Complexities Of Allergic Disease

Last time we discussed the main players involved in the immune response to allergens, in the reaction called Type I hypersensitivity. We know that hay fever and other allergies are a result of atopy, the genetic predisposition to mount excessive IgE-mediated immune responses. Atopy is derived from a Greek word that means unusual or out-of-place. Although the immune overreaction is indeed out of place, the prevalence of allergic disease in society is not. Approximately 25% of the world’s population suffers from allergies, making it one of the most common chronic diseases. Unfortunately, this number is actually increasing, so researchers are trying to understand the factors that contribute to allergic disease.

Advances in genome sequencing and the completion of the Human Genome Project have allowed scientists to use genome-wide association studies (GWAS) in attempts to identify certain disease-causing genes. While many candidate genes have been described for hay fever, each search appears to reveal additional candidates. It has become clear that hay fever is a complex disease, driven by genetics and environmental exposures, both pre- and postnatal. Because of this complexity, atopy does not follow a Mendelian model of inheritance, like eye or hair color.

To perform GWAS, researchers collect blood or tissue samples from individuals with the disease of interest and from symptom-free control subjects. In many allergy studies, the controls are within the same family, which helps tease apart genetic differences that might actually contribute to disease. This is helpful because 300,000 to 1 million changes in the DNA are tested. These changes called single nucleotide polymorphisms (SNPs), a type of mutation that indicates a single change in the DNA base pair. If certain SNPs appear more frequently in the individuals with the disease, they are said to be associated with that disease. Additional DNA sequencing is performed to determine the exact change, and then ideally that SNP is studied in the lab to understand the consequence of the change on cellular function.

Sometimes mutations give super-human agility, strength, or intelligence. Other times they set us up to have wild and potentially unnecessary symptoms like Beast’s blue fur. Or perhaps equally annoying, the itchy watery eyes, nose, and throat from hay fever that come from a super-human response to harmless allergens.

A few notable candidate genes have been identified as associated with hay fever or with higher levels of circulating IgE antibodies, as we learned is a hallmark of atopy. Cytokines are the main signaling molecules that trigger activation of B cells to produce IgE antibodies, and not surprisingly, people with hay fever have mutations in genes that encode for cytokines or regulate their production. Also associated with hay fever are changes that enhance and stabilize the IgE receptor on mast cells and basophils, contributing to more intense symptoms. Genes responsible for airway smooth muscle contractions, contributing to cough and wheeze, are also implicated. SNPs have been identified in the genes encoding chemical mediators that cause ongoing symptoms such as leukotrienes, and in the specialized effector cells involved later in allergic inflammation response, such as eosinophils.

These are just a few examples of genes; dozens of others are being studied to learn exactly how they contribute to hay fever. Furthermore, some genes are only associated with allergies in the context of specific environments, further complicating the identification of true disease-causing genes. One clue that environmental factors influence allergies comes from studies of twins. Twin studies have shown that between monozygotic (identical) twins there is on average a 65% (range, 42-82%) chance that if one twin has allergies, the other will also have them. Between dizygotic (fraternal) twins, there is on average a 33% concordance rate (range 15-52%).

Some differences in twins are obvious, but other differences like allergies require epidemiological studies to tease apart.

The “hygiene hypothesis,” proposed by D. Strachan in 1989, became a popular basis to explore the increased incidence in allergic disease. Strachan observed that increased family size was associated with lower rate of allergies. He proposed that if allergies were prevented by early childhood infections, unhygienic contact with older siblings may protect against hay fever. Immune responses to pathogens like bacteria and viruses use a T-helper 1 (Th1) cell response. We know that Type I hypersensitivity reactions are mediated by Th2 cells’ stimulation of B cells to produce IgE antibodies. So the theory is that early childhood infections bias the immune system towards a Th1 response and suppress Th2 responses.

If Strachan’s hypothesis is correct, the Bates family should be allergen-free.

Strachan performed additional epidemiological studies to investigate the hypothesis that infections and larger family size protect against hay fever. He published a report in 2000 stating that decreases in family size do not appear to explain the increased incidence of allergies. Many additional studies looking into the protective effects of childhood infections have shown inconsistent results; some show a “protective” effect whereas others show either no association or early childhood infections correlated with development of allergies.

The “hygiene hypothesis” developed into a much broader “microflora hypothesis” which proposes that urbanization and a Western lifestyle limits our exposure to bacteria, viruses and parasites in general. Clean water, increased Cesarean sections, reduction in breastfeeding, increased antibiotic and antibacterial use, and reduced exposure to farm animals have limited our exposure to our microbial “old friends”. According to this idea, these “old friends” have evolved with us to the point where we require them for proper immune function.

 

“The Wonder Years” cast knew that we get by with a little help from our friends.

