Researchers say they have found the ‘smoking gun’ for tackling life-long allergies

Being able to simply turn off your allergies sounds like a dream—but a new discovery shaking the foundations of allergy research might have just made that possible.

For the first time, researchers say, a team has isolated a cell responsible for remembering allergies and triggering the production of antibodies that cause the allergic reaction.

It’s a “ground-breaking discovery,” researchers say, which paves way for treatments that could potentially shut off an allergic response completely.

“Before the discovery of this cell, we didn’t really know exactly what it was that we were trying to go after. And so now, basically, we have the smoking gun, we know this is the thing that is keeping people allergic,” Josh Koenig, assistant professor with McMaster’s Department of Medicine and co-lead of the study, told in a phone interview Tuesday.

“And our job now is to find ways to inactivate it.”

Researchers with McMaster University and Denmark-based pharmaceutical company ALK-Abello discovered that a type-2 memory B cell (MBC2) was making the antibodies found in allergic reactions. People without allergies had very few memory B cells, if any, researchers found.

B cells are one of the types of immune cells that work to protect our body during an immune response.

Prior to this research’s publication in the peer-reviewed journal Science Translational Medicine this Wednesday, this specific type of cell had never been described before, Koenig said, adding that their work is being published parallel to a second study confirming the presence of this cell in children with peanut allergies.

Allergies have always been a bit of an anomaly in the medical world, because it’s not a disease that is continually progressing and spurring a constant immune response, nor a chronic condition that needs ongoing management.

“With allergies, people can avoid their food for a long time, but they still stay allergic, and how the immune system remembers how to stay allergic like that is something that’s not well understood,” Koenig said.

Researchers have been working on this puzzle for around 15 years, he said.

“We know that how the immune system works is every time it sees the allergen through, say, an accidental exposure, that the immune systems will wake up, and it will start making more of the thing that makes you allergic, which are antibodies. Antibodies make people allergic,” Koenig said.

When a person with a serious shellfish allergy goes into anaphylactic shock after accidentally eating a piece of shrimp, the anaphylactic reaction is these IGE antibodies at work. But their production has to be triggered by another cell.

“We kind of started by wondering, ‘Well, is there a type of cell that will hold this memory that will basically be the ones who contribute to that allergic antibody production? And the answer turned out to be yes.”

In order to find out whether there was a specific foot soldier among the memory B cells that was in charge of remembering allergies, researchers created a type of fluorescent molecule called, tetramers, out of allergens to locate memory B cells, building on previous research by Koenig and his team. They also used single cell sequencing, using computers to arrange more than 90,000 cells into groupings based on their physical similarities.

“Basically, we took a bunch of B cells out of people’s blood who are allergic,” Koenig said. “And then we looked at every single cell and looked at all of the genes that that cell makes.”

A big portion of their data relied on clinical samples from ALK-Abello, which had a cohort of people taking an immunotherapy drug for their allergies.

“Basically, they were taking a little bit of their allergen every single day,” Koenig explained. “And in the first little while of taking that therapy, their immune system actually makes many more allergic antibodies.”

This allowed researchers to study the production of allergic antibodies without actively triggering dangerous allergic responses.

The immunotherapy drug addressed allergies to birch, a seasonal allergy, or allergies to dust, “something that’s common for asthmatics,” Koenig said.

“In both of those contexts, we found those cells.”

Researchers also looked at people with peanut allergies, one of the most common food allergies. MBC2 was found to be producing antibodies in those people as well—suggesting this cell could be the culprit behind a wide scope of allergies.

“What underlies these different conditions is the same thing,” Koenig said. “And so how we’re thinking about it is that basically any allergy that has these allergic antibodies—which is pretty well all of them—these are the ones that have these types of cells (MBC2).”

Massive potential for treatments

The implications are vast, researchers say.

If an allergic reaction is the destructive stampede caused by someone shouting ‘fire’ in a packed auditorium, MBC2 is the person who yelled. It’s not the cause of the damage itself, but if it could be stopped from triggering the production of allergic antibodies, there would, theoretically, be no allergic reaction.

“The discovery really pinpoints two potential therapeutic approaches we might be able to take,” Kelly Bruton, a postdoctoral fellow at Stanford University, said in a press release. Bruton co-led the research with Koenig when she was a PhD student at McMaster.

“The first is targeting those MBC2s and eliminating them from an allergic person. The other option could involve changing their function and have them do something that’s not going to be ultimately harmful when the individual is exposed to the allergen.”

Koenig said his colleagues are already working on understanding how to inactivate the cell, and that many other pharmaceutical companies will be able to come up with their own drugs that target this cell to shut it off without damaging the surrounding cells.

So will we start seeing medication that can shut off a peanut allergy on the shelves any day now? Not yet, Koenig says.

Ensuring the safety and efficacy of new drugs takes a long time, and so we’re looking a “a minimum of five years” to even understand how to apply this information into a drug and start the regulatory process.

“If there’s stuff that ends up getting into these clinical trials from this work, that five to 10 year time point is possible,” Koenig said. “Or if we need to make completely new things, it may be even longer than that.”

This research received funding from the Schroeder Allergy and Immunology Research Institute, Food Allergy Canada, ALK Abelló A/S, the Zych Family, the Satov Family, the Canadian Allergy Asthma and Immunology Foundation, and the Cancer Research Institute Irvington Postdoctoral Fellowship, according to the release.

There’s still a huge host of unanswered questions about allergies, Koenig said.

For instance, researchers don’t know what causes some allergic reactions to be so severe, or why the same person might have varying levels of severity in their allergic reactions over the span of their life.

We also still don’t know why the body produces MBC2 in the first place in people with allergies. The mistake likely happens even earlier, with the body seeing something it doesn’t recognize and then creating MBC2 in order to remember that the body is suspicious of a certain substance.

“We think that they are really mediators of this disease, or they’re really the ones that are keeping people allergic in that long term,” Koenig said. “How it emerges, how the cell comes to exist, is still a mystery that we need to figure out.”

But we don’t need to understand why the severity varies or why MBC2 emerges in order to target it for therapies.

“The really important thing is, before, we couldn’t even see the horizon, didn’t know what it was that we were trying to (target),” Koenig said. “Now, the horizon’s in view. And we know exactly where we need to go and what we need to do.”


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