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Saturday, March 5, 2016

The Contributions of Allergic Sensitization and Respiratory Pathogens to Asthma Inception

Childhood asthma is the most common chronic disease among grade school children, and is responsible for the greatest number of school days missed.  Fortunately, there are now efficient management strategies to minimize the effect of asthma for many children, but what are the factors that lead to its development in the first place?  In this month’s issue of JACI, Jackson and colleagues discuss the risk factors that contribute to the development of asthma (J Allergy Clin Immunol 2016; 137(3): 659-665) .

As the authors explain, asthma starts long before the first wheeze.  In the first few years of life, as young immune systems encounter the environment around them, children who are more likely to eventually develop asthma tend to develop sensitization to aeroallergens and have recurrent lower respiratory infections.  This can happen alone, but new evidence suggests that they feed off each other, leading to a mix where asthma becomes a likely outcome.

Nearly all wheezing illnesses in the first few years of life are due to respiratory viruses.  New molecular techniques have shown that there is a wide variety of viruses that can cause upper and lower respiratory tract infections.  Among these, respiratory syncytial virus (RSV) and rhinoviruses (RV) are the most common pathogens.  Indeed, one third of children who have had RSV bronchiolitis develop recurring wheezing episodes, and one study showed that passively immunization against RSV led to an 80% reduction in the risk of recurrent wheezing in nonatopic children.  Rhinovirus, which was previously thought to only cause upper respiratory tract infections, is now known to cause lower respiratory tract infections too.  And, at least in one Finnish study, 60% of children with RV who wheezed in the first two years of life continued on to develop asthma five years later.  Bacteria may also play a role, but the evidence is preliminary and mixed: some bacterial infections are associated with wheezing and asthma, but exposure to other bacteria may actually be protective.

Additionally, it’s been known for some time that environmental allergies are major contributors to asthma.  In addition, they increase the chance that children will get wheezing respiratory infections.  Part of it is because allergic sensitization leads to enhanced airway responsiveness due to respiratory viral infections.  Another important factor is that allergen exposure impairs antiviral responses, such as production of Interferons I & III.  Interestingly, the use of omalizumab, a medication targeting IgE, the type of antibody responsible for allergens, also leads to a decrease in virus-induced asthma exacerbations.

Of course, there is so much more to the story.  What makes certain children more susceptible to viral infections and allergies is still unknown.  17q21, CDHR3 and IL-33 polymorphisms offer possible answers, but they are only pieces of the puzzle.  The biggest question on the horizon is can we ward off asthma by preventing allergen sensitization or avoiding  severe respiratory infections.  More research is needed, but there’s at least some glimmer of hope that we can finally stop asthma before it actually sets in.

Leveraging Gene-Environment Interactions and Endotypes for Asthma Gene Discovery

Asthma is a pressing public health problem in many developed countries.  But we don’t really know what causes asthma.  In this month’s issue of JACI, Drs. Bønnelykke and Ober talk about the genes and the gene-environment interactions that are thought to underlie susceptibility to developing asthma (J Allergy Clin Immunol 2016; 137(3): 667-679).

So far, there have been about 15 genes strongly linked to asthma, based on large genome-wide association studies (GWAS).  But each of these individual gene variants confers only a very modest increase in asthma risk.  Clearly, there remains a lot of missing information.  Although a significant portion of the risk for asthma may be attributed to environmental exposures, genetic variants may play a stronger role among subgroups of asthmatics who share similar clinical characteristics or similar exposures, as the article discusses.

To tease this apart, genome-wide interaction studies (GWIS) have been conducted to associate specific gene variants to asthma in the presence of specific environmental exposures.  Additionally, previous studies have already shown interactions between genes, early life viral wheezing illnesses, and asthma onset in childhood.  In particular, genetic variants at the 17q locus are associated with asthma among children with significant rhinovirus infections (common colds) during early childhood, but not among children who do not get very sick with rhinovirus infection.  Interestingly, these same variants at the 17q locus are associated with protection from developing asthma among children exposed to farm animals in early life.  Similarly, a variant of the CDHR3 gene, which encodes for a receptor for one type of rhinovirus, is associated with risk of severe childhood asthma.

There are several challenges to performing GWIS studies. For example, environmental exposures can be difficult to measure precisely and it is often impossible to dissect effects of a specific exposure from other related factors. An alternative approach is to study gene-environment interactions in cell models where single exposures can be studied in isolation and effects can be directly attributed to the exposure. Drs. Bønnelykke and Ober suggest that future studies using this approach will complement and guide human studies and thereby help understanding the complex mechanisms of asthma. 

Regardless, the roots of asthma seem to lurk at the intersections between genetic susceptibility and environmental exposures.  As Drs. Bønnelykke and Ober explain, future studies will require targeted, thoughtful research linking particular exposures in combination with genetic variants to asthma risk.

The microbial environment and its influence on asthma prevention in early life

It’s a tale of two farming communities: one run by the Amish, who retain very traditional farming practices with horses for field work, and other run by Hutterites, who have embraced modern farming technologies.  Despite coming from the same genetic background and having otherwise similar lifestyles, the Hutterites have a greater than 40% rate of allergen sensitization, while the Amish have a rate lower than 7.5%.  What can account for such a difference?  As Dr. von Mutius outlines in this month’s issue of JACI, it’s likely in the billions of bacteria that colonize the skin, gut, and respiratory passages as well as those that live all over your house, workplace, and everywhere in between (J Allergy Clin Immunol 2016; 137(3): 680-689).

Believe it or not, it’s only been within the past few years that we’ve even found out about all these bacteria.  New technology has enabled scientists to take a closer look at the microbiome, the collection of microbes that colonize virtually everything around and within us.  These microbiomes are diverse and dynamic; and can provide fingerprints about the world around us.  Cat and dog ownership can be predicted by the presence of certain bacteria.  More significantly, the presence of certain bacteria, like H. influenzae, M. catarrhalis, and S. pneumoniae in the throats of 1 month old infants, and somewhat predict the development of persistent wheeze and asthma by age 6.

This is seen in larger epidemiologic studies.  Children who enter daycare before their first birthday are at much lower risk of developing allergen sensitization compared to those who enter after their second birthday.  And, as mentioned above, upbringing on a farm with animal husbandry, especially around dairy animals, confers significant protection.  This is extended to urban environments as well, where exposure to high levels of cockroach, mouse, and cat allergens in the presence of Firmicutes and Bacteroidetes bacteria actually conferred some protection against asthma.

This field is evolving tremendously, and there are still a lot of unanswered questions.  We still don’t know which particular microbes are protective and whether increased diversity really does help to prevent sensitization to allergens.  Nevertheless, with newer, more sensitive technologies that can scan and identify bacterial and other microbial DNA, we’re on the path towards better understanding how our microbial environment shapes our susceptibility to asthma, allergies, and other immune disorders.