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Monday, May 3, 2010

Food allergy: An immunological picture of atopy development

What, exactly, does the phenotypic evolution of food allergy look like? Which factors, such as environment or genotype, exert the most influence? Is food allergen avoidance the key or is it irrelevant? The NIH/NIAID-supported Consortium of Food Allergy Research (CoFAR) has established an infant cohort with likely milk and/or egg allergy with the intent to describe and characterize the natural history of food allergies in children in hopes of being able to answer these questions.

In this month's issue of the JACI, Sicherer et al. present early results from the 1st of several studies being conducted by CoFAR. [Access this article for free at:] Their question: Among infants presenting with a clinical reaction to milk and/or egg, and a positive prick skin test (PST) to either, or children with moderate to severe atopic dermatitis and a positive skin test to milk or egg, what factors will be associated with developing a peanut allergy and resolution or persistence of milk/egg allergy? The authors note that known clinical allergy to peanuts was an exclusion; nevertheless, almost 70% of the infants had evidence of sensitization to peanut, with 27% having greatly elevated peanut-IgE (> 5 kUA/L). They compare sensitivity of PST and serum IgE and report significant association of wheal size and IgE concentrations across milk, egg, and peanut. They do note that there was unexpected discordance between peanut PST and peanut-specific serum IgE, where some infants have one positive and the other negative. In these cases, the serum IgE is more sensitive than the PST in detecting sensitization, which is in contradiction to the conventional wisdom that PST in infants is more sensitive.

In vitro analyses demonstrate that CD25 and IL4 expression are up-regulated in milk and peanut sensitized infants; this is not the case for egg sensitivity, where there was only a slight increase in CD25 expression and no related increase in IL4. The authors further address Th2 bias by looking at GATA3/Tbet ratios. Surprisingly, they found no increased GATA3/Tbet ratios, though GATA3 was detectable. Since Sicherer et al. speculate that Th2 activation is the background to food allergy, what is providing the increased IL4? The authors suggest that basophils may have been the source of IL4 in the sensitized infants.

Wrapping up, Sicherer et al. address the astonishingly high prevalence of peanut sensitization in their cohort and suggest that this indicates a need for caution in introducing peanut to infants with the enrollment characteristics and that clinical testing for food allergy may be warranted.

We asked first author Scott Sicherer, MD, for his take on the study's findings:

JACI: In your opinion, what is the most likely point of exposure leading to peanut sensitization in the infants?

Dr. Sicherer: We will be evaluating potential determinants that could include maternal ingestion, household exposure and other factors, but these are under analysis.

JACI: The findings associated with CD25 and IL4 gene expression under egg stimulation were not remarkable and you attributed this to possible effects of using whole egg extracts. What mechanism might account for the diminished IL4 expression associated with whole extracts?

Dr. Sicherer: We were surprised that egg behaved differently in the in vitro studies and are currently considering the possibility that if we had used a stimulant that was enriched with a major egg allergen, for example ovomucoid, we may have seen a response that was more similar to the milk (caseins) or peanut response.

JACI: Is it conceivable that basophils might be the source of IL4?

Dr. Sicherer: Our preparations were enriched for CD25. Basophils constitutively express CD25, are enriched with mononuclear cells during density gradient isolation and produce high levels of IL-4 in sensitized subjects. Recently, basophils have been implicated in allergy model systems for playing an important role in priming and enhancing memory Th2 responses. Murine basophils have been shown to express IL-4 in the absence of detectable GATA-3 or c-maf, expression, suggesting that IL-4 may be regulated distinctly in these cells. Thus, new paradigms are emerging that basophils play a key role in directing Th2 responses and our data may provide additional support for this observation. Preliminary studies utilizing flow cytometry revealed that basophils (CD3- CD123+ CD203+ HLA-DR dim and IL4+) are present in the CD25 preparation.

Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.

Vitamin D and corticosteroid use in children

Evidence is accumulating rapidly for the association between vitamin D insufficiency, lung function, and corticosteroid use and sensitivity. Pivotal studies have been published examining a number of parameters, including effect of latitude, skin pigmentation, and body mass index.

In this month's JACI, Searing et al. provide the first report on prevalence of vitamin D insufficiency or deficiency in children with asthma living in latitudes higher than 20° N. [This article can be accessed for free at] Several significant correlations are reported: age, BMI, and positive skin tests are inversely correlated to vitamin D levels, while FEV1% and FEV1/FVC ratio are significantly correlated to vitamin D level.

The authors demonstrate significant association between inhaled corticosteroids, oral steroid use, and total steroid dose with low levels of vitamin D. They suggest that insufficient vitamin D might increase asthma severity, requiring greater treatment intervention or possibly that down-regulation of glucocorticoid pathways due to insufficient vitamin D dictates the need for increased steroid doses.

In vitro analyses of vitamin D activity in PBMCs demonstrated that vitamin D augments induction of MKP-1 and IL10 by steroids. Additionally, effects were observed that support vitamin D supplementation to increase steroid sensitivity, thereby permitting lower doses to obtain an optimal response.

We asked Dr. Daniel Searing, first author on the paper, about the implications of this research:

JACI: Is there baseline evidence of decreased vitamin D levels secondary to corticosteroid exposure in pediatric asthma patients?

Dr. Searing: Our study demonstrated correlations between vitamin D levels and steroid exposure in pediatric asthmatic patients from northern latitudes. To our knowledge, this is the first study looking at vitamin D levels in this patient population. Our study was not designed to examine causation of the low vitamin D levels. We are conducting a study currently looking to examine vitamin D levels in patients with asthma while also controlling for other known confounders (age, BMI, etc) to examine how strong the correlation of corticosteroid use and vitamin D levels is.

JACI: Is it possible that vitamin D insufficiency/deficiency is iatrogenic in children with asthma?

Dr. Searing: It is possible that low vitamin D levels are iatrogenic. However, the vitamin D levels in our patients with asthma seem to mirror levels in the general pediatric population. Whether escalating amounts of corticosteroid therapy in worsening asthma directly lower vitamin D levels versus other potential causes, such as vitamin D having effects on glucocorticoid pathways that leads to higher doses to achieve treatment effect is unknown at the present time. Future studies will help clarify this issue.

Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.