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Do Allergies Develop in the Womb

Do Allergies Develop in the Womb?

Michelle L. North PhD and Anne K. Ellis MD MSc FRCPC FAAAAI

The prevalence of allergic diseases has been rapidly rising over the past twenty-five years, creating a so-called allergy epidemic. While environmental allergies—those that cause sneezing and wheezing—have mostly leveled off, rates of food allergies in children have skyrocketed (1). The question is, why? Many ideas have been suggested to explain the allergy epidemic, one of first being the “hygiene hypothesis” that proposes that we are too antiseptic for our own good. Global warming has also been implicated, as higher temperatures may lead to longer pollen seasons. Other theories surround increasing traffic-related air pollution, crop fertilization, food processing, and antibiotic use. Though these hypotheses are relevant, all are lacking concrete proof, and although studies have shown that allergies do run in families, genetics alone cannot explain these troubling trends.

But what if we could link environmental changes to specific physiological responses that do not only change ourselves, but our children and future generations as well?Epigenetics may help explain such important gene-environment interactions. Intense research in this upcoming field is yielding clues as to how and why allergies, as well as other diseases of the immune system, are getting worse.

Epigenetics is the study of the interaction of genes and the environment, and how certain characteristics can be passed from one generation to the next without changing the DNA code (2) itself. It involves chemical modifications of a person’s genetic material, such that the epigenome can be thought of as the clothing of the genome. Some layers change significantly during development and can be modified throughout life in response to environmental factors, whereas other layers remain relatively permanent.Differences in these layers, or chemical modifications, lead to differences in gene expression—when and how genes are activated. This may explain why individuals with the same or similar DNA may have very different health outcomes.

Chemical modifications responsible for changes in the “epigenetic code” include DNA methylation and histone modification. DNA methylation involves the addition of a chemical group (a “methyl” group) to DNA residues that generally results in gene silencing, turning off the expression of this gene. Histone modification is similar, but involves chemical changes to DNA packaging proteins known as histones. These various changes allow genes to be either “open” or “closed” based on how tightly they are bound by their histone proteins, and work together with DNA methylation to affect how accessible the DNA is for expression.

Epigenetic modifications have been shown to control the efficacy of important immune cells known as Regulatory T cells (Tregs). Tregs are crucial in preventing “over-reactions” of the immune system, which as families with allergies can appreciate, can be dangerous. For reasons we don’t yet completely understand, a “harmless” peanut protein can be recognized as a deadly parasite, unleashing the full force of the immune system.In general, Tregs act as peacekeepers, and stop the immune system from overreacting to certain triggers. Their development in the prenatal environment is critically important to the maturing immune system, and may set up some children to be vulnerable to these over-reactions.

DNA methylation has been demonstrated to down-regulate the master Treg transcription factor FOXP3—a protein responsible for binding specific DNA sequences and controlling the flow of genetic information. Disrupt FOXP3 and the effectiveness of the peacekeeper cells will be compromised, making the immune system unable to dampen escalating immune reactions.Research is still investigating exactly what environmental exposures might be responsible for this epigenetic modification in utero. Recently, Nadeau and colleagues examined FOXP3 DNA methylation in Tregs as it related to ambient air pollution exposure (3). They found that asthmatic children from an area with high air pollution levels had increased methylation in their blood Tregs, compared with asthmatic children from an area with low air pollution levels. Thus, epigenetic modifications in important immune system cells are altered by environmental factors.

In addition to air pollution and its immune-modulating effects, other environmental exposures are known to induce epigenetic changes. There is evidence that prenatal exposures known to increase the risk of childhood allergy, such as maternal smoking, may act at least in part through epigenetic modifications. Smoking during pregnancy has been shown to induce changes in DNA methylation in exposed children, some of which carry over to grandchildren (4).

The prenatal environment may have lasting effects on health outcomes, mediated at least in some way through epigenetic mechanisms as evidenced by current research. However, to fully understand why only certain children develop allergies, it is necessary to better examine the complex immune and environmental factors at play in utero and in early life. Prospective studies are needed—for instance, birth cohorts that begin during pregnancy and follow up with the family over time to see if the child develops allergies. This type of study allows us to collect data pertaining to environmental exposures and biological samples before children develop allergies, and is the only way to isolate the root causes of allergic disease.

At Queen’s University and Kingston General Hospital (KGH) we have established the Kingston Allergy Cord blood Epigenetics (KACE) cohort. Due to the demographics of the area, the KACE cohort includes both rural and urban participants, and therefore encompasses children having different prenatal and early postnatal environmental exposures.The study focuses specifically on investigating the developmental origins of allergic disease. Over time, we hope to more definitively know if epigenetics can be used to predict which children will be affected by allergic disease. It is certain, however, that thus far research has only scratched the surface regarding how epigenetic events in utero and early life act to have long-standing consequences on our health.

For more information about Kingston Allergy Research visit: http://kingstonallergy.ca.

A modified version of this blog was originally posted at: http://asthmaallergieschildren.com/2012/06/01/why-use-an-environmental-exposure-unit-to-study-allergic-rhinitis/.

References:

1. Prescott S, Allen KJ. Food allergy: Riding the second wave of the allergy epidemic. Pediatr Allergy Immunol 2011;22:155-160.

2. North MLN, and Ellis, A.K. . The role of epigenetics in the developmental origins of allergic disease. . Ann Allergy Asthma Immunol 2011;DOI: 10.1016/j.anai.2011.02.008

3. Nadeau K, McDonald-Hyman C, Noth EM, Pratt B, Hammond SK, Balmes J, Tager I. Ambient air pollution impairs regulatory t-cell function in asthma. J Allergy Clin Immunol 2010;126:845-852 e810.

4. Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD. Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 2009;180:462-467.