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Background: Delgocitinib ointment, a topical Janus kinase inhibitor, is used as treatment of patients with atopic dermatitis (AD) aged ≥2 years in Japan. Although initiating appropriate and early treatment upon the onset of AD in childhood is important, the safety and efficacy of delgocitinib ointment in infants with AD have not been established. Methods: This phase 3 study was conducted from October 2020 to June 2022 (number JapicCTI-205412). Eligible Japanese infants with AD aged 6 to

Objective: The study aimed to conduct a systematic review of the literature to verify the association between exposure to pesticides and allergic diseases (asthma, allergic rhinitis, and atopic dermatitis) in children and adolescents. Method: A systematic review and meta-analysis were performed using the PRISMA method with the question “What is the association between exposure to pesticides and allergic diseases in children (asthma, allergic rhinitis, and atopic dermatitis)?” MEDLINE, EMBASE, SciELO, and Cochrane electronic databases were searched throughout the period in the literature up to September 2020. A total of 1296 studies were found, and 24 were selected. Results: Exposure to pesticides showed a two-fold greater risk of developing or exacerbating asthma in children and adolescents (odds ratio [OR] = 2.14 95% confidence interval [CI] 1.26-3.64, p < 0.01). There was no association between exposure to pesticides and the development of allergic rhinitis (OR = 2.73, 95% CI 0.13-57.8, p = 0.52) and atopic dermatitis (OR = 2.19, 95% CI 0.51-9.36, p = 0.29). Conclusions: Exposure to pesticides increases the risk of developing or exacerbating asthma in children and adolescents. There was no evidence of an association between exposure to pesticides and the development of allergic rhinitis and atopic dermatitis in children and adolescents, possibly due to the low number of studies found in this review.

Atopic dermatitis (AD) is a chronic inflammatory skin disease where Th2-type immune responses are dominant. In the lesional skin of AD, keratinocytes show differentiation defects and secrete proinflammatory cytokines and chemokines, amplifying Th2-type responses in AD. We previously reported that inducible loss of B-cell lymphoma 6 (Bcl6), a transcription repressor and a master transcriptional regulator of follicular helper T cells and germinal center B cells, in the whole body results in upregulation of Th2-related cytokines in mouse skin. However, the role of Bcl6 in keratinocytes remains to be clarified. Here, we observed that BCL6 positively regulates the expression of keratinocyte differentiation markers and plasma membrane localization of adherence junctional proteins in keratinocyte cell culture. Although keratinocyte-specific loss of Bcl6 alone did not induce AD-like skin inflammation, it aggravates MC903-induced AD-like skin inflammation in mice. In addition, Bcl6 expression is decreased in the epidermis of lesional skin from MC903-induced AD-like skin inflammation in mice. These results strongly suggest that Bcl6 downregulation in keratinocytes contributes to the development and aggravation of AD-like skin inflammation in mice., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Severe asthma (SA) affects 2% to 5% of asthmatic children. Atopic dermatitis can affect up to 34% of children with SA (cwSA). Atopic dermatitis and asthma share common genetic and immunological features. However, not all children with SA suffer from AD, and it remains unclear whether the overall immune profiles of these children are similar. In this study, seventeen cwSA (9.8 [7.1-13.2] years; seven with and ten without AD) were enrolled. Bronchoalveolar lavage (BAL) and blood samples were collected from these patients. Seventy-three cytokines/chemokines and distinct immune T cell populations were evaluated in blood and BAL. We found that BAL and blood immune profiles of cwSA with and without AD were globally similar. However, specific differences were observed, namely lower frequency of Tc2, Th17 and IL-17-producing mucosal associated invariant T (MAIT-17) cells and higher CD8/CD4 ratio and IL-22 concentrations in BAL and of CCL19 concentrations in plasma from cwSA with AD. Further, in contrast with cwSA without AD, we found a positive correlation between a set of plasma cytokines and almost all cytokines in BAL in cwSA with AD. In conclusion, this study shows the major immune differences between cwSA with and without AD in BAL and blood suggesting that distinct endotypes may be implicated in the inflammatory responses observed in these pediatric patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Hebei Spirit oil spill accident occurred in December 2007, approximately 10 km off the coast of Taean, South Korea, a location notably close to residential areas. Crude oil substances have been detected in various environmental mediums since the accident, yet previous studies have primarily focused on the acute effects of oil exposure due to the short latency period of allergic diseases. Therefore, this study evaluated the