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Asthma is the most common chronic condition in children and the third leading cause of hospitalization in pediatrics. The genome-wide association study catalog reports 140 studies with genome-wide significance. A polygenic risk score (PRS) with predictive value across ancestries has not been evaluated for this important trait.This study aimed to train and validate a PRS relying on genetic determinants for asthma to provide predictions for disease occurrence in pediatric cohorts of diverse ancestries.This study applied a Bayesian regression framework method using the Trans-National Asthma Genetic Consortium genome-wide association study summary statistics to derive a multiancestral PRS score, used one Electronic Medical Records and Genomics (eMERGE) cohort as a training set, used a second independent eMERGE cohort to validate the score, and used the UK Biobank data to replicate the findings. A phenome-wide association study was performed using the PRS to identify shared genetic etiology with other phenotypes.The multiancestral asthma PRS was associated with asthma in the 2 pediatric validation datasets. Overall, the multiancestral asthma PRS has an area under the curve (AUC) of 0.70 (95% CI, 0.69-0.72) in the pediatric validation 1 and AUC of 0.66 (0.65-0.66) in the pediatric validation 2 datasets. We found significant discrimination across pediatric subcohorts of European (AUC, 95% CI, 0.60 and 0.66), African (AUC, 95% CI, 0.61 and 0.66), admixed American (AUC, 0.64 and 0.70), Southeast Asian (AUC, 0.65), and East Asian (AUC, 0.73) ancestry. Pediatric participants with the top 5% PRS had 2.80 to 5.82 increased odds of asthma compared to the bottom 5% across the training, validation 1, and validation 2 cohorts when adjusted for ancestry. Phenome-wide association study analysis confirmed the strong association of the identified PRS with asthma (odds ratio, 2.71, PsubFDR/sub = 3.71 × 10sup-65/sup) and related phenotypes.A multiancestral PRS for asthma based on Bayesian posterior genomic effect sizes identifies increased odds of pediatric asthma.

Citrullination, the post-translational modification of arginine residues, is catalyzed by the four catalytically active peptidylarginine deiminase (PAD or PADI) isozymes and alters charge to affect target protein structure and function. PADs were initially characterized in rodent uteri and, since then, have been described in other female tissues including ovaries, breast, and the lactotrope and gonadotrope cells of the anterior pituitary gland. In these tissues and cells, estrogen robustly stimulates PAD expression resulting in changes in levels over the course of the female reproductive cycle. The best-characterized targets for PADs are arginine residues in histone tails, which, when citrullinated, alter chromatin structure and gene expression. Methodological advances have allowed for the identification of tissue-specific citrullinomes, which reveal that PADs citrullinate a wide range of enzymes and structural proteins to alter cell function. In contrast to their important physiological roles, PADs and citrullinated proteins are also involved in several female-specific diseases including autoimmune disorders and reproductive cancers. Herein, we review current knowledge regarding PAD expression and function and highlight the role of protein citrullination in both normal female reproductive tissues and associated diseases.

Peptidylarginine deiminases (PAD) enzymes were initially characterized in uteri, but since then little research has examined their function in this tissue. PADs post-translationally convert arginine residues in target proteins to citrulline and are highly expressed in ovine caruncle epithelia and ovine uterine luminal epithelial (OLE)-derived cell line. Progesterone (P4) not only maintains the uterine epithelia but also regulates the expression of endometrial genes that code for proteins that comprise the histotroph and are critical during early pregnancy. Given this, we tested whether P4 stimulates PAD-catalyzed histone citrullination to epigenetically regulate expression of the histotroph gene insulin-like growth factor binding protein 1 (IGFBP1) in OLE cells. 100 nM P4 significantly increases IGFBP1 mRNA expression; however, this increase is attenuated by pre-treating OLE cells with 100 nM progesterone receptor antagonist RU486 or 2 µM of a pan-PAD inhibitor. P4 treatment of OLE cells also stimulates citrullination of histone H3 arginine residues 2, 8, and 17 leading to enrichment of the ovine IGFBP1 gene promoter. Since PAD2 nuclear translocation and catalytic activity require calcium, we next investigated whether P4 triggers calcium influx in OLE cells. OLE cells were pre-treated with 10 nM nicardipine, an L-type calcium channel blocker, followed by stimulation with P4. Using fura2-AM imaging, we found that P4 initiates a rapid calcium influx through L-type calcium channels in OLE cells. Furthermore, this influx is necessary for PAD2 nuclear translocation and resulting citrullination of histone H3 arginine residues 2, 8, and 17. Our work suggests that P4 stimulates rapid calcium influx through L-type calcium channels initiating PAD-catalyzed histone citrullination and an increase in IGFBP1 expression.

