Could Epigenetics Explain the Origins of Allergic Disease?

Could epigenetics explain the origins of allergic disease?

Finally, spring is here – that wonderful time of year when the temperature starts to rise and everything is in bloom. But for many of us, it also marks the beginning of allergy season. That means itchy watery eyes, sneezing, running nose, coughing and overall misery.

But allergies don’t just affect people in the spring and they are not all related to weather. According to the Centers for Disease Control and Prevention (1), more than 50 million Americans have an allergy of some kind, and allergies are now the sixth leading cause of chronic illness in the United States. More impressive may be the fact that allergic diseases have increased dramatically over the past two decades. While environmental allergies, the type that makes you sneeze and wheeze, seems to have leveled off in the past ten years, food allergies, predominately in children, have been escalating. Hailed as the “second wave” in the growing allergy epidemic, food allergies may have lagged behind the original wave of asthma and allergic rhinitis, but have arrived with vast and significant implications (2).

Studies have shown that allergies are indeed inherited, but more than genetics is needed to explain this disturbing trend. In fact, several ideas have come forth to explain the allergy epidemic. For instance, the  “hygiene hypothesis” (3) suggests that we may be too sanitary for our own good and that our immune system is not being allowed to develop naturally. Others blame global warming for the increase in allergies. As the planet gets increasingly warmer and CO2 levels rise, seasonal changes increase pollen levels and other allergy triggers like ground level ozone. And still, there are more suggestions like increased traffic and air pollution, over fertilized and processed food, and  too many prescribed antibiotics and other drugs. While all these explanations are valid, what they lack is conclusive evidence.

The epigenetics link

Research in the field of epigenetics is linking changes in the environment to more specific physiological responses. Studies on changes in gene function in relation to environmental influences are providing evidence to explain how and why allergies, as well as other diseases of the immune system, exist and progress. These changes, called epigenetic modifications, not only affect us directly, but they also can affect our children and even future generations. DNA methylation and histone modifications are important mechanisms studied in epigenetics. DNA methylation occurs on top of or above the genome when cytosine residues are modified by the addition of a methyl (CH3) group, resulting in what is known as gene silencing – genes are in essence “turned off” and not activated. Histones which are proteins found in the cell nuclei that help package the DNA can also undergo modification. Working together, both mechanisms affect how available DNA is for expression.

It’s in the genes – epigenetic inheritance

It would be nice to think that we all start out as a blank slate, ready to be shaped by our own life experiences. But that’s not entirely true. It just so happens that for some reason, certain epigenetic markers or tags (DNA methylation, histone modifications) remain in place, passing from one generation to the next. This process is called epigenetic inheritance (4) and it challenges the notion that only DNA code is inherited. The truth is there’s a probability that whatever our parents experienced, like smoking or perhaps a bad pollen season, could affect us. How this happens is not fully understood, but new research is uncovering more about how these epigenetic modifications are maintained.

In a study analyzing the behavior of a sperm and an egg upon conception, researchers found that paternal DNA starts out highly methylated within the sperm. Yet, after fertilization, the father’s genome experiences rapid demethylation, while the mother’s genome demethylates more gradually (5). Some parental epigenetic marks are lost, while some are kept. This process, known as epigenetic imprinting, results in only one allele (one active copy) being expressed. Imprinted genes are particularly sensitive to environmental signals because there is only one active copy and no back up (6). Any further epigenetic modifications will have a greater impact on gene expression. By studying imprinting, scientists may be able to explain why certain diseases, like asthma and allergies appear to come from the mother, while others come from the father.

Hypersensitivity begins in the womb

As if there wasn’t enough to worry about during pregnancy, we are now learning that “hypersensitivity”, a condition that causes the immune system to overreact –to, let’s say, a peanut – may be set up in the prenatal environment. Any parent of a child with a food allergy knows all too well how detrimental this kind of overreaction can be. In a healthy immune system, regulatory T cells (Tregs) maintain immune homeostasis. They suppress the function of other T cells and limit the immune response to certain triggers, thus preventing an overreaction. DNA methylation controls the “master” Treg transcription factor FOXP3. This protein which binds to specific DNA sequences controls the flow of genetic information. Any disruption in this flow and the effectiveness of the Tregs cells will be compromised.

In a study examining umbilical cord blood, it was shown that babies born to allergic mothers had a reduced number of Tregs. This was further studied to show that the children with lower Tregs were also at high risk to develop sensitivity to food allergens and atopic dermatitis (the start of atopic march) during the first year of life (7). The results indicate that epigenetic mechanisms like DNA methylation may mediate significant crosstalk activity between the immune system of the mother and of that of her developing infant.

