Early life exposure to a dietary allergen : characteristics, and consequences for allergic sensitisation and disease

Allergic diseases have become an important public health issue. While the genetic basis for allergy is well established, genetic factors must interact with environmental influences to determine disease development. This complex interaction most likely occurs in early life since distinctive alterations of immune responsiveness, which may predict an allergic phenotype, are apparent at birth. Demonstration of raised IgE and allergen-specific T-cell reactivity at birth has inferred that exposure of the naive immune system to allergens may occur antenatally. Animal models have shown that the dose, timing, route and form of antigen exposure regulate whether tolerance or immune priming occurs. Also long-term T_H1-like (tolerant) and T_H2-like (allergic) memory against individual antigens occurs during the first exposures, and once consolidated, is not readily reversible. Consequently, the nature of early life exposure to an allergen may contribute to the complex process that determines allergic sensitisation and disease manifestation. Therefore, the hypothesis of this thesis was that 'the characteristics of early life exposure to dietary egg allergen determine infant atopic phenotype Hen egg ovalbumin (OVA) was the dietary allergen investigated. Egg allergy is common in infancy & has implications for later inhalant sensitisation and respiratory allergic disease. An OVA detection ELISA was developed. By this method OVA was found in maternal blood throughout pregnancy, cord blood, amniotic fluid and breast milk, thus confirming direct exposure to dietary allergen in early life. The dose, timing & routes of allergen passage were described & OVA form in breast milk, maternal & cord blood evaluated by gel filtration sample separation and ELISA. OVA was found only in free form in breast milk, but in blood was present both as free antigen and in complex with IgG, the form depending on specific IgG concentration. Thus maternal IgG may determine mode of fetal allergen presentation. Maternal IgG could also inhibit antigen detection, an effect dependent on concentration and functional affinity. This raises the possibility that maternal IgG may block presentation of allergenic epitopes in vivo, with implications for immune regulation. Women, with a personal or partner history of atopy, were randomised to dietary egg exclusion or a normal healthy diet from 17-20 weeks of pregnancy till the end of breast-feeding. OVA was present in as many blood & breast milk samples of egg avoiding as control women. Atopic women had higher levels of serum OVA than non-atopic women, while atopic & egg-avoiding women more often had OVA in breast milk, and in higher quantities, than non-atopic, egg avoiding women. These data suggest that dietary exclusion, particularly by atopic women, does NOT eliminate allergen exposure in early life. Antenatal OVA exposure, in the context of an egg-avoiding & atopic mother, was associated with a greater risk of an atopic phenotype at 6 months of age. Also, exposure via breast milk from an atopic mother suggested a greater risk of later atopy. Maternal serum OVA IgG concentration was shown to mark compliance to an egg exclusion diet & differences in cord concentrations were related to subsequent atopy. These data imply modulatory influences of maternal IgG & atopic environment over developing immune responses and raise the possibility that dietary exclusion as a primary allergy prevention strategy may have adverse consequences. Postnatally, differencesin OVA IgG and IgG subclasses were identified for persistently egg sensitised children & elevated OVA IgGI was associated with later asthma. This suggests that serum OVA IgGl measurement might be used as an adjunct to skin testing and serum IgE measurement to predict allergic respiratory disease. This work has provided insight into mechanisms that may modulate early life programming of atopy and has proposed factofsfor consideration in primary allergy prevention strategies. Furthermore, the potential for a serological measurement in infancy to predict long-lasting respiratory disease offersthe prospect of early implementation of secondary allergy prevention measures.