Anne Marie Singh

Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.

The Future of Biologics: Applications for Food Allergy

Allergic diseases affect millions worldwide, with growing evidence of an increase in allergy occurrence over the past few decades. Current treatments for allergy include corticosteroids to reduce inflammation and allergen immunotherapy; however, some subjects experience treatment-resistant inflammation or adverse reactions to these treatments, and there are currently no approved therapeutics for the treatment of food allergy. There is a dire need for new therapeutic approaches for patients with poorly controlled atopic diseases and a need to improve the safety and effectiveness of allergen immunotherapy. Improved understanding of allergy through animal models and clinical trials has unveiled potential targets for new therapies, leading to the development of several biologics to treat allergic diseases. This review focuses on the mechanisms that contribute to allergy, with an emphasis on future targets for biologics for the treatment of food allergy. These biologics include immunotherapy with novel anti-IgE antibodies and analogs, small-molecule inhibitors of cell signaling, anti-type 2 cytokine mAbs, and TH1-promoting adjuvants.

Natural History of Food-Triggered Atopic Dermatitis and Development of Immediate Reactions in Children

BACKGROUND Case reports suggest that children with food-triggered atopic dermatitis (AD) on elimination diets may develop immediate reactions on accidental ingestion or reintroduction of an avoided food. OBJECTIVE The objective of this study was to systematically study the incidence and risk factors associated with these immediate reactions. METHODS A retrospective chart review of 298 patients presenting to a tertiary-care allergy-immunology clinic based on concern for food-triggered AD was performed. Data regarding triggering foods, laboratory testing, and clinical reactions were collected prospectively from the initial visit. Food-triggered AD was diagnosed by an allergist-immunologist with clinical evaluation and laboratory testing. We identified immediate reactions as any reaction to a food for which there was evidence of sIgE and for which patients developed timely allergic signs and symptoms. Differences between children with and without new immediate reactions were determined by a Mann-Whitney, χ(2), or Fishers exact test as appropriate. RESULTS A total of 19% of patients with food-triggered AD and no previous history of immediate reactions developed new immediate food reactions after initiation of an elimination diet. Seventy percent of reactions were cutaneous but 30% were anaphylaxis. Cows milk and egg were the most common foods causing immediate-type reactions. Avoidance of a food was associated with increased risk of developing immediate reactions to that food (P < .01). Risk was not related to specific IgE level nor a specific food. CONCLUSION A significant number of patients with food-triggered AD may develop immediate-type reactions. Strict elimination diets need to be thoughtfully prescribed as they may lead to decreased oral tolerance.

Naturally occurring tolerance acquisition to foods in previously allergic children is characterized by antigen specificity and associated with increased subsets of regulatory T cells.

Food allergy affects approximately 6–8% of children, and increasing in prevalence. Some children naturally outgrow their food allergy without intervention, but the mechanisms by which this occurs remain poorly understood. We sought to investigate the role of regulatory T cells in the development of naturally acquired tolerance.

Gut Microbiome and the Development of Food Allergy and Allergic Disease

The impact of gut microbiome on human development, nutritional needs, and disease has become evident with advances in the ability to study these complex communities of microorganisms, and there is growing appreciation for the role of the microbiome in immune regulation. Several studies have examined associations between changes in the commensal microbiota and the development of asthma, allergic rhinitis, and asthma, but far less have evaluated the impact of the microbiome on the development of food allergy. This article reviews the human gastrointestinal microbiome, focusing on the theory and evidence for its role in the development of IgE-mediated food allergy and other allergic diseases.

Inhaled corticosteroid use is associated with increased circulating T regulatory cells in children with asthma

BackgroundT regulatory (Treg) cells are important in balancing immune responses and dysregulation of Treg cells has been implicated in the pathogenesis of multiple disease states including asthma. In this study, our primary aim was to determine Treg cell frequency in the peripheral blood of children with and without asthma. The secondary aim was to explore the association between Treg cell frequency with allergen sensitization, disease severity and medication use.MethodsPeripheral blood mononuclear cells from healthy control subjects (N = 93) and asthmatic children of varying disease severity (N = 66) were characterized by multi-parameter flow cytometry.ResultsOur findings demonstrate that children with asthma had a significantly increased frequency of Treg cells compared to children without asthma. Using a multivariate model, increased Treg cell frequency in children with asthma was most directly associated with inhaled corticosteroid use, and not asthma severity, allergic sensitization, or atopic status of the asthma.ConclusionWe conclude that low dose, local airway administration of corticosteroids is sufficient to impact the frequency of Treg cells in the peripheral blood. These data highlight the importance of considering medication exposure when studying Treg cells and suggest inhaled corticosteroid use in asthmatics may improve disease control through increased Treg cell frequency.