long-term effects of oil spill exposure on allergic disorders. Our study included adult residents who had participated in the Health Effects Research on Hebei Spirit Oil Spill (HEROS) study up to five years post-incident, which was a prospective cohort to monitor the health status of Taean residents. We used two indicators to assess oil spill exposure, namely the distance from the initial contaminated coastline to each participant's residence and the number of days participants had engaged in oil clean-up work. Current symptoms such as asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and multimorbidity were considered allergic disorders. In the baseline survey, the prevalence of asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and allergic multimorbidity symptoms was associated with both exposure indicators; however, these associations were not observed in the two consecutive surveys. Significant longitudinal associations between oil spill exposure indicators and the four allergic disorders, as well as multimorbidity incidences, were observed during a five-year follow-up period. Our results suggest that oil spill exposure can affect acute and long-term allergic symptoms in residents near the accident site., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The human skin microbiome consists of many species of bacteria, including Staphylococcus aureus and S. epidermidis. Individuals with atopic dermatitis (AD) have an increased relative abundance of S. aureus, which exacerbates the inflammation of AD. Although S. epidermidis, a main component of healthy skin microbiota, inhibits the growth of S. aureus, the balance between S. epidermidis and S. aureus is disrupted in the skin of individuals with AD. In this study, we found that Citrobacter koseri isolated from patients with AD produces substances that inhibit the growth of S. epidermidis. Heat-treated culture supernatant (CS) of C. koseri inhibited the growth of S. epidermidis but not S. aureus. The genome of C. koseri has gene clusters related to siderophores and the heat-treated CS of C. koseri contained a high concentration of siderophores compared with the control medium. The inhibitory activity of C. koseri CS against the growth of S. epidermidis was decreased by the addition of iron, but not copper or zinc. Deferoxamine, an iron-chelating agent, also inhibited the growth of S. epidermidis, but not that of S. aureus. These findings suggest that C. koseri inhibits the growth of S. epidermidis by interfering with its iron utilization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The ongoing COhort for Childhood Origin of Asthma and allergic diseases (COCOA) study is a prospective birth cohort investigating the origin and natural courses of childhood allergic diseases, including atopic dermatitis, food allergy, allergic rhinitis and asthma, with long-term prognosis. Initiated under the premise that allergic diseases result from a complex interplay of immune development alterations, environmental exposures, and host susceptibility, the COCOA study explores these dynamic interactions during prenatal and postnatal periods, framed within the hygiene and microbial hypotheses alongside the developmental origins of health and disease (DOHaD) hypothesis. The scope of the COCOA study extends to genetic predispositions, indoor and outdoor environmental variables affecting mothers and their offsprings such as outdoor and indoor air pollution, psychological factors, diets, and the microbiomes of skin, gut, and airway. We have embarked on in-depth investigations of diverse risk factors and the pathophysiological underpinnings of allergic diseases. By employing multi-omics approaches-proteomics, transcriptomics, and metabolomics-we gain deeper insights into the distinct pathophysiological processes across various endotypes of childhood allergic diseases, incorporating the exposome using extensive resources within the COCOA study. Integration with large-scale datasets, such as national health insurance records, enhances robustness and mitigates potential limitations inherent to birth cohort studies. As part of global networks focused on childhood allergic diseases, the COCOA study fosters collaborative research across multiple cohorts. The findings from the COCOA study are instrumental in informing precision medicine strategies for childhood allergic diseases, underpinning the establishment of disease trajectories., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Delgocitinib ointment, a topical Janus kinase inhibitor, is used as treatment of patients with atopic dermatitis (AD) aged ≥2 years in Japan. Although initiating appropriate and early treatment upon the onset of AD in childhood is important, the safety and efficacy of delgocitinib ointment in infants with AD have not been established., Methods: This phase 3 study was conducted from October 2020 to June 2022 (number JapicCTI-205412). Eligible Japanese infants with AD aged 6 to <24 months received 0.25% or 0.5% of delgocitinib ointment twice daily for 52 weeks in an open-label uncontrolled manner. Topical corticosteroids