Atopic dermatitis (AD) is the most common inflammatory skin disease in the industrialized world and has multiple causes. Over the past decade, data from both experimental models and patients have ...highlighted the primary pathogenic role of skin barrier deficiency in patients with AD. Increased access of environmental agents into the skin results in chronic inflammation and contributes to the systemic “atopic (allergic) march.” In addition, persistent skin inflammation further attenuates skin barrier function, resulting in a positive feedback loop between the skin epithelium and the immune system that drives pathology. Understanding the mechanisms of skin barrier maintenance is essential for improving management of AD and limiting downstream atopic manifestations. In this article we review the latest developments in our understanding of the pathomechanisms of skin barrier deficiency, with a particular focus on the formation of the stratum corneum, the outermost layer of the skin, which contributes significantly to skin barrier function.
Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown.
We sought to ...characterize age-related changes in the AD profile.
We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years).
Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P = .873), dendritic cell infiltrates (CD1b+ and FcεRI+, P < .05) decreased with age. TH2 measures (IL5, IL13, CCL13, CCL18, and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with TH2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = −0.24 and r = −0.23, respectively; P < .05). TH22-secreted IL22 expression levels also decreased with age uniquely in patients with AD (P < .05). Expression of TH1-related (IFNG, IL12/23p40, STAT1, and CXCL9; P < .05 for CXCL9) and TH17-related (IL17A and IL20; P < .05 for IL20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin LOR and filaggrin FLG, P < .05), whereas expression of S100As (S100A8, P < .01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P < .05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with TH2 downregulation (CCL26; r = −0.32, P < .1) and TH1 upregulation (IFN-γ; r = 0.48, P < .01) with age.
The adult AD profile varies with age. Although TH1/TH17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in TH2/TH22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD.
Animal studies have suggested that transient receptor potential ion channels and G-protein coupled receptors play important roles in itch transmission. TRPV3 gain-of-function mutations have been ...identified in patients with Olmsted syndrome, which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of protease-activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis, whereas their inhibition attenuated scratching and inflammatory responses in mouse atopic dermatitis models. These results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in atopic dermatitis.
The heterogeneous course, severity, and treatment responses among patients with atopic dermatitis (AD; eczema) highlight the complexity of this multifactorial disease. Prior studies have used ...traditional typing methods on cultivated isolates or sequenced a bacterial marker gene to study the skin microbial communities of AD patients. Shotgun metagenomic sequence analysis provides much greater resolution, elucidating multiple levels of microbial community assembly ranging from kingdom to species and strain-level diversification. We analyzed microbial temporal dynamics from a cohort of pediatric AD patients sampled throughout the disease course. Species-level investigation of AD flares showed greater
predominance in patients with more severe disease and
predominance in patients with less severe disease. At the strain level, metagenomic sequencing analyses demonstrated clonal
strains in more severe patients and heterogeneous
strain communities in all patients. To investigate strain-level biological effects of
, we topically colonized mice with human strains isolated from AD patients and controls. This cutaneous colonization model demonstrated
strain-specific differences in eliciting skin inflammation and immune signatures characteristic of AD patients. Specifically,
isolates from AD patients with more severe flares induced epidermal thickening and expansion of cutaneous T helper 2 (T
2) and T
17 cells. Integrating high-resolution sequencing, culturing, and animal models demonstrated how functional differences of staphylococcal strains may contribute to the complexity of AD disease.
Atopic dermatitis (AD) is a clinically defined, highly pruritic, chronic inflammatory skin disease of children and adults. The diagnosis is made using evaluated clinical criteria. Disease activity is ...best measured with a composite score assessing both objective signs and subjective symptoms, such as SCORAD. The management of AD must consider the clinical and pathogenic variabilities of the disease and also target flare prevention. Basic therapy includes hydrating topical treatment, as well as avoidance of specific and unspecific provocation factors. Anti‐inflammatory treatment of visible skin lesions is based on topical glucocorticosteroids and the topical calcineurin inhibitors tacrolimus and pimecrolimus. Topical calcineurin inhibitors are preferred in sensitive locations. Tacrolimus and mid‐potent steroids are proven for proactive therapy, which is long‐term intermittent anti‐inflammatory therapy of the frequently relapsing skin areas. Systemic anti‐inflammatory or immunosuppressive treatment is indicated for severe refractory cases. Biologicals targeting key mechanisms of the atopic immune response are promising emerging treatment options. Microbial colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R‐blockers) may diminish pruritus, but do not have sufficient effect on lesions. Adjuvant therapy includes UV irradiation, preferably UVA1 or narrow‐band UVB 311 nm. Dietary recommendations should be patient specific and elimination diets should only be advised in case of proven food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress‐induced exacerbations. ‘Eczema school’ educational programmes have been proven to be helpful for children and adults.
