Prenatal Events and the Development of Food Allergies
Professor Susan Prescott, PhD, MD
Paediatric Immunologist, Princess Margaret Hospital for Children, and
Winthrop Professor, School of Paediatrics and Child Health
University of Western Australia
Food allergy is now a substantial and evolving public health issue, recently emerging as a poorly understood ‘second wave’ of the allergy epidemic 1. In regions like Australia, there has been a 5-fold increase in food anaphylaxis in preschool children over the last decade 2 and challenge-proven IgE-mediated food allergy now affects up to 10% of infants 3. The greatest burden of this new epidemic is in young children, who are not only experiencing the most dramatic increase in food allergy, but also earlier presentations 2 and increasing persistence 4 of disease. As these younger generations reach adulthood, the burden of allergic diseases is expected to increase even more.
This dramatic and unprecedented rise in food allergy reinforces the pressing need to better define the events responsible in order to instigate earlier preventive strategies. There is no doubt that modern environmental changes must be disrupting the natural processes of oral tolerance in very early infancy. New data generated from our randomised controlled trials aimed at earlier introduction of allergenic foods have revealed worrying new evidence that a significant proportion of 4-6 month old infants already have established egg-sensitisation and clinical reactivity prior to the randomisation process. In some cases, the ‘first’ introduction of egg at <5 months induced anaphylaxis. This clearly indicates that the processes leading to egg sensitisation are already strongly established by this age in many infants, and that much earlier preventive interventions will ultimately be needed. Importantly, in all cases there was no previous history known direct ingestion of egg by the infant, indicating previous exposure through other routes potentially through breast milk or across the placenta. While cutaneous sensitisation has been proposed in children with eczema, this does not appear to explain rates of reactivity in children with no eczema. Differences in neonatal immune function of these individuals (including effector 5 and regulatory T cell function6) suggest these events are initiated in utero and consolidated in the very early postnatal period.
Previous strategies to prevent food allergy through ‘allergen avoidance’ have not only failed, but have instead been associated with increased risk of disease 7. This together with other observations in humans and animals has suggested two main avenues of research, 1) the role of earlier introduction of allergenic foods, and 2) a range of other environmental strategies to promote more tolerogenic conditions during initial allergen encounter7. Environmental and lifestyle interventions currently under investigation include microbial agents (probiotics), dietary and nutritional modulation (vitamin D, oligosaccharide prebiotics and long chain fatty acids) in pregnancy and the early postnatal period. Observational studies also suggest that adverse conditions such as stress (raised cortisol levels) in pregnancy and infancy8, and exposure to pro-inflammatory agents (such as cigarette smoking and diesel exhaust) 9 are also associated with and increase risk of allergic disease. Investigating the relative contribution of these and other environmental factors as ‘causes’ and/or ‘solutions’ to the rise in food allergy remains an enormous challenge that may take many decades to unravel. In the process we need a more thorough understanding of the developing immune system and the events that lead to oral tolerance. This should ideally include identification of predisposing genes, critical environmental determinants and maternal-fetal interactions which pave pathways to disease.
1. Prescott SL, Allen KA. Food Allergy: Riding the second wave of the allergy epidemic. Paediatric Allergy
Immunology. 2011; 22:155–60.
2. Mullins RJ. Paediatric food allergy trends in a community-based specialist allergy practice, 1995-2006. Med
J Aust 2007; 186:618-21.
3. Osborne NJ, Koplin JJ, Martin PE, Gurrin LC, Lowe AJ, Matheson MC, et al. Prevalence of challenge-proven
IgE-mediated food allergy using population-based sampling and predetermined challenge criteria in infants. J
Allergy Clin Immunol 2011; 127:668-76.
4. Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history of egg allergy. J Allergy Clin Immunol 2007;
5. Martino D, Bosco A, McKenna K, Hollams E, Mok D, Holt PG, et al. T-cell activation genes differentially expressed
at birth in CD4+ T-cells from children who develop IgE food allergy. Allergy ePub ahead of print Nov 2011.
6. Smith M, Tourigny MR, Noakes P, Thornton CA, Tulic MK, Prescott SL. Children with egg allergy have evidence
of reduced neonatal CD4(+)CD25(+)CD127(lo/-) regulatory T cell function. J Allergy Clin Immunol 2008;
121:1460-6, 6 e1-7.
7. Prescott SL, Smith P, Tang MLK, Palmer DJ, Sinn J, Huntley SJ, et al. The importance of early complementary
feeding in the development of oral tolerance: concerns and controversies. Pediatr Allergy Immunol 2008;
8. Stenius F, Borres M, Bottai M, Lilja G, Lindblad F, Pershagen G, et al. Salivary cortisol levels and allergy in
children: The ALADDIN birth cohort. J Allergy Clin Immunol 2011; 28:1335-39.
9. Martino D, Prescott SL. Epigenetics and prenatal influences on asthma and allergic airways disease. Chest
2011; 139:640 – 7.