were allowed to apply for worsening AD during the treatment period at the investigators' discretion., Results: A total of 22 infants were enrolled. Adverse events (AEs) were reported in 21 (95.5%) infants and were mostly mild. No treatment-related AEs were reported. The Modified Eczema Area and Severity Index (mEASI) score continuously decreased until week 4, and the score reduction was maintained until week 52. The mean percent changes in the mEASI score from baseline were -73.5% at week 4, -81.7% at week 28, and -81.9% at week 52. Delgocitinib was not detected in the plasma of most infants (68.2%-95.2%)., Conclusions: Delgocitinib ointment is well tolerated and effective for up to 52 weeks when applied to Japanese infants with AD., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are common inflammatory diseases. We previously reported attenuated contact hypersensitivity (CHS) responses in AD model mice using 2,4-dinitrofluorobenzene, reflecting clinical experiments. However, previous studies have not addressed the commonality of findings across haptens and mechanisms focused on dendritic cells (DCs). Thus, this study evaluated CHS responses to fluorescein isothiocyanate (FITC) and DC migration and maturation in the sensitization phase of CHS in AD. CHS responses to FITC were compared between NC/Nga mice without and with AD induction (non-AD and AD mice, respectively). T-cell responses and DC migration and maturation after FITC-induced sensitization were examined in the draining lymph nodes of non-AD and AD mice. AD mice demonstrated reduced CHS responses to FITC under decreased T-cell proliferation following sensitization and interferon-γ production by hapten-specific T cells compared with non-AD mice. In addition, the number of FITC + CD11c + MHC class II high migratory DCs 24 h after FITC sensitization was comparable between non-AD and AD mice. However, FITC + CD11c + MHC class II high migratory DCs in AD mice exhibited lower expression levels of CD80 and CD86 and higher expression levels of PD-L1 and mRNA of transforming growth factor beta than non-AD mice. These findings suggest that attenuated CHS responses may be hapten-independent and the induction of the tolerogenic phenotype of hapten-bearing DCs can contribute to reduced T-cell proliferation after sensitization and CHS responses in AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early identification of infants at high risk of allergies can improve the efficacy of preventive interventions. However, an established quantifiable risk assessment method in the early postnatal period does not exist. TARC (or CCL17) is a Th2 chemokine used as an activity marker for atopic dermatitis (AD). Therefore, we evaluated the association between cord blood TARC (cTARC) and the development of allergic diseases in childhood., Methods: This is a high-risk birth cohort for allergy, consisting of children with a family history of allergy. We collected 263 pairs of maternal and child cord blood samples perinatally and child blood samples at ages 1, 2, and 5 years. TARC and allergen-specific immunoglobulin E levels were measured, and the relationship between allergic diseases was analyzed., Results: The median cTARC was 989 pg/mL (interquartile range [IQR]: 667-1430 pg/mL). The cTARC levels in children who developed AD were higher than those in children who did not develop AD, and the association strengthened with younger age (median [IQR] at 1 year: 1285 [816-1965] vs. 933 [662-1330] pg/mL, p < 0.01; at 2 years: 1114 [787-1753] vs. 950 [660-1373] pg/mL, p = 0.02). In the multivariate analysis, cTARC was associated with AD, egg white sensitization, food allergy, allergic rhinitis, and Japanese cedar pollen sensitization., Conclusions: cTARC was associated with the development of allergic diseases and allergen sensitization in early childhood. These results suggest that, infantile AD-mediated atopic march starts during fetal life, and this immune status is reflected in the cTARC at birth., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background: Atopic Dermatitis (AD) is a multifactorial cutaneous disorder associated with chronic inflammation of the skin. Growing evidence points to TGF-β/SMAD signaling as a key player in mediating inflammation and the subsequent tissue remodeling, often resulting in fibrosis. This study investigates the role of a core transcription factor involved in TGF-β signaling i.e., SMAD3 genetic variants (rs4147358) in AD predisposition and its association with SMAD3 mRNA expression, serum IgE levels, and sensitization to various allergens in AD patients., Methods: A total of 246 subjects including 134 AD cases and 112 matched healthy controls were genotyped for SMAD3 intronic SNP by PCR-RFLP. mRNA expression of SMAD3 was determined by quantitative Real-Time PCR (qRT-PCR), Vitamin-D levels by chemiluminescence, and total serum IgE levels by ELISA. In-vivo allergy testing was performed for the evaluation of allergic reactions to house dust mites (HDM) and food allergens., Results: A significantly higher frequency of mutant genotype AA (cases: 19.4% vs controls: 