The diversity of our microbiome is decreasing, which may have detrimental effects on general health and the efficiency of our immune system. W. Parker proposed the term “biome depletion” to describe this current phenomenon. A few recommendations can be found here to increase microbial diversity in the gut.

Just like the Biodome, our biomes are not closed systems and can let in and respond to passer-byers, for better or for worse. In the case of Pauly Shore, it’s always for the worse.

If there weren’t already enough factors to consider in development of allergies, let’s peel back another layer. In addition to acquiring genes and microbiota from mothers during birthing and breastfeeding, in utero we are largely influenced by our mother’s environment through epigenetics. We’ve discussed epigenetics previously; briefly, it describes changes in the DNA and DNA-associated structural proteins that act to turn genes on or off. Epigenetic regulation either gives a green light or red light to production of specific gene products, or can act as a volume knob to finally tune gene expression. The process is plastic, allowing our genes to respond to the present environment.

Upon conception, epigenetic reprogramming occurs in the zygote, like a reset button. However, some epigenetic marks remain and are inherited by the offspring. So before and largely during pregnancy, the mother encounters various environments and the body responds using epigenetics to regulate genes at the appropriate time. These changes occur in the embryo or fetus as well, as a way to prime the baby for its eventual environment.

There is evidence that the immune system is under epigenetic regulation. At birth, atopy-prone infants tend to have diminished Th1 cell responses, thought to be influenced by the maternal environment. Additionally, maternal diet, microbial exposure, and smoking can influence epigenetic regulation of key genes involved in immune regulation and allergy development.

While there is no consensus on allergy prevention, there are many options for treatment of allergies, which will be discussed in the final allergy article in this series – coming soon!

Contributed by:  Julia van Rensburg, Ph.D.

Follow Julia on Twitter.

Dávila I, Mullol J, Ferrer M, Bartra J, del Cuvillo A, Montoro J, Jáuregui I, Sastre J, & Valero A (2009). Genetic aspects of allergic rhinitis. Journal of investigational allergology & clinical immunology, 19 Suppl 1, 25-31 PMID: 19476051

Grammatikos AP (2008). The genetic and environmental basis of atopic diseases. Annals of medicine, 40 (7), 482-95 PMID: 18608118

Strachan DP (2000). Family size, infection and atopy: the first decade of the "hygiene hypothesis". Thorax, 55 Suppl 1 PMID: 10943631

Parker W (2014). The "hygiene hypothesis" for allergic disease is a misnomer. BMJ (Clinical research ed.), 348 PMID: 25161287

Martino D, & Prescott S (2011). Epigenetics and prenatal influences on asthma and allergic airways disease. Chest, 139 (3), 640-7 PMID: 21362650

The Avengers: Is It Possible Someone Could Turn Into A Hulk?

"The Avengers: Age of Ultron" has finally arrived, reuniting fans with their favorite superheroes and introducing them to new ones to cheer on, like Quicksilver.  

 

 

Judging from the never-ending string of successful superhero films, it seems safe to say that we're obsessed with champions of justice who harbor extraordinary abilities. No doubt we've shared this fascination with superpowers since the beginning. Some of us are born faster, stronger, smarter - causing the rest of us to wonder whether we can tap into some hidden superpower within ourselves. We love hearing stories of genius and watching talent shows, just to catch a glimpse of someone crossing the threshold of what we thought was the boundary of human capability.

Stanford biologist Sebastian Alvarado is no exception, but he is endeavoring to put some scientific plausibility behind some of our favorite superheroes. Take the Hulk, for instance. The Hulk is the muscular green beast that scrawny scientist Bruce Banner transforms into whenever he gets enraged.

A lot of scientists can identify with Dr. Banner’s plight, and I have seen many undergo an analogous transformation while reading their grant reviews.

 

How did Dr. Banner gain this blessing and curse? As a scientist, he was researching how people summoned these unusual bursts of strength. Using himself as a guinea pig, he exposed himself to gamma radiation in an attempt to become stronger. There was no noticeable effect at first, but when Dr. Banner got angry, his skin turned green and his muscles burst out of his shirt. Since Dr. Banner is a good guy, the Hulk is generally a good beast, although somewhat messy. When the anger subsides, Dr. Banner returns to his modest, wimpy self and heads to the store to buy new clothes.

The comic book tale prompted Dr. Alvarado to wonder:  is this even remotely possible? He addresses the question in the video below.

 

Let’s clarify a few of these points for those who might be less familiar with the concepts. First, gamma radiation blasts your DNA (chromosomes) apart. As Dr. Alvarado mentioned, there are enzymes that will “heal” the DNA, but it doesn’t always heal correctly, which might result in new genes (and the loss of other genes). Second, we are learning more and more that genes are regulated in a surprising number of ways. They are not merely binary switches that turn on and off, but rather they are controlled more like volume knobs. Epigenetics refers to the factors in your cells that have their fingers on those volume knobs.

