B cell repertoire in children with skin barrier dysfunction supports altered IgE maturation associated with allergic food sensitization.

The skin is a major immune organ and skin barrier dysfunction is a major risk factor for the development of the inappropriate immune response seen in allergic disease. Skin barrier disruption alters the landscape of antigens experienced by the immune system and the downstream impacts on the antibody repertoire remain poorly characterized, particularly for the IgE isotype responsible for allergic specificity and in early life, when allergic disease is developing. In this study, we sequenced antibody gene repertoires from a large and well-characterized cohort of children with atopic dermatitis and found that food sensitization was associated with lower mutation frequencies in the IgE compartment.

Treatment by biomarker-informed endotype vs guideline care in children with difficult-to-treat asthma.

Background: Asthma is heterogeneous, contributing to difficulty in disease management.

Objective: To develop a biomarker-informed treatment model for difficult-to-treat (DTT) asthma and conduct a pilot feasibility study.

Methods: School-aged children (n = 21) with DTT asthma were enrolled and completed 3 medical visits (V1-V3).

Skin depletion of Kif3a resembles the pediatric atopic dermatitis transcriptome profile.

Skin deficiency of kinesin family member 3A causes disrupted skin barrier function and promotes development of atopic dermatitis (AD). It is not known how well Kif3aK14∆/∆ mice approximate the human AD transcriptome. To determine the skin transcriptomic profile of Kif3aK14∆/∆ mice and compare it with other murine AD models and human AD, we performed RNA-seq of full-thickness skin and epidermis from 3- and 8-week-old Kif3aK14∆/∆ mice and compared the differentially expressed genes (DEGs) with transcriptomic datasets from mite-induced NC/Nga, flaky tail (Tmem79ma/ma Flgft/ft), and filaggrin-mutant (Flgft/ft) mice, as well as human AD transcriptome datasets including meta-analysis derived atopic dermatitis [MADAD] and the pediatric atopic dermatitis [PAD].

Longitudinal atopic dermatitis endotypes: An atopic march paradigm that includes Black children.

Background: The atopic march has been studied mostly in White populations, biasing our current paradigms.

Objective: We sought to define the atopic march in Black and White children and explore mechanisms for racial differences.

Methods: Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (n = 601), we assessed longitudinal sensitization, food allergy (FA), allergic rhinitis, risk of asthma development (through the Pediatric Asthma Risk Score), Scoring for Atopic Dermatitis (SCORAD), transepidermal water loss, skin filaggrin (FLG) expression, exposures, and genetic heritability to define AD progression endotypes in Black and White children.

Novel role for caspase recruitment domain family member 14 and its genetic variant rs11652075 in skin filaggrin homeostasis.

Background: Low epidermal filaggrin (FLG) is a risk factor for atopic dermatitis (AD) and allergic comorbidity. FLG mutations do not fully explain the variation in epidermal FLG levels, highlighting that other genetic loci may also regulate FLG expression.

Objective: We sought to identify genetic loci that regulate FLG expression and elucidate their functional and mechanistic consequences.

Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk.

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3a mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD.

Biofilm propensity of Staphylococcus aureus skin isolates is associated with increased atopic dermatitis severity and barrier dysfunction in the MPAACH pediatric cohort.

Background: Atopic dermatitis (AD) patients are often colonized with Staphylococcus aureus, and staphylococcal biofilms have been reported on adult AD skin lesions. The commensal S epidermidis can antagonize S aureus, although its role in AD is unclear. We sought to characterize S aureus and S epidermidis colonization and biofilm propensity and determine their associations with AD severity, barrier function, and epidermal gene expression in the first US early-life cohort of children with AD, the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH).

Simultaneous skin biome and keratinocyte genomic capture reveals microbiome differences by depth of sampling.

Novel skin tape strip method allows for simultaneous collection of the skin microbiome and underlying host DNA and RNA, and reveals that microbial ecology is dependent on the depth of sampling.

Events in Normal Skin Promote Early-Life Atopic Dermatitis-The MPAACH Cohort.

Background: Nonlesional skin in atopic dermatitis (AD) is abnormal, but the pathobiology of lesional and nonlesional skin and the definition of endotypes are poorly understood.

Objective: To define lesional and nonlesional endotypes of AD by building the first US-based early-life prospective cohort of children with AD, the Mechanisms of Progression from AD to Asthma in Children cohort.

Methods: We assessed lesional and nonlesional skin transepidermal water loss, filaggrin (FLG) and alarmin (S100A8, S100A9) expression, staphylococcal colonization, and patterns of aeroallergen and food sensitization to define nonlesional and lesional phenotypes and endotypes.

Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs.

Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how these signals are interpreted in the genome is poorly understood. Here we identified the transcriptomes of foregut and hindgut progenitors, which are conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/β-catenin acts as a genome-wide toggle between foregut and hindgut programs.

Structure of neuroblastoma suppressor of tumorigenicity 1 (NBL1): insights for the functional variability across bone morphogenetic protein (BMP) antagonists.

Bone morphogenetic proteins (BMPs) are antagonized through the action of numerous extracellular protein antagonists, including members from the differential screening-selected gene aberrative in neuroblastoma (DAN) family. In vivo, misregulation of the balance between BMP signaling and DAN inhibition can lead to numerous disease states, including cancer, kidney nephropathy, and pulmonary arterial hypertension. Despite this importance, very little information is available describing how DAN family proteins effectively inhibit BMP ligands.