five CD8+ T‐cell metaclusters. A CD4+ skin‐homing IL‐13+monocytokine and a novel IL‐13+IL‐21+ multicytokine metaclusters were increased in AD vs. controls (p <.01). While IL‐13 signature characterized both clusters, levels were significantly higher in the IL‐21+ group. Both clusters correlated with AD severity (r = 0.49, p =.029). Manual gating corroborated these results and identified additional multicytokine subsets in AD. Immunohistochemistry and immunofluorescence, validated by mRNA expression, displayed significantly increasedIL‐21 counts and colocalization with IL‐13/IL‐4R in AD skin. Conclusion: A multicytokine signature characterizes moderate‐to‐severe AD, possibly explaining partial therapeutic responses to one cytokine targeting, particularly in severe patients. Prominent IL‐21 signature in blood and skin hints for a potential pathogenic role of IL‐21 in AD. [ABSTRACT FROM AUTHOR]

The cytokine interleukin‐31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper‐reactivity. In AD, IL‐31 has been identified as one of the main "drivers" of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL‐31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2‐associated cytokines including IL‐31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL‐31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL‐31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti‐IL‐31 antibody. Accordingly, inhibition of IL‐31‐downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL‐31‐mediated‐signaling needs to be clarified. Targeting the IL‐31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future. [ABSTRACT FROM AUTHOR]

Background: The antimicrobial ribonuclease RNase 7 is abundantly expressed in the epidermis of lesional skin of atopic dermatitis (AD). Host RNase inhibitor (RI) binds to RNase 7 and blocks its ribonuclease activity. This study aimed to evaluate the impact of RNase 7-RI interactions on AD., Methods: Cultured human primary keratinocytes, with siRNA-mediated downregulation of RNase 7 and RI, were stimulated with the synthetic RNA polyinosinic-polycytidylic acid (poly I:C). Induction of proinflammatory mediators was analyzed by real-time PCR and ELISA. RI expression in AD non-lesional and lesional skin biopsies and healthy controls was analyzed by real-time PCR and immunostaining. RI protein release in vivo on the AD skin surface was determined by western blot. Antimicrobial and ribonuclease assays were used to investigate the functional role of RI., Results: RNase 7 inhibited the RNA-induced expression of proinflammatory mediators in keratinocytes. Accordingly, downregulation of RNase 7 in keratinocytes enhanced RNA-mediated induction of proinflammatory mediators, whereas downregulation of RI had the opposite effect. RI was released by damaged keratinocytes and epidermis. In vivo expression and release of RI on the skin surface were enhanced in lesional AD skin. Rinsing solution from the surface of lesional AD skin blocked the ribonuclease activity of RNase 7. The anti-Staphylococcus aureus activity of RNase 7 was abrogated by RI., Conclusions: Our data suggest a novel role of RI as a trigger factor of inflammation in AD by blocking the ribonuclease and antimicrobial activity of RNase 7, thereby enhancing RNA-mediated inflammation and S. aureus growth., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Efforts to profile atopic dermatitis (AD) tissues have intensified, yet comprehensive analysis of systemic immune landscapes in severe AD remains crucial., Methods: Employing single-cell RNA sequencing, we analyzed over 300,000 peripheral blood mononuclear cells from 12 severe AD patients (Eczema area and severity index (EASI) > 21) and six healthy controls., Results: Results revealed significant immune cell shifts in AD patients, including increased Th2 cell abundance, reduced NK cell clusters with compromised cytotoxicity, and correlated Type 2 innate lymphoid cell proportions with disease severity. Moreover, unique monocyte clusters reflecting activated innate immunity emerged in very severe AD (EASI > 30). While overall dendritic cells (DCs) counts decreased, a distinct Th2-priming subset termed "Th2&#95;DC" correlated strongly with disease severity, validated across skin tissue data, and flow cytometry with additional independent severe AD samples. Beyond the recognized role of Th2 adaptive immunity, our findings highlight significant innate immune cell alterations in severe AD, implicating their roles in disease pathogenesis and therapeutic potentials., Conclusion: Apart from the widely recognized role of Th2 adaptive immunity in AD pathogenesis, alterations in innate immune cells and impaired cytotoxic cells have also been observed in severe AD. The impact of these alterations on disease pathogenesis and the effectiveness of potential therapeutic targets requires further investigation., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)-13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2-year impacts of IL-13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate-to-severe AD., Methods: Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long-term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay., Results: Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 (IL4R, IL31, CCL17, and CCL26), Th1 (IFNG), and Th17/Th22 (IL22, S100A7, S100A8, and S100A9) pathways as well as increased expression of epidermal differentiation and barrier genes (CLDN1 and LOR). Tralokinumab also shifted atherosclerosis signaling pathway genes (SELE, IL-37, and S100A8) toward non-lesional expression., Conclusion: Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non-lesional levels, further highlighting the key role of IL-13 in the pathogenesis of AD., Clinical Trial Registration: NCT03131648, NCT03587805., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Keywords: atopic dermatitis; Hanifin EN atopic dermatitis Hanifin 2257 2259 3 07/04/22 20220701 NES 220701 "Work hard, play hard" remains a common refrain from Dr. Jon Hanifin whose reputation for zest for life and adventure is outmatched only by his scientific accomplishments (Figure 1A). In 1971, 2 days after arriving home from Japan, Dr. Hanifin met with Dr. Lobitz in Portland, Oregon and joined the faculty at Oregon Health & Science University (OHSU) (Figure 1B). Dr. Lobitz encouraged Dr. Hanifin to begin studying lymphocytes in patients with atopic dermatitis (AD). [Extracted from the article]