IgE‐associated food allergy alters the presentation of paediatric eosinophilic esophagitis

Links between food allergens and eosinophilic esophagitis (EoE) have been established, but the interplay between EoE‐ and IgE‐associated immediate hypersensitivity to foods remains unclear.

Diagnosis of Food Allergy

The prevalence of food allergies has been on the increase over the last 2 decades. Diagnosing food allergies can be complicated, as there are multiple types that have distinct clinical and immunologic features. Food allergies are broadly classified into immunoglobulin E (IgE)-mediated, non-IgE-mediated, or mixed food allergic reactions. This review focuses on the clinical manifestations of the different categories of food allergies and the different tests available to guide the clinician toward an accurate diagnosis.

Food allergy emergency preparedness in Illinois schools: rural disparity in guideline implementation

FIGURE 1. Treatment of severe allergic reactions at schools. A, School personnel responding to severe allergic reactions. Although they were not always available, school nurses responded to severe allergic reactions an overwhelmingly majority of the time. There was no difference between community types. B, Reasons specified for not giving epinephrine for a severe reaction. C, Rural communities reported epinephrine unavailability more often than urban and suburban communities (85.7% vs 42.4% vs 40%, *P 1⁄4 .037). TO THE EDITOR:

Cytokine responses to egg protein in previously allergic children who developed tolerance naturally

Egg allergy is the second most common food allergy in childhood, characteristics are listed in eTable 1, available online). Patients with with 1% to 2% of Americans affected.1,2 Although approximately 70% of children outgrow this allergy,3 few studies have explored the mechanism by which children naturally outgrow the allergy (natural tolerance [NT]). Most studies have compared children with allergy with those who were never allergic, have not evaluated allergen-specific responses, or have only focused on treatment inducing desensitization (oral immunotherapy). Although not previously demonstrated in food allergy, tolerance to venom has been associated with elevation of interleukin (IL)-10.4 Our hypothesis was that peripheral blood mononuclear cells (PBMCs) stimulated with ovalbumin (OVA) in NT has increased allergenspecific IL-10 production. The objective was to determine the PBMC cytokine response to egg protein in previously allergic patients who developed NT and thus differentiate them from children with allergy. Food allergy was defined by an allergist-immunologist as a history of IgE-mediated reaction to egg (anaphylaxis, urticaria, or significant vomiting) within 2 hours of food ingestion and positive laboratory testing (skin prick mean wheal diameter 4 mm larger than saline wheal and/or specific IgE [sIgE] level 2 kU/L). Nonallergic (control) was defined as no history of clinical reactivity to egg. NT was defined as a clinical and laboratory history of egg allergy but passing an open food challenge to 1 scrambled egg within 6 months of recruitment. The PBMCs were stimulated with or without OVA or with anti-CD3 and anti-CD28. After 48 hours, the supernatant was collected and cytokines were analyzed using multiplex assays (eMethods). Patient characteristics, fold stimulation, and sIgE/sIgG4 ratio were compared using the Mann-Whitney or Kruskal-Wallis test. Cytokine data were logarithmically transformed, dose-dependent responses were analyzed with repeated-measures analysis of variance (ANOVA), and comparisons at specific doses were performed with ANOVA or t test. Data analysis was performed using SAS 9.3 (SAS Institute, Cary, North Carolina) and SPSS 14 (SPSS, Inc, Chicago, Illinois), with a 2-sided type I error rate of 5%. Forty children (11 with NT, 20 with allergy, and 9 without allergy; median age 6 years, range 2e18 years) were recruited from a cross-sectional, caseecontrol convenience sample (patient