SEE ALSO:   Birth Season Could Epigenetically Determine Your Allergy Risk

In another study, researchers found that dendritic cells, the cells responsible for processing antigen material and presenting it to the T cells, may be at fault for the maternal transmission of allergic risk. Dendritic cells collected from mice born to allergic mothers showed remarkable differences in the degree of methylation than normal mice and exhibited higher antigen presentation activity (8). It was also discovered that transferring these allergic dendritic cells into normal mice increased allergic susceptibility in the recipient mice. While more studies are needed to confirm these results in humans, the findings suggest that epigenetic imprinting does occur in the immune system and can lead to a higher level of allergic sensitivity.

Allergy effects of in utero exposures

Epigenetic imprinting in utero is affected by other environmental factors such as a mother’s diet. And while we are already aware of how important diet is for prenatal care, epigenetics is demonstrating some of the possible mechanisms at work. In mouse studies, researchers have found that diets rich in methyl donors, like folate, during pregnancy result in offspring having an increased risk for allergies and asthma. This increased risk was also evident in future generations (9).

In human pregnancy, taking folate supplements is recommended for the prevention of congenital abnormalities. Yet, these findings suggest that over supplementation may result in unexpected biological consequences.

In a retrospective cohort study investigating the role of epigenetic control in the onset of allergic diseases, it was shown that mothers who suffered from allergic symptoms very early in pregnancy were more likely to have offspring with allergies. This was compared to mothers who did not suffer from allergies in early pregnancy, taking into account family history of allergies and total allergic response during pregnancy (10). These results indicate that gene-environment interactions during embryonic development may modify the epigenetic code in ways that may potentially lead to allergic disease.

Environmental exposure affects our genes  

We hear all the time how environmental exposure to pollutants is the cause of many diseases and probably the most preventable through aversion. Now, rapidly growing evidence is linking environmental exposures such as air pollution and smoking to epigenetic variations, including changes in DNA methylation and histone modifications. And, prenatal exposures to these substances, which are known to increase the likelihood of childhood allergies, may be mediated through these epigenetic alterations. For instance, allergic children of mothers who smoked during pregnancy show changes in DNA methylation. These changes are then carried over to the next generation (grandchildren) who are similarly affected with allergies (11).

Direct exposure to air pollution also has immune-modulating effects. In a study assessing asthma in children from areas with different pollution levels, researchers found that FOXP3 DNA methylation in Tregs was elevated in the blood of asthmatic children from highly polluted areas, compared to that of asthmatic children in low level pollution areas. Treg cells, the immune response suppressors, are directly linked to asthma pathogenesis. Their impairment caused by hypermethylation of the FOXP3 gene associated highly with pollution exposure and worsened asthma scores (12). These examples give proof that epigenetic modifications in vital immune system cells can be modified by environmental factors.

Further research is needed

Research in epigenetics has advanced our understanding of how the environment can induce changes in gene expression and in the development of allergic diseases. Some research has already begun to pinpoint genes for new potential drug targets for asthma and allergies, but further studies are needed to identify precise networks that regulate gene expression and the key environmental exposures driving susceptibility to allergic disease. Epigenetic mechanisms are dynamic and potentially reversible with therapeutic intervention. With this in mind, there is hope that someday soon, we will either have a cure or, or at least, figure out whether a lifestyle, nutrition, or environmental change could reduce allergies and end the allergic epidemic.

 

References:

  1. Centers for Disease Control and Prevention. Allergies. Web.
  2. Prescott S, (2011). Food allergy: Riding the second wave of the allergy epidemic. Pediatr Allergy Immunol. 22:155-160.
  3. H Okada, (2010). The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 160: 1–9.
  4. University of Utah Health Science. Epigenetics and Inheritance. Web.
  5. Mayer W, (2000). Embryogenesis: Demethylation of the zygotic paternal genome. Nature. 403:501-502.
  6. University of Utah Health Science. Genomic Imprinting. Web.
  7. Hinz D, (2012). Cord blood tregs with stable foxp3 expression are influenced by prenatal environment and associated with atopic dermatitis at the age of one year. Allergy. 67:380-389.
  8. Fedulov, AV, (2011) Allergy Risk Is Mediated by Dendritic Cells with Congenital Epigenetic Changes. Am J Respir Cell Mol Biol. 44:285–292.
  9. Hollingsworth JW, (2008) In utero supplementation with methyl donors enhances allergic airway disease in mice. J Clin Invest. 118:3462-9.
  10. Shinohara M, (2007) Symptoms of allergic rhinitis in women during early pregnancy are associated with higher prevalence of allergic rhinitis in their offspring. Allergol Int. 56:411-417
  11. Breton CV,(2009) Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med.180:462-467.
  12. Nadeau K, (2010) Ambient air pollution impairs regulatory t-cell function in asthma. J Allergy Clin Immunol.126:845-852 e810.

Source: North, ML (2012) Do Allergies Develop in the Womb?. AsthmaAllergiesChildren.com.

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