8.9%) (OR = 2.8, CI = 1.2 - 6.7, p = 0.01) was observed in AD cases. The mutant allele 'A' also showed a 1.9-fold higher risk for AD compared to the wild allele 'C' indicating that the carriers of the A allele have a higher risk for AD predisposition (OR-1.9, CI = 1.3-2.8, p < 0.001). In addition, quantitative analysis of SMAD3 mRNA in peripheral blood showed 2.8-fold increased expression in AD cases as compared to healthy controls. Stratification analysis revealed the association of the mutant AA genotype with deficient serum Vitamin D levels (p = 0.02) and SMAD3 mRNA overexpression with HDM sensitization (p = 0.03). Furthermore, no significant association of genotypes with SMAD3 mRNA expression was observed., Conclusion: Our study indicates that SMAD3 intronic SNP bears a significant risk of AD development. Moreover, overexpression of SMAD3 mRNA and its association with HDM sensitization highlights the possible role of this gene in AD pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Background: Immediate allergy caused by natto, a popular Japanese food prepared by fermenting soybeans with Bacillus subtilis var. natto, has been reported. Polygamma glutamic acid (PGA) in the sticky substance around natto beans has been reported to be a causative allergen of natto allergy. However, some of our patients with natto allergy were negative for PGA in the skin prick test (SPT). The sticky substance of natto beans contains a subtilisin family serine protease, nattokinase, along with PGA. In this study, we aimed to examine the antigenicity of nattokinase in natto allergy., Methods: Eight patients, who developed symptoms after ingesting natto and positively reacted to natto (seven to the sticky substance in natto and one to the whole natto product) in their SPT, were enrolled in this study. To analyze IgE reactivity, we performed immunoblotting, ELISA, and SPT for natto (bean and sticky substance), and/or PGA, and/or nattokinase and/or cultured B. subtilis var. natto extract., Results: In the SPT, four cases each were PGA-positive and PGA-negative. Immunoblotting of the sera from PGA-negative patients showed a protein band at 30 kDa, which was identified as nattokinase. Three PGA-negative cases, but not three PGA-positive cases, showed a positive reaction to nattokinase in the SPT and had a history of atopic dermatitis. The ELISA for nattokinase revealed a positive reaction of PGA-negative cases and negative reaction of PGA-positive cases in the SPT., Conclusions: We identified a subtilisin family serine protease, nattokinase, as a novel allergen in natto allergy patients unsensitized to PGA., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

The activation of group 2 innate lymphoid cells (ILC2s) is controlled by various tissue-derived factors, including cytokines, whereas T cells respond to foreign antigens. This review discusses the tissue-specific properties of ILC2s in skin and their involvement in human skin diseases. In a steady state, cutaneous ILC2s contribute to tissue homeostasis. In the keratinocytes of patients with atopic dermatitis (AD), the inflammatory cytokine interleukin-33 (IL-33) is overexpressed. ILC2s are stimulated by IL-33-stimulated basophils through IL-4 to produce type 2 cytokines, such as IL-5 and IL-13. According to several studies, ILC2 expression is upregulated in human AD skin lesions, and it is involved in AD pathogenesis. Dupilumab, an antibody against IL-4 receptor α, lowered the number and percentage of ILC2s in the peripheral blood of patients with AD. Cutaneous ILC2s are divided into two subgroups: circulating and skin-resident ILC2s. However, ILC2s are homogeneous cell populations that are highly diverse and plastic, and there is no consensus on the classification that should be used. The variations in the definition for cutaneous ILC2s in different studies make comparisons among studies difficult, and in particular, the weak expression of the IL-33 receptor ST2 in cutaneous ILC2s and its lack of markers have posed a great challenge to researchers. Therefore, further comprehensive analytical studies are warranted., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

OX40 is an important costimulatory molecule for T-cell expansion and survival. Because OX40 is expressed on most T-cell subsets, it is an attractive therapeutic target for a variety of T-cell‒mediated diseases. Clinical trials are already underway for some skin inflammatory diseases. In this review, we present various observations that improve our understanding of how OX40-targeted therapy can be applied for skin inflammatory diseases, such as atopic dermatitis and psoriasis, T helper (Th)2- and Th17-mediated diseases, respectively. The important OX40/OX40L-mediated interaction between T cells and other immune cells is also discussed in terms of skin autoimmune diseases, such as alopecia areata and pemphigus. Regulatory T cells (Tregs) highly express OX40, and the skin harbors a large Treg population; thus, understanding how OX40-targeted treatment acts on Tregs is vital for the development of therapeutic strategies for various skin