IMPORTANCE: Associations between atopic eczema and cancer are unclear, with competing theories that increased immune surveillance decreases cancer risk and that immune stimulation increases cancer ...risk. Establishing baseline cancer risk in people with atopic eczema is important before exploring the association between new biologic drugs for atopic eczema and cancer risk. OBJECTIVE: To investigate whether atopic eczema is associated with cancer. DESIGN, SETTING, AND PARTICIPANTS: Matched cohort studies were conducted from January 2, 1998, to March 31, 2016, in England and from January 1, 1982, to June 30, 2016, in Denmark. We conducted our analyses between July 2018 and July 2019. The setting was English primary care and nationwide Danish data. Participants with atopic eczema (adults only in England and any age in Denmark) were matched on age, sex, and calendar period (as well as primary care practice in England only) to those without atopic eczema. EXPOSURE: Atopic eczema. MAIN OUTCOMES AND MEASURES: Overall cancer risk and risk of specific cancers were compared in people with and without atopic eczema. RESULTS: In England, matched cohorts included 471 970 individuals with atopic eczema (median IQR age, 41.1 24.9-60.7 years; 276 510 58.6% female) and 2 239 775 individuals without atopic eczema (median IQR age, 39.8 25.9-58.4 years; 1 301 074 58.1% female). In Denmark, matched cohorts included 44 945 individuals with atopic eczema (median IQR age, 13.7 1.7-21.1 years; 22 826 50.8% female) and 445 673 individuals without atopic eczema (median IQR age, 13.5 1.7-20.8 years; 226 323 50.8% female). Little evidence was found of associations between atopic eczema and overall cancer (adjusted hazard ratio HR, 1.04; 99% CI, 1.02-1.06 in England and 1.05; 99% CI, 0.95-1.16 in Denmark) or for most specific cancers. However, noncutaneous lymphoma risk was increased in people with atopic eczema in England (adjusted HR, 1.19; 99% CI, 1.07-1.34 for non-Hodgkin lymphoma NHL and 1.48; 99% CI, 1.07-2.04 for Hodgkin lymphoma). Lymphoma risk was increased in people with greater eczema severity vs those without atopic eczema (NHL adjusted HR, 1.06; 99% CI, 0.90-1.25 for mild eczema; 1.24; 99% CI, 1.04-1.48 for moderate eczema; and 2.08; 99% CI, 1.42-3.04 for severe eczema). Danish point estimates also showed increased lymphoma risk in people with moderate to severe eczema compared with those without atopic eczema (minimally adjusted HR, 1.31; 99% CI, 0.76-2.26 for NHL and 1.35; 99% CI, 0.65-2.82 for Hodgkin lymphoma), but the 99% CIs were wide. CONCLUSIONS AND RELEVANCE: The findings from 2 large population-based studies performed in different settings do not support associations between atopic eczema and most cancers. However, an association was observed between atopic eczema and lymphoma, particularly NHL, that increased with eczema severity. This finding warrants further study as new immunomodulatory systemic therapeutics are brought to market that may alter cancer risk.
Atopic dermatitis is the most prevalent chronic inflammatory skin condition globally. The burden of atopic dermatitis on children and adults is extensive and there is also significant impact on the ...lives of patient caregivers and family members. It is important to be able to measure this impact to inform clinical decisions and to plan appropriate patient and carer support. The current impact of atopic dermatitis on children and adults can be measured using several different quality of life questionnaires: the most frequently used are the Dermatology Quality of Life (DLQI), Children's Dermatology Quality of Life and Infants Dermatology Quality of Life. The impact on partners and family can be measured using several atopic dermatitis specific questionnaires or the Family DLQI or the generic Family Reported Outcome Measure, FROM-16.
Atopic dermatitis (AD) is a chronic, pruritic, inflammatory dermatosis that affects up to 25% of children and 2% to 3% of adults. This guideline addresses important clinical questions that arise in ...the management and care of AD, providing updated and expanded recommendations based on the available evidence. In this first of 4 sections, methods for the diagnosis and monitoring of disease, outcomes measures for assessment, and common clinical associations that affect patients with AD are discussed. Known risk factors for the development of disease are also reviewed.
Background Exposure to food allergens through a disrupted skin barrier has been recognized as a potential factor in the increasing prevalence of food allergy. Objective We sought to test the ...immunologic mechanisms by which epicutaneous sensitization to food allergens predisposes to intestinal food allergy. Methods Mice were epicutaneously sensitized with ovalbumin or peanut on an atopic dermatitis–like skin lesion, followed by intragastric antigen challenge. Antigen-specific serum IgE levels and TH 2 cytokine responses were measured by ELISA. Expression of type 2 cytokines and mast cell proteases in the intestine were measured by using real-time PCR. Accumulation of basophils in the skin and mast cells in the intestine was examined by using flow cytometry. In vivo basophil depletion was achieved by using diphtheria toxin treatment of Baso-DTR mice. For cell-transfer studies, the basophil population was expanded in vivo by means of hydrodynamic tail vein injection of thymic stromal lymphopoietin (TSLP) cDNA plasmid. Results Sensitization to food allergens through an atopic dermatitis–like skin lesion is associated with an expansion of TSLP-elicited basophils in the skin that promote antigen-specific TH 2 cytokine responses, increased antigen-specific serum IgE levels, and accumulation of mast cells in the intestine, promoting the development of intestinal food allergy. Critically, disruption of TSLP responses or depletion of basophils reduced the susceptibility to intestinal food allergy, whereas transfer of TSLP-elicited basophils into intact skin promoted disease. Conclusion Epicutaneous sensitization on a disrupted skin barrier is associated with accumulation of TSLP-elicited basophils, which are necessary and sufficient to promote antigen-induced intestinal food allergy.
Background Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight ...junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway. Objective We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1). Methods Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina's BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD. Results We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with TH 2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations. Conclusion Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.
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