Food Allergy Diagnosis and Therapy

Where Are We Now?

Aleena Syed; Arunima Kohli1; Kari C Nadeau

Disclosures

Immunotherapy. 2013;5(9):931-944. 

In This Article

Pathophysiology & Primary Prevention

Pathophysiology

FA is currently regarded as a dysregulation of normal immune tolerance mechanisms. All food proteins are recognized as foreign antigens by the gut,[11] but only allergic individuals demonstrate an immune response to these antigens. Tolerance, in normal individuals, is therefore believed to be a suppression of this response.[2]

Development of FA is characterized by two stages:

  • Sensitization, in which the allergic reaction pathways to the allergen are established;

  • Elicitation, in which the immune system carries out an inflammatory response upon allergen re-exposure.

During sensitization, dendritic cells,[12] the major class of APCs in the gut,[13] present the allergen to T cells, stimulating the production of Th2 cytokines: IL-4, IL-5 and IL-13. These cytokines, in turn, stimulate B-cell class switching to produce the antibody IgE, which then binds to its high-affinity receptor on mast cells and basophils.[2] Cytokines and chemokines induce T and B cells, thus perpetuating the allergic response.[13] Acute symptoms include urticaria, flushing, angioedema, abdominal pain, nausea, vomiting, diarrhea, wheezing, coughing and/or bronchospasm, rhinorrhea and hypotension or syncope.[2]

Not all foods are allergenic; in fact, of the over 12,000 food allergens known, only a small number induce allergies.[7] Further questions are raised by spontaneous resolution of FAs. Children usually outgrow allergies to milk, egg, soy and wheat, but not peanut or tree nut allergies.[7] Why this happens, and why only some FAs resolve independently while others remain, is unclear. Studies suggest IgE-binding patterns and, in various cases, IgE recognition of specific epitopes or amino acid sequences in peptides, may in some part be related to allergen severity and persistence.[14]

The environment of the gut is also likely to be crucial. Intestinal permeability is positively associated with increased FA incidence; a study of food-allergic infants demonstrated they had greater intestinal permeability compared with healthy infants, an effect that lasted even after 6 months on an exclusion diet.[15,16] Likely to be even more important are the microbiota found in the gut. The hygiene hypothesis suggests that changes in the pattern of intestinal colonization during infancy and decreased exposure to infectious agents in childhood are important factors in the development of allergic disease, and may help explain why allergy prevalence is increasing.[17,18] Antibiotic use[19] and exposure to pets, farms and farm animals[20–23] have been linked to decreased atopy risk. In addition, differences have been found in gut microbial flora between allergic and nonallergic children,[24,25] suggesting certain microbes may be more important to sensitization than others.

Work by Gupta et al. has provided considerable data regarding the current state of pediatric FA in the USA. A comprehensive survey of American children, published in 2011, found FA prevalence of 8%, with slightly higher prevalence found in children of Asian or African descent. A total of 38.7% of allergic children reported severe reactions, mostly to peanut, tree nut, shellfish, soy and fin fish. In addition, 2.4% of all children were found to have more than one FA, highlighting the need for greater general understanding of the disease and the development of multiple allergen therapies.[26]

FA has a strong genetic component. Multiple studies have reported a strong family association,[27] with one UK study finding a seven-fold increase in peanut allergy risk if an individual has a peanut-allergic parent or sibling.[28] A study in a Chicago cohort found varying heritabilities associated with different allergens.[29] A study of peanut allergy in twins found a much higher concordance for the allergy between identical twins than between fraternal twins (64.3 vs 6.8%, respectively), with an estimated heritability of 81.6%.[30] Studies have also found associations with race and ancestry.[31]

Primary Prevention

The American Academy of Pediatrics, in 2000, outlined heavy dietary restrictions for allergenic foods through breastfeeding and the first 3 years of life; however, recently, in the absence of sufficient data, has retracted most of these guidelines.[32] National Institute of Allergy and Infectious Diseases, too, holds that there are insufficient data to suggest maternal diet influences the development or course of FA in children.[33] There is also considerable debate regarding whether sensitization can occur in utero.[28,34]

Several observational cohort studies have found that earlier introduction of foods may decrease allergy risk, and that delayed introduction of foods and/or extended breastfeeding may increase allergy risk.[12,35–38] These studies are still underway and we are awaiting further results from these randomized control trials. One particularly prominent study, and one of the first to look at early exposures in a large, geographically diverse cohort of subjects, was published by Lack's group in the UK in 2008, which compared Jewish children in the UK, who avoided peanuts for most of their first few years of life, with Jewish children in Israel, who were introduced to peanuts early during weaning and who continued to eat it more frequently and in greater amounts than children in the UK.[38] The study controlled for various factors including method of preparation, and the group found significantly lower rates of peanut allergy in Israeli Jewish children than British Jewish children. This provided evidence that early exposure to highly allergenic foods might be preventative for allergies to these foods; further research into this is ongoing.[38]

Building on this idea, nutrition and diet have also been implicated in the development or prevention of FA. Vitamin D, in particular, has been implicated in dendritic cell and Treg cell tolerogenic activity,[39–41] and may directly induce tolerogenic behavior in B cells.[42] Its potential role in FA is supported by geography – prevalence of allergic disease increases with distance from the equator[43–47] – and has been hypothesized as a potential mechanism involved in the association of fall (and to some degree, winter) births with higher FA incidence.[48] However, findings when evaluating serum vitamin D measurements in allergic and nonallergic patients have been inconsistent, with some studies finding a positive association between increased vitamin D concentrations and increased FAs in addition to those studies finding a negative association.[49–51]

Other dietary and nutritional factors associated with FA include: dietary fats (omega-6 vs omega-3 long-chain polyunsaturated fatty acids, with the latter inconclusively positively associated with decreased FA incidence); antioxidant supplements such as vitamin C, E and β-carotene; vitamin A; zinc; and a Mediterranean diet.[52]

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