diseases., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Inborn errors of immunity (IEI) are caused by monogenic variants that affect the host response to bacterial, viral, and fungal pathogens. As such, individuals with IEI often present with severe, recurrent, and life-threatening infections. However, the spectrum of disease due to IEI is very broad and extends to include autoimmunity, malignancy, and atopic diseases such as eczema, atopic dermatitis, and food and environmental allergies. Here, I review IEI that affect cytokine signaling pathways that dysregulate CD4 + T-cell differentiation, resulting in increased T-helper-2 (Th2) cell development, function, and pathogenicity. These are elegant examples of how rare IEI can provide unique insights into more common pathologies such as allergic disease that are impacting the general population at increased frequency., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Atopic dermatitis (AD) is an inflammatory disease driven in part by type 2 helper T (Th2) cytokines and skin barrier disruption alleviating the entry of allergens. Thymic stromal lymphopoietin (TSLP), an epithelial cell‒derived cytokine, is known to aggravate AD symptoms by activating Th2. In addition, regulatory T cells (Tregs) inhibit inflammatory cells such as Th2. However, the relationship between TSLP and Tregs in AD is unclear. A murine dermatitis model was induced by applying oxazolone to the ear skin of mice. Prophylactic and therapeutic responses were analyzed by immunizing mice intranasally with a pneumococcal pep27 mutant (Δpep27 mutant), attenuated strain by reducing the virulence of a pathogen. Intranasal immunization with a pneumococcal pep27 mutant could elicit anti-inflammatory Treg-relevant factors and epithelial barrier genes (loricrin, involucrin, filaggrin, and small proline-rich repeat proteins). Thus, pneumococcal pep27-mutant immunization suppressed epidermal collapse, IgE, TSLP, and upregulation of Th2 expression by upregulating Treg activity. In contrast, Treg inhibition aggravated AD symptoms through the upregulation of TSLP and Th2 and the repression of epithelial barrier function compared with that of the noninhibited pneumococcal Δpep27-mutant group. Taken together, immunization with pneumococcal Δpep27 mutant upregulated Treg and epithelial barrier function and inhibited TSLP and Th2 to relieve AD symptoms., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Eczema patients are commonly immunoglobulin (Ig)E polysensitized. Although atopic dermatitis (AD) phenotypes have been recognized, IgE sensitization patterns based on AD phenotypes have not been well illustrated. We aimed to investigate how eczema phenotypes impact IgE component sensitization patterns., Methods: This birth cohort study investigated a general population in the Tokyo Children's Health, Illness, and Development Study (T-Child Study) until children reached the age of 13 years. Eczema was assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. Allergen component specific IgE antibody titers were measured using a multiplex array ImmunoCAP ISAC., Results: Persistent eczema phenotype until adolescence was strongly associated with allergic march symptoms, such as wheezing and hay fever, and oral allergy symptoms, and IgE component sensitizations of airborne (Japanese cedar, house dust mite, Timothy, cat, and dog) and cross-reactive allergens (Bet v 1 family) compared to early-remission and late-onset eczema. On the other hand, late-onset eczema did not show any strong associations with allergic symptoms and IgE sensitization. Adolescents with persistent eczema have high comorbidity of symptoms of pollen-food allergy syndrome., Conclusions: Early-onset eczema is deeply connected with the later allergic march, and late-onset eczema differs from the phenotype of allergic march. Early-onset eczema characterizing IgE sensitization was likely to be an extrinsic type, and late-onset eczema, which was not related to IgE sensitization, was likely an intrinsic type. Pollen-Food Allergy Syndrome is one of the allergic features in allergic march., (Copyright © 2022 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Purpose: Parental exposures prior to conception might influence asthma and allergy risk in offspring. As occupational exposures are established risk factors for asthma and allergies, we investigated if parental occupational exposures prior to conception cause wheeze and eczema in offspring during the first year of life., Methods: We analysed data of 436 families from an offspring cohort based on a follow-up study of German participants of the International Study of Asthma and Allergies in Childhood (ISAAC). Offspring cohort data was collected between 2009 and 2019. Occupational exposures were based on participants' work histories and measured by a Job-Exposure-Matrix. We used Bayesian logistic regression models for analysis. Inference and confounder selection were based on directed acyclic graphs., Results: In mothers, for both allergic and irritative occupational exposures prior to conception suggestive effects on offspring eczema