Solving the protein puzzle behind our allergy miseries
For the one in three Americans with allergies, being proactive is the name of the game.
Extra caution when trying a new dish, avoiding certain furry friends, and popping Zyrtec or Allegra each spring when the world is cloaked in pollen.
Ask biochemist Maksymilian Chruszcz about allergies, though, and he’ll tell you this — we can do better.
At Michigan State University, Chruszcz leads one of the few labs in the country studying allergies through the unique proteins that provoke them.
By revealing the molecular structures of specific allergens found in everything from pollen to kiwis to dust mites, his team is achieving breakthroughs that could mean better diagnoses and first-ever medical treatments.
“When it comes to allergies, we’re often told, ‘Take an antihistamine,’ but that’s not solving anything,” said Chruszcz, the WF Patenge Chair in the Department of Biochemistry and Molecular Biology.
“Instead of treating the symptoms, we’d like to treat the disease.”
Who goes there?
At the heart of Chruszcz’s work are efforts to understand the unfortunate case of mistaken identity that leads to allergies in the first place.
Picture the scene: like an over-zealous bouncer, your immune system interprets a birch tree pollen molecule as a harmful intruder, and so begins producing high-powered antibodies called immunoglobulin E, or IgE
These antibodies are typically deployed in tough fights against parasitic worms.
Having been “sensitized” to this new threat, the next time you inhale birch pollen, your IgE kickstart a cellular process that unleashes a whirlwind of defensive, inflammatory chemicals.
This means itchy eyes, runny nose and all-around misery.
Using analytical tools like X-ray crystallography, Chruszcz is defining the molecular properties of allergen proteins and just how they interact with antibodies — no small task given how little is known on the subject.
“Of the 1200 or so officially registered allergens, only a fraction of them have been characterized from a biochemical and structural point of view,” said Chruszcz, who joined MSU as part of its new Applied Immunology Center for Education and Research.
“We encounter thousands of proteins in daily life. So, we’re asking, what makes an allergen an ‘allergen,’ and why do some people become sensitized?”
Better tests, new treatments
Looking closer, Chruszcz is especially keen to map what are called “epitopes.” These are the precise locations where antibodies bind to an allergen and where an immune response truly begins.
By mutating a handful of epitopes, researchers hope to develop allergens with greatly reduced IgE binding.
Known as hypoallergens, these types of immunotherapies can help the body build up tolerance on its own with minimal side effects and even prompt the production of other protective antibodies upon re-exposure to an allergen.
“IgE are actually very rare, making up less than 1% of our overall antibodies,” said Chruszcz, who explained how the vast majority are immunoglobulin G, or IgG.
For almost two decades now, Chruszcz has worked with the biotechnology company InBio on developing such immunotherapy treatments for those allergic to dust mites — allergens thought to be key triggers of allergic asthma.
The precise characterization of allergen proteins also promises a more accurate picture of allergies on a case-by-case basis.
Forgoing usual allergy tests that are often poorly standardized, researchers like Chruszcz can use what’s called component-resolved diagnostics to pinpoint the exact protein behind an allergic reaction.
"We can discover very detailed interactions between molecules. We can not only tell a particular person they’re sensitized to peanuts, but what two or three proteins are causing their condition," said Chruszcz.
"Going even further, we can find out the exact fragments of an allergen that are responsible for triggering an allergic reaction. In principle, we can create an antibody cocktail to provide personalized treatment."
Blame it on the pollen
The Chruszcz Group’s protein research is breaking further ground when it comes to understanding a unique ailment that many adults with food allergies likely have without even knowing it.
The culprit, known as pollen-food allergy syndrome, is another instance of our body’s defense system getting its wires crossed.
Through what’s called cross reactivity, the antibodies produced to recognize one specific allergen will cause an allergic reaction after encountering a similar-looking molecule.
“Unfortunately for us, pollen proteins are very close to those found in raw fruits and vegetables,” said Chruszcz.
“So, someone who has a nasty pollen allergy can one day have a similar reaction when eating carrots, apples or celery.”
Studying cross reactivity has led Chruszcz to new collaborations and surprising finds, with his lab gaining an international following for their protein detective work.
At the moment, only two other labs in the country are working on similar allergen science, with the Chruszcz Group being the sole academic team in the field.
“Not many people are working on this, so we’ll get requests from across the world asking us, ‘What is this molecule?’” said Chruszcz
Recently, the group was contacted by researchers in Australia curious about protein allergens found in crocodile meat, which were strikingly similar to those in fish.
“You don’t see a connection right away, but from the perspective of the protein family, there’s always a link with sequence or structure,” he added, noting how something as common as a person’s shellfish allergy might develop from cross-reactivity with dust mite allergens.
Into the unknown
For Chruszcz, allergen research is a field that rarely runs out of strange, interesting and perplexing discoveries. For every question answered, it seems another two appear.
“I love working on allergens because many times, we have no clue what the function of a particular protein is in the source organism,” he said.
Last year when researchers used CRISPR to knock out the gene responsible for an allergen found in cat saliva, that gene appeared nonessential for overall feline health.
Allergy science is also a complex meeting point of intertwining variables, from biochemistry and immunology to environmental conditions and even cultural-historical trends.
“Today, we have access to food from completely different parts of the world, meaning we’re exposed to totally unfamiliar proteins,” said Chruszcz, who pointed out how invasive plant species present new allergen challenges, as does the rise in popular exotic pets.
For his team, this just means more mystery molecules to characterize, and more opportunities to help develop therapeutics that could one day save us some sneezing, wheezing and itchy eyes.
“We’ll have our work cut out for us for a long time,” added Chruszcz.
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