We discussed epigenetics in a previous article covering Ozzy Osbourne’s genome; in the case of the Hulk, epigenetics provides an attractive means to account for how Dr. Banner can switch between Hulk and normal guy. Between transformations, Dr. Banner’s genes are not changing, but which ones are active – and the degree they are active – is changing. For example, epigenetic factors can crank up genes controlling muscle development when they receive a signal in the form of a stress hormone that increases during temper tantrums. As this hormone subsides, other epigenetic factors return the volume of those genes to their normal level. You can think of genes as the selection of music, but epigenetic factors are the DJs.

 

So what kinds of epigenetic factors are there? We are discovering a dizzying array of cellular components that can alter gene expression, which can result in changes in physical appearance, behavior, mental abilities, and more. It has long been known that chemical modification (i.e. methylation, delivered by enzymes called DNMTs – DNA methyltransferases) of DNA itself can shut down genes. DNA methylation marks are like orange construction cones blocking the highway. Scientists then discovered that histone proteins, which congregate in bundles of 8 to form nucleosomes, could also be chemically modified in several different ways. The nucleosomes give DNA the “beads on a string" appearance shown below.

This is your DNA, not a pearl necklace! The DNA "string" wraps around the "beads", which are nucleosomes composed of 8 histone proteins. Once thought to merely help package DNA, we now know these nucleosomes are major contributors to the regulation of genes on the DNA.

These proteins were long thought to be just scaffolding components for the DNA, but now we know they play a major role in directing the activity level of nearby genes. Numerous chemical modifications, such as acetylation, methylation, phosphorylation (and more), can take place on multiple places of each histone protein. These may alter the binding between nucleosomes and DNA, making certain genes more accessible, or these modifications may form a cellular “code” that can affect gene expression levels.

Histones can also be moved, replaced, or evicted by epigenetic factors called SWI/SNF ATPases. As the name implies, these enzymes require energy from ATP to affect gene expression. More recently, it has also been found that small non-coding RNA molecules can regulate genes.

A summary of the major epigenetic factors that can regulate the "volume" of gene expression.

While these complex methods a cell employs to influence gene expression offer a potential explanation for how someone could temporarily become a Hulk, it is by no means probable. Most massive gamma radiation doses would destroy genes that are essential to survival. But it is fun to use cutting-edge science to put just a tiny hint of credence behind the superpowers. And even more fun to think that with enough knowledge we may be able to modulate epigenetic factors to treat disease or maximize human potential.

Contributed by:  Bill Sullivan

Follow Bill on Twitter.

Falkenberg KJ, & Johnstone RW (2014). Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nature reviews. Drug discovery PMID: 25131830

Haggarty P, Hoad G, Harris SE, Starr JM, Fox HC, Deary IJ, & Whalley LJ (2010). Human intelligence and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. PloS one, 5 (6) PMID: 20593030

Is it really possible for someone to turn into THE HULK? Don’t make me angry.

We are obsessed with superheroes. Humans have probably shared this fascination with superpowers since the beginning. Some of us are born faster, stronger, smarter - causing the rest of us to wonder whether we can tap into some hidden superpower within ourselves. We love hearing stories of genius and watching talent shows, just to catch a glimpse of someone crossing the threshold of what we thought was the boundary of human capability.

Stanford biologist Sebastian Alvarado is no exception, but he is endeavoring to put some scientific plausibility behind some of our favorite superheroes. Take the Hulk, for instance. The Hulk is the muscular green beast that scrawny scientist Bruce Banner transforms into whenever he gets enraged. A lot of scientists can identify with Dr. Banner’s plight, and I have seen many undergo an analogous transformation upon reading their grant reviews.

 

How did Dr. Banner gain this blessing and curse? As a scientist, he was researching how people summoned extraordinary bursts of strength. Using himself as a guinea pig, he exposed himself to gamma radiation in an attempt to become stronger. There was no noticeable effect at first, but when Dr. Banner got angry, his skin turned green and his muscles burst out of his shirt. Since Dr. Banner is a good guy, the Hulk is generally a good beast, although somewhat messy. When the anger subsides, Dr. Banner returns to his modest, wimpy self.

The comic book tale prompted Dr. Alvarado to wonder:  is this even remotely possible? He addresses the question in the video below.

 

Let’s clarify a few of these points for those who might be less familiar with the concepts. First, gamma radiation blasts your DNA (chromosomes) apart. As Dr. Alvarado mentioned, there are enzymes that will “heal” the DNA, but it doesn’t always heal correctly, which might result in new genes (and the loss of other genes). Second, we are learning more and more that genes are regulated in a surprising number of ways. They are not merely binary switches that turn on and off, but rather they are controlled more like volume knobs. Epigenetics refers to the factors in your cells that have their fingers on those volume knobs.