during the first year of life were found (allergens: odds ratio (OR) 1.22, 95% compatibility interval (CI) 0.92-1.57; irritants: OR 1.36, 95% CI 0.99-1.77), while no relation with wheeze was suggested., Conclusions: Our results suggest that reduction of asthma-related occupational exposures might not only reduce the burden of disease for occupationally induced or aggravated asthma and allergies in employees but also in their children., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic skin diseases can substantially affect a patient's physical, psychologic, and social well-being. Physicians may play a critical role in identifying and managing the psychologic sequelae of the most common chronic skin conditions. Acne, atopic dermatitis, psoriasis, vitiligo, alopecia areata, and hidradenitis suppurativa are chronic dermatologic diseases that put patients at high risk for symptoms of depression, anxiety, and decreased quality of life. Both general and disease-specific scales exist to assess the quality of life in patients with chronic skin disease, the most common being the Dermatology Life Quality Index. The general management approach to the patient with chronic skin disease should incorporate acknowledgment and validation of the patient's struggles; patient education on the potential effect of disease and prognosis; medical management of the dermatologic lesions; coaching on stress management; and psychotherapy. Psychotherapies include talk therapy (eg, cognitive behavioral therapy), arousal-reducing therapies (eg, meditation, relaxation), and behavioral therapies (eg, habit reversal therapy). Improved understanding, identification, and management of the psychiatric and psychologic aspects of the most common chronic skin conditions by dermatologists and other health care providers may positively affect patient outcomes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Atopic dermatitis results in profound changes in the function of the skin that include diminished barrier function and altered production of antimicrobial peptides. Our previous work in a model of allergic skin inflammation identified a defect in the wound healing process that was dependent on IL-4. In this report, we show that allergic skin inflammation results in a dramatic decrease in the presence of the Vγ3+ dendritic epidermal T-cell (DETC) population of γδ T cells in the skin. In mice that express an active signal transducer and activator of transcription 6 in T cells, DETCs are lost early in life. The loss of DETCs is entirely dependent on IL-4 and is recovered with a genetic deficiency of IL-4. Moreover, injection of IL-4 into wild-type mice results in acute loss of the DETC population. A similar loss of DETCs was observed in mice treated topically with MC903. Wounding of skin from Stat6VT-transgenic or MC903-treated mice resulted in decreased production of DETC-dependent cytokines in the skin, coincident with diminished wound closure. Importantly, intradermal injection of the DETC-produced cytokine fibroblast GF 7 rescued the rate of wound closure in mice with allergic skin inflammation. Together, these results suggest that the atopic environment diminishes prohealing T-cell populations in the skin, resulting in attenuated wound healing responses., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of Interest This work was partly funded by Dairy Goat Co-Operative. EC is an employee of Dairy Goat Co-Operative.

Atopic dermatitis is a skin disorder caused by skin dryness and barrier dysfunction, resulting in skin inflammation and chronic itch (or pruritus). The pathogenesis of atopic dermatitis is thought to be initiated by a lowering of the itch threshold due to dry skin. This lowering of the itch threshold is at least partially due to the increase in intraepidermal nerve fibers and sensitization of sensory nerves by interleukin (IL)-33 produced and secreted by keratinocytes. Such skin is easily prone to itch due to mechanical stimuli, such as rubbing of clothing and chemical stimuli from itch mediators. In patients with atopic dermatitis, once itch occurs, further itch is induced by scratching, and the associated scratching breaks down the skin barrier. Disruption of the skin barrier allows entry into the epidermis of external foreign substances, such as allergens derived from house dust mites, leading to an increased induction of type 2 inflammatory responses. As a result, type 2 cytokines IL-4, IL-13, and IL-31 are mainly secreted by Th2 cells, and their action on sensory nerve fibers causes further itch sensitization. These sequences of events are thought to occur simultaneously in patients with atopic dermatitis, leading to a vicious itch-scratch cycle. This vicious cycle becomes a negative spiral that leads to disease burden. Therefore, controlling itch is essential for the treatment of atopic dermatitis. In this review, we summarize and discuss advances in the mechanisms of peripheral itch sensitization in atopic dermatitis, focusing on skin barrier-neuro-immune triadic connectivity., (Copyright © 2022 Japanese Society of Allergology. All rights reserved.)