Mutation of the Glucosinolate Biosynthesis Enzyme Cytochrome P450 83A1 Monooxygenase Increases Camalexin Accumulation and Powdery Mildew Resistance

Small secondary metabolites, including glucosinolates and the major phytoalexin camalexin, play important roles in immunity in Arabidopsis thaliana. We isolated an Arabidopsis mutant with increased resistance to the powdery mildew fungus Golovinomyces cichoracearum and identified a mutation in the gene encoding cytochrome P450 83A1 monooxygenase (CYP83A1), which functions in glucosinolate biosynthesis. The cyp83a1-3 mutant exhibited enhanced defense responses to G. cichoracearum and double mutant analysis showed that this enhanced resistance requires NPR1, EDS1, and PAD4, but not SID2 or EDS5. In cyp83a1-3 mutants, the expression of genes related to camalexin synthesis increased upon G. cichoracearum infection. Significantly, the cyp83a1-3 mutant also accumulated higher levels of camalexin. Decreasing camalexin levels by mutation of the camalexin synthetase gene PAD3 or the camalexin synthesis regulator AtWRKY33 compromised the powdery mildew resistance in these mutants. Consistent with these observations, overexpression of PAD3 increased camalexin levels and enhanced resistance to G. cichoracearum. Taken together, our data indicate that accumulation of higher levels of camalexin contributes to increased resistance to powdery mildew

Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth

Mutation of the glucosinolate biosynthesis enzyme cytochrome P450 83A1 monooxygenase increases camalexin accumulation and powdery mildew resistance

Small secondary metabolites, including glucosinolates and the major phytoalexin camalexin, play important roles in immunity in Arabidopsis thaliana. We isolated an Arabidopsis mutant with increased resistance to the powdery mildew fungus Golovinomyces cichoracearum and identified a mutation in the gene encoding cytochrome P450 83A1 monooxygenase (CYP83A1), which functions in glucosinolate biosynthesis. The cyp83a1-3 mutant exhibited enhanced defense responses to G. cichoracearum and double mutant analysis showed that this enhanced resistance requires NPR1, EDS1, and PAD4, but not SID2 or EDS5. In cyp83a1-3 mutants, the expression of genes related to camalexin synthesis increased upon G. cichoracearum infection. Significantly, the cyp83a1-3 mutant also accumulated higher levels of camalexin. Decreasing camalexin levels by mutation of the camalexin synthetase gene PAD3 or the camalexin synthesis regulator AtWRKY33 compromised the powdery mildew resistance in these mutants. Consistent with these observations, overexpression of PAD3 increased camalexin levels and enhanced resistance to G. cichoracearum. Taken together, our data indicate that accumulation of higher levels of camalexin contributes to increased resistance to powdery mildew

Ovomucoid specific immunoglobulin E as a predictor of tolerance to cooked egg

Background: Ovomucoid is the dominant allergen in hen's egg. Although several studies evaluated the utility of ovomucoid specific immunoglobulin E (sIgE) levels in predicting baked (e.g., muffin or cupcake) or raw egg food challenge outcomes, studies that evaluated ovomucoid sIgE as a predictor of cooked egg (e.g., scrambled or hard boiled) challenge outcomes are limited. Objective: To determine the relation of ovomucoid sIgE levels with cooked egg food challenge outcomes. Methods: A retrospective review of 44 children who underwent cooked egg food challenge and who had the ovomucoid sIgE level measured. Results: Thirty-six of 44 children (81.8%) passed cooked egg challenge. The ovomucoid sIgE level predicted cooked egg challenge outcome (passed median, <0.35 kU/L [range, <0.35–0.64 kU/L]; failed median, 0.40 kU/L [range, <0.35–3.13 kU/L]; p = 0.004). Ovomucoid sIgE levels correlated with egg white (EW) sIgE levels (Spearman correlation coefficient, 0.588; p < 0.001). Receiver operating characteristic curve analysis of ovomucoid and EW sIgE demonstrated areas under the curve of 0.711 and 0.766, respectively. No significant difference was observed among those immunologic parameters in their abilities to predict cooked egg challenge outcome (p = 0.559). Conclusion: The ovomucoid sIgE level may be helpful in predicting cooked egg challenge outcomes. However, our study did not support a role for ovomucoid sIgE replacing EW sIgE testing in evaluating egg allergy

The COVID-19 Pandemic and Mental Health-Related School-Nurse Visits in U.S. Schools

OBJECTIVES: No studies have examined school-nurse visits related to mental health (MH) during the COVID-19 pandemic. We examined changes in the rate of MH-related school-nurse visits before and during the COVID-19 pandemic. METHODS: We analyzed school-nurse visit data (n=3,445,240) for subjects Grade K-12 in U.S. public schools using electronic health record software (SchoolCare, Ramsey, NJ). Data between January 1-December 31 in 2019 (pre-COVID-19 pandemic) vs. January 1-December 31 in 2020 (during COVID-19 pandemic) were compared. For each year, total visits to a school-nurse were calculated for general MH, anxiety, and self-harm. The exposure was number of school-nurse visits in each time period (2019 vs. 2020). The main outcome was change in the rate of general MH, anxiety, and self-harm visits in 2019 vs. 2020. RESULTS: There were 2,302,239 total school-nurse visits in 2019 vs. 1,143,001 in 2020. During the COVID-19 pandemic, the rate of visits for general MH increased by 30% (4.7 to 6.1 per 10,000 visits, 95%CI [18%,43%]; p\u3c0.001), and visits for anxiety increased by 25% (24.8 to 31 per 10,000 visits, 95%CI [20%,30%]; p\u3c0.001). There was no significant difference in self-harm visits across all ages during the COVID-19 pandemic. CONCLUSIONS: Our study found a significant increase in the rate of school-nurse visits for MH and anxiety during the COVID-19 pandemic, suggesting the pediatric population is at-risk for increased negative MH-effects associated with the pandemic and highlights a critical role of school-nurses in identifying youth with potential MH-needs