Objective To discuss the skin microbiome modulates immunity by interactions between skin immunology with keratinocytes to combat pathogens. Allergic disorders are classified by immunoglobulin E sensitivity and aberrant TH2 cell responses, and an increasing number of studies have described the associations with skin microbiome fluctuations. In this review, we discuss commensal-epidermal homeostasis and its influence on allergic disease. Data Sources All included references were obtained from the PubMed database. Study Selections Studies addressing relevant aspects of commensal-epidermal homeostasis, skin microbiome dysbiosis, microbiome-targeted therapeutics, and prevention in allergy were included. Results Homeostasis between the commensal microbiome and the epidermis is important in protecting against allergic disease. Commensals promote antiallergic TH1 and TH17 immunophenotypes within the skin and induce keratinocytes to secrete antimicrobial peptides and alarmins that enhance barrier function and antagonize proallergic organisms. Perturbations in this homeostasis, however, is associated with allergic disease development. Atopic dermatitis is associated with decreases in skin commensals and increases in the pathogen, Staphylococcus aureus. Fluctuations in the skin microbiome contributes to decreased barrier dysfunction, allergic sensitization, and TH2 cytokine secretion. Little is known about how the skin microbiome affects food allergy, allergic rhinitis, and asthma, and it is poorly understood how cutaneous inflammation influences systemic allergic responses. Therapies are targeted toward maintenance of the skin barrier, replacement of healthy commensals, and anti-TH2 biologic therapy. Conclusion Although the effects of commensal-epidermal homeostasis on allergy within the skin are becoming increasingly clear, future studies are necessary to assess its effects on extracutaneous allergic disorders and explore potential therapeutics targeting the skin microbiome.

The caspase activation and recruitment domain-coiled-coil (CARD-CC) family of proteins-CARD9, CARD10, CARD11, and CARD14-is collectively expressed across nearly all tissues of the body and is a crucial mediator of immunologic signaling as part of the CARD-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (CBM) complex. Dysfunction or dysregulation of CBM proteins has been linked to numerous clinical manifestations known as "CBM-opathies." The CBM-opathy spectrum encompasses diseases ranging from mucocutaneous fungal infections and psoriasis to combined immunodeficiency and lymphoproliferative diseases; however, there is accumulating evidence that the CARD-CC family members also contribute to the pathogenesis and progression of allergic inflammation and allergic diseases. Here, we review the 4 CARD-CC paralogs, as well as B-cell lymphoma/leukemia 10 and mucosa-associated lymphoid tissue lymphoma translocation protein 1, and their individual and collective roles in the pathogenesis and progression of allergic inflammation and 4 major allergic diseases (allergic asthma, atopic dermatitis, food allergy, and allergic rhinitis).

BACKGROUND: In addition to its involvement in both the innate and adaptive immune systems, vitamin D has also been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE: To explore the role of circulating vitamin D levels in allergic sensitization. METHODS: Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N=323) enrolled in the Mechanisms of Progression from AD to Asthma in Children (MPAACH) cohort, a prospective early-life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in keratinocytes was measured by quantitative PCR. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS: Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs. 32.9 ng/ml; p < 0.001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels < 27.2 ng/ml (Rho = −0.45; p=0.026). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels ≥ 27.2 ng/ml. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION: Despite lower vitamin D levels in Black participants, sensitization load was associated with non-lesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.

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. Methods A genome-wide association study of quantified skin FLG expression in lesional and baseline non(never)-lesional skin of children with AD in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort was conducted. Clustered regularly interspaced short palindromic repeat approaches were used to create isogenic human keratinocytes differing only at the identified variant rs11652075, and caspase recruitment domain family member 14 (CARD14)-deficient keratinocytes for subsequent mechanistic studies. Results The genome-wide association study identified the CARD14 rs11652075 variant to be associated with FLG expression in non(never)-lesional skin of children with AD. Rs11652075 is a CARD14 expression quantitative trait locus in human skin and primary human keratinocytes. The T variant destroys a functional cytosine-phosphate-guanine site, resulting in reduced cytosine-phosphate-guanine methylation at this site (but not neighboring sites) in TT and CT compared with CC primary human keratinocytes and Mechanisms of Progression of Atopic Dermatitis to Asthma in Children children's skin samples, and rs11652075 increases CARD14 expression in an allele-specific fashion. Furthermore, studies in clustered regularly interspaced short palindromic repeat-generated CC and TT isogenic keratinocytes, as well as CARD14-haplosufficient and deficient keratinocytes, reveal that IL-17A regulates FLG expression via CARD14, and that the underlying mechanisms are dependent on the rs11652075 genotype. Conclusions Our study identifies CARD14 as a novel regulator of FLG expression in the skin of children with AD. Furthermore, CARD14 regulates skin FLG homeostasis in an rs11652075-dependent fashion.

