Food allergy is thought to result from a defect in either the establishment or maintenance of oral tolerance. While T regulatory cells (Tregs) are often credited as being essential mediators of tolerance to food antigens, few studies have evaluated allergen-specific Tregs in patients with food allergy. This, in part, is due to technical difficulties in identifying these cells. We therefore developed an assay that allows us to identify and distinguish peanut-specific T effector (ps-Teff; CD154+CD137-) and T regulatory cells (ps-Tregs; CD154-CD137+) based on differential upregulation of CD154 and CD137. We performed this assay on blood from peanut allergic (PA) and nonallergic (NA) children (median age 8 and 12 years, respectively). The frequency of ps-Teffs was similar in allergic and nonallergic subjects, although allergic patients showed pronounced Th2 skewing whereas nonallergic subjects exhibited a Th1 bias, which is consistent with prior studies. While ps-Tregs from both groups of subjects uniformly expressed Foxp3 and lacked effector cytokine expression, there was no difference in the percentage or absolute number of ps-Tregs between the groups. Because some studies have suggested that the stability and suppressive capacity of Tregs from allergic children may be diminished, we measured the methylation status across 11 CpG sites within the Treg specific demethylated region (TSDR) of intron 1 of the FOXP3 locus in sorted ps-Tregs from each cohort of children. Demethylation of this region has previously been shown to be critical in maintaining a suppressive Treg phenotype in both mice and humans. We found no differences in the extent of FOXP3 methylation in either ps-Tregs or ps-Teffs between NA and PA subjects, suggesting similar stability of ps-Tregs between these groups. We further found that ps-Tregs from NA and PA subjects were equally capable of suppressing the proliferation of autologous ps-Teffs. Collectively, these data demonstrate that established peanut allergy in humans is not associated with a deficiency in the frequency, stability or suppressive function of ps-Tregs. Most available data suggest that peanut and other food allergies develop very early in life. We therefore studied PBMCs from three groups of one-year old infants: 1) peanut allergic; 2) nonallergic (NA); and 3) peanut sensitized (PS), defined by a negative oral food challenge (OFC) to peanut but positive IgE testing to peanut. Similar to our older cohort, we found no difference in the frequency or absolute number of either ps-Teffs or ps-Tregs across the 3 groups of infants, suggesting that a transient deficiency in ps-Tregs early in life, when peanut is first introduced, does not contribute to the development of peanut allergy. Already at this young age, both sensitized and allergic infants had a significantly higher percentage of IL13+ ps-Teffs compared to the nonallergic group, while very few IFN-gamma-producing Teffs were seen in any of the infants. These data indicate that an initial deficiency in Th1 responses to peanut does not cause peanut allergy, but failure of IFN-gamma+ ps-Teffs to expand may contribute to disease persistence as a Th1-dominated immune response to peanut was only seen in nonallergic children once they introduced peanut into their diet. Both Tregs and Teffs acquire expression of homing receptors that reflect the tissue site of their initial activation. T cells that first encounter antigen in the skin express cutaneous lymphocyte antigen (CLA), while those activated in the gut express 47. A higher percentage of ps-Teffs from peanut-sensitized and allergic infants expressed CLA, and correspondingly fewer ps-Teffs expressed 47, compared to their nonallergic counterparts. Furthermore, effector cytokines were only produced by the CLA+ subset of ps-Teffs. Importantly, expression of CLA and 47 on ps-Tregs was not different among the 3 groups of infants, showing that lack of proper ps-Treg homing is not responsible for the development of Th2 effector responses in peanut sensitized or allergic children. These data are consistent with a model in which environmental peanut exposure in combination with a disrupted skin barrier promotes sensitization to peanut. The globally high prevalence of food allergy has led to an ever-increasing need for food allergy testing in clinical practice. Current tools for diagnosing food allergy, including both food-specific IgE (fs-IgE) and skin prick tests (SPTs), often detect sensitization to foods that are not associated with symptoms upon ingestion, which can lead to unnecessary food avoidance. This not only impairs quality of life but may unnecessarily put these patients at risk for impaired growth. This limitation is especially an issue among patients with coexistent atopic dermatitis (AD) who often have high total serum IgE levels. While sleep disturbance and increased metabolic demands are thought to stunt growth in AD patients, the role that coexistent food allergy has on their growth and development has not been well-studied. To investigate this question, we studied 77 children with moderate-severe AD. The subjects were categorized into three groups: 1) those with IgE-mediated food allergy to the 5 most common food allergens (IgE FA); 2) those avoiding any of these 5 foods due to worsening of their AD upon ingestion of the food (Skin Only); 3) those clinically nonallergic to food who were following an unrestricted diet (No FA). Peanut was the most commonly avoided food in both groups, followed by egg and milk. 71% and 60% of the IgE FA and Skin Only subjects were avoiding 2 or more foods, respectively. In models adjusting for age, gender, asthma, and EoE, the BMI Z-score and weight Z-score of the IgE FA group were both significantly lower than in the Skin Only and No FA groups. There was no significant difference in height Z-scores. The average BMI Z-score of the IgE FA subset was normal, although their weight and height Z-scores were both significantly below zero. In contrast, the average BMI Z-scores in both the Skin Only and No FA groups were significantly above zero. In fact, 30% of the Skin Only group and 48% of the No FA groups were overweight (BMI between the 85th and 95th percentile) or obese (BMI 95th percentile), compared to 16% in the IgE FA group. The average weight Z-score of those with No FA was also significantly above zero. While AD severity as measured by SCORAD was not associated with BMI Z-score in the Skin Only or IgE FA groups, there was a significant positive relationship between SCORAD and BMI Z-score in children with AD and No FA. Prior studies have suggested that children with milk allergy are at particularly high risk for growth impairment compared to other types of food allergy. While we observed no difference in BMI Z-scores between those avoiding and not avoiding milk, the height Z-scores in the milk avoidance group were significantly lower than those not avoiding milk, and a similar trend was seen for weight Z-score. The height and weight Z-scores of the children avoiding milk were significantly below zero; this was not the case for the children who were not avoiding milk. Collectively, our data indicate that children with co-morbid AD and IgE FA are at significant risk for growth deficiency, particularly if they are avoiding milk. Remarkably, children with moderate-severe AD alone (No FA group), as well as those in the Skin Only category, were more likely to have an elevated BMI and weight. Our findings are in keeping with recent studies demonstrating that obesity in early childhood is associated with higher rates of eczema, as well as with more severe disease. We also saw a positive correlation between SCORAD and BMI in the No FA subjects.
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