The Development of Age-Based Food Allergy Educational Handouts for Caregivers and Patients-A Work Group Report of the AAAAI Adverse Reactions to Foods Committee

BACKGROUND: Food allergy education is an ongoing process that must address unique safety concerns and psychosocial challenges at each developmental stage. Families require reliable information that is targeted to specific developmental stages to support the integration of food allergy management into daily life. OBJECTIVE: The purpose of this project was to develop age-specific, evidence-based patient education handouts with practical recommendations for managing and coping with food allergies at different developmental stages. METHODS: Handout content was based on: (1) practice guidelines for food allergy management; (2) literature addressing psychosocial and educational needs of patients with food allergy and their caregivers; and (3) clinical experience of the project team. Fifty-seven caregivers of patients (aged 0-21 years) with food allergy and 2 young adults with food allergy reviewed a draft of the handouts and completed an online survey to assess handout acceptability and usability and identify areas for improvement. Handouts were revised based on participant feedback. RESULTS: The majority of participants (79%) rated the amount of information in the age-specific handouts as just right, versus not enough (9%) or too much information (12%). Sixty-three percent reported that they would be very likely to use the handouts as a resource and 35% somewhat likely. Almost all participants (88%-100% by item) agreed that the handouts used elements of plain language writing and clear communication. CONCLUSION: Caregivers rated the age-based food allergy education handouts as understandable and useful. We anticipate that these handouts could be used during health care visits and directly accessed online by families

Atopic dermatitis mediates the association between an IL4RA variant and food allergy in school-aged children

BACKGROUND: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests. OBJECTIVE: To test the hypothesis that AD mediates the relationship between an interleukin-4 receptor alpha chain gene (IL4RA) variant, the IL4Rα-R576 polymorphism, and FA. METHODS: 433 children with asthma enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA allele. Surveys were administered to determine FA, AD and associated allergic responses. Mediation analysis was performed adjusting for race and ethnicity, age, gender, and household income. Multivariate models were used to determine the association between genotype and FA severity. RESULTS: AD was reported in 193 (45%) and FA in 80 children (19%). Each risk allele increased odds of AD 1.39-fold ([1.03 - 1.87], P = 0.03), and AD increased odds of FA 3.67-fold ([2.05 - 6.57], P \u3c 0.01). There was an indirect effect of genotype, mediated by AD, predicting FA; each risk allele increased the odds of FA by 1.13 (OR [95% CI]: Q/R = 1.13 [1.02 - 1.24], R/R = 1.28 [1.04 - 1.51]; P = \u3c0.01). Each risk allele increased the odds of severe FA symptoms 2.68-fold ([1.26 - 5.71], P = 0.01). CONCLUSION: In a cohort of asthmatic children, AD is part of the causal pathway between an IL4RA variant and FA. This variant is associated with increased risk of severe FA reactions. Addressing AD in children with an IL4RA polymorphism may modulate the risk of FA

A Slice of Food Protein-Induced Enterocolitis Syndrome (FPIES): Insights from 441 Children with FPIES as Provided by Caregivers in the International FPIES Association

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated gastrointestinal food allergy. There is little known about the demographic characteristics, food triggers, and risk factors for FPIES. OBJECTIVE: To characterize the demographic characteristics, food triggers, risk factors, and management in children with FPIES. METHODS: We retrospectively analyzed surveys completed by 410 caregiver-members of the International FPIES Association, both at a conference for families affected by FPIES and online. RESULTS: Most of the children were female (50.7%), white (86.2%), and atopic (54.8%), with a median age of 2 years (ranging from 2 months to 19 years). The most common food groups avoided were grains (60.0%), cow\u27s milk (52.4%), vegetables (42.7%), and fruits (38.0%). Avocado was the most commonly avoided fruit. Avoiding avocado was associated with increased likelihood of avoiding banana (P \u3c .001). Of these children, 69.4% avoided at least 2 food groups because of FPIES, and 20.3% had a first-degree relative with FPIES. Having a first-degree relative with FPIES was associated with increased likelihood of avoiding multiple food groups (P = .035). CONCLUSIONS: The most common food group avoided was grains, consistent with recent literature. Avocado avoidance was higher than previously reported, and this is the first report of an association between avocado and banana avoidance in FPIES. Avoiding multiple food groups because of FPIES was more common than previously reported. A large proportion of children in our cohort had first-degree relatives with FPIES, and, furthermore, having a first-degree relative with FPIES was significantly associated with the affected child avoiding multiple food groups