To discuss the skin microbiome modulates immunity by interactions between skin immunology with keratinocytes to combat pathogens. Allergic disorders are classified by immunoglobulin E sensitivity and aberrant TAll included references were obtained from the PubMed database.Studies addressing relevant aspects of commensal-epidermal homeostasis, skin microbiome dysbiosis, microbiome-targeted therapeutics, and prevention in allergy were included.Homeostasis between the commensal microbiome and the epidermis is important in protecting against allergic disease. Commensals promote antiallergic TAlthough the effects of commensal-epidermal homeostasis on allergy within the skin are becoming increasingly clear, future studies are necessary to assess its effects on extracutaneous allergic disorders and explore potential therapeutics targeting the skin microbiome.

Climate models predict widespread increases in both drought intensity and duration in the next decades. Although water deficiency is a significant determinant of plant survival, limited understanding of plant responses to extreme drought impedes forecasts of both forest and crop productivity under increasing aridity. Drought induces a suite of physiological responses; however, we lack an accurate mechanistic description of plant response to lethal drought that would improve predictive understanding of mortality under altered climate conditions. Here, proxies for leaf cellular damage, chlorophyll a fluorescence, and electrolyte leakage were directly associated with failure to recover from drought upon rewatering in Brassicarapa (genotype R500) and thus define the exact timing of drought-induced death. We validated our results using a second genotype (imb211) that differs substantially in life history traits. Our study demonstrates that whereas changes in carbon dynamics and water transport are critical indicators of drought stress, they can be unrelated to visible metrics of mortality, i.e. lack of meristematic activity and regrowth. In contrast, membrane failure at the cellular scale is the most proximate cause of death. This hypothesis was corroborated in two gymnosperms (Picea engelmannii and Pinus contorta) that experienced lethal water stress in the field and in laboratory conditions. We suggest that measurement of chlorophyll a fluorescence can be used to operationally define plant death arising from drought, and improved plant characterization can enhance surface model predictions of drought mortality and its consequences to ecosystem services at a global scale.

Atopic dermatitis (AD) is a common chronic inflammatory disease associated with skin barrier dysfunction. AD often precedes the development of atopic co-morbidities, including food allergy, asthma and allergic rhinitis. The contributions of natural killer (NK) cells to pathogenesis of AD and progression to allergic disease are unclear. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples collected from n=82 children participating in the Mechanisms of Progression of Atopic Dermatitis to Asthma (MPAACH) study, a cohort of toddlers with AD. The children underwent skin prick testing to 11 aeroallergens and 6 foods, and wheezing was defined as one or more episodes of wheezing in the past 12 months. We used flow cytometry to evaluate the phenotype of NK cells in patient PBMC from MPAACH subjects. Our analyses revealed that CD56brightNK cells derived from sensitized children expressed significantly less NKG2D (73.8 ± 3.0 % versus 82.3 ± 2.7 %, respectively, p=0.020) and more TIM-3 (440 ± 462 versus 353 ± 391 median fluorescence intensity, respectively, p=0.085) compared to non-sensitized children. Increased expression of TIM-3 on CD56neg NK cells was also associated with wheezing (47.5 ± 0.51 % versus 19.2 ± 0.40 %, p=0.020). Collectively, these observations suggest that changes within the NK-cell repertoire may promote progressive development of AD and atopic co-morbidities in early life.

Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas are unknown. To begin to address these issues, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4, and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA sequencing and chromatin immunoprecipitation (ChIP) studies show that the expression of microRNAs (miRNAs) let-7c-2, 23b, and 29c is suppressed by histone citrullination. Our studies demonstrate that these miRNAs directly target the mRNA of the oncogenes encoding HMGA, insulin-like growth factor 1 (IGF-1), and N-MYC, which are highly implicated in human prolactinoma/somatoprolactinoma pathogenesis. Our results are the first to define a direct role for PAD-catalyzed histone citrullination in miRNA expression, which may underlie the etiology of prolactinoma and somatoprolactinoma tumors through regulation of oncogene expression.