B and C, H2R mRNA expression in IL-4 stimulated M2 macrophages, D and E, H4R mRNA expression in IL-4 stimulated M2 macrophages, F and G, H4R mRNA expression in IL-13 stimulated M2 macrophages. Expression of histamine receptors H2R and H4R are predominantly regulated via the IL-4/IL-13 receptor type II on human M2 macrophages Keywords: atopic dermatitis; histamine; macrophages EN atopic dermatitis histamine macrophages 2886 2890 5 09/03/21 20210901 NES 210901 ACKNOWLEDGEMENTS The authors would like to thank Brigitta Koether for excellent technical assistance. [Extracted from the article]

Moreover, the paucity of available IgE reduces IgE-CD23 interactions on B-cells, reducing Th2 differentiation and IgE synthesis. Keywords: allergy treament; asthma; atopic dermatitis; biologics; urticaria EN allergy treament asthma atopic dermatitis biologics urticaria 2934 2937 4 09/03/21 20210901 NES 210901 Advances in molecular biology alongside the accelerated development of gene and cell engineering have contributed to the development of several endotype-targeted biological therapies against chronic immune-mediated allergic diseases. Allergy treament, asthma, atopic dermatitis, biologics, urticaria Conventional therapies for asthma, chronic rhinosinusitis with polyposis (CRSwNP), chronic spontaneous urticarial, and atopic dermatitis (AD) are not without limitations, and as such the advent of biological therapies have provided a promising alternative treatment option. [Extracted from the article]

Keywords: atopic dermatitis; environment; epidemiology; hygiene hypothesis; Pediatrics EN atopic dermatitis environment epidemiology hygiene hypothesis Pediatrics 2890 2893 4 09/03/21 20210901 NES 210901 Abbreviations CNIs Calcineurin inhibitors ISAAC International Study of Asthma and Allergies in Childhood NCCHD National Center for Child Health and Development REC Research Ethics Committee Th1 T helper cells type 1 Th2 T helper cells type 2 Treg Regulatory T cells ACKNOWLEDGMENTS We are grateful to Toshinao Kawai, Department of Immunology, National Center for Child Health and Development, Tokyo, Japan, for useful discussions. Atopic dermatitis, environment, epidemiology, hygiene hypothesis, Pediatrics Pediatric allergies are associated with the environment during the fetal period, including maternal therapeutic drugs.3 Therefore, we conducted a retrospective cohort study using chart review and a questionnaire survey to investigate the relationship between intrauterine exposure to immunosuppressants and postnatal allergies. [Extracted from the article]