We discussed epigenetics in a previous article covering Ozzy Osbourne’s genome; in the case of the Hulk, epigenetics provides an attractive means to account for how Dr. Banner can switch between Hulk and normal guy. Between transformations, Dr. Banner’s genes are not changing, but which ones are active – and the degree they are active – is changing. For example, epigenetic factors can crank up genes controlling muscle development when they receive a signal in the form of a stress hormone that increases during temper tantrums. As this hormone subsides, other epigenetic factors return the volume of those genes to their normal level. You can think of genes as the selection of music, but epigenetic factors are the DJs.

 

So what kinds of epigenetic factors are there? We are discovering a dizzying array of cellular components that can alter gene expression, which can result in changes in physical appearance, behavior, mental abilities, and more. It has long been known that chemical modification (i.e. methylation, delivered by enzymes called DNMTs – DNA methyltransferases) of DNA itself can shut down genes. DNA methylation marks are like orange construction cones blocking the highway. Scientists then discovered that histone proteins, which congregate in bundles of 8 to form nucleosomes, could also be chemically modified in several different ways. The nucleosomes give DNA the “beads on a string" appearance shown below.

This is your DNA, not a pearl necklace! The DNA "string" wraps around the "beads", which are nucleosomes composed of 8 histone proteins. Once thought to merely help package DNA, we now know these nucleosomes are major contributors to the regulation of genes on the DNA.

These proteins were long thought to be just scaffolding components for the DNA, but now we know they play a major role in directing the activity level of nearby genes. Numerous different chemical modifications, such as acetylation, methylation, phosphorylation (and more), can take place on multiple places of each histone protein. These may alter the binding between nucleosomes and DNA, making certain genes more accessible, or these modifications may form a cellular “code” that can affect gene expression levels.

Histones can also be moved, replaced, or evicted by epigenetic factors called SWI/SNF ATPases. As the name implies, these enzymes require energy from ATP to affect gene expression. More recently, it has also been found that small non-coding RNA molecules can regulate genes.

A summary of the major epigenetic factors that can regulate the "volume" of gene expression.

While these complex methods a cell employs to influence gene expression offer a potential explanation for how someone could temporarily become a Hulk, it is by no means probable. Most massive gamma radiation doses would destroy genes that are essential to survival. But it is fun to use cutting-edge science to put just a tiny hint of credence behind the superpowers. And even more fun to think that with enough knowledge we may be able to modulate epigenetic factors to treat disease or maximize human potential.

Contributed by:  Bill Sullivan

Follow Bill on Twitter.

Falkenberg KJ, & Johnstone RW (2014). Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nature reviews. Drug discovery PMID: 25131830

Haggarty P, Hoad G, Harris SE, Starr JM, Fox HC, Deary IJ, & Whalley LJ (2010). Human intelligence and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking. PloS one, 5 (6) PMID: 20593030

The Friday Five

Highlighting some of the coolest science news we’ve seen lately.

1. Ever wonder if a blood-sucking insect gets drunk after sucking an intoxicated person’s blood?

2. You can't hurry love...but scientists have calculated how many soul mates you have in the world. Find out how they did this and how many are waiting for you. Go get 'em, tiger, then play them this song!

3. First, scientists made the "nude" mouse, and now they made one that is see through! Scientists have also recently created the invisible mouse, but no one can seem to find it (ba dum dum).

4. Scientists have reported that the memory of starvation can be inherited through the passage of small RNAs to offspring...for at least three generations (in worms, at least). You're not only what you eat, but you're what your great great grandparents ate!

5. It's not all in your head...music can make you feel powerful – especially pumping up the bass! Rock on, tiger.

Bonus!

Last month we wrote about the sequencing of Ozzy Osbourne’s genome. Here is a great video explaining how the human genome is sequenced.

Science quote of the week:

“All of science is nothing more than the refinement of everyday thinking.” –Albert Einstein

Contributed by:  Bill Sullivan

Follow Bill on Twitter: @wjsullivan

Rechavi, O., Houri-Ze’evi, L., Anava, S., Goh, W., Kerk, S., Hannon, G., & Hobert, O. (2014). Starvation-Induced Transgenerational Inheritance of Small RNAs in C. elegans Cell, 158 (2), 277-287 DOI: 10.1016/j.cell.2014.06.020

Yang B, Treweek JB, Kulkarni RP, Deverman BE, Chen CK, Lubeck E, Shah S, Cai L, & Gradinaru V (2014). Single-Cell Phenotyping within Transparent Intact Tissue through Whole-Body Clearing. Cell PMID: 25088144

Hsu, D., Huang, L., Nordgren, L., Rucker, D., & Galinsky, A. (2014). The Music of Power: Perceptual and Behavioral Consequences of Powerful Music Social Psychological and Personality Science DOI: 10.1177/1948550614542345