Roughly one in five people in the United States experiences some form of allergy, making allergies one of the most common, and often life-altering, health conditions.
From pollen and dust mites to foods like peanuts, our allergic reactions can range from mildly irritating to life-threatening.
Despite how common they are, scientists still don’t fully understand why some people develop allergies while others don’t, or why symptoms vary so widely from person to person.
Caroline Sokol, MD, PhD, a physician-investigator in the Division of Allergy & Immunology at Massachusetts General Hospital, is working to answer those questions.
In this Q&A, she shares how her research is reshaping our understanding of allergies by identifying surprising links between the nervous and immune systems—and what those findings could mean for future treatments for patients.
Q: How has your research evolved over time, and what have you discovered about allergies?
My research began with a fundamental question: What is it about allergens that causes the body to detect and react to them?
Early on, we discovered that many allergens have toxic activity. They damage cells, and that damage is sensed by the body.
But for years, we couldn’t identify which immune cells were responsible for detecting allergens. We kept drawing blanks.
A turning point in my research came from a personal moment. My three-year-old son was stung by a bee—his first exposure to a strong allergen.
As an allergist, I knew how potent bee venom is, but his reaction wasn’t about immunity—it was pure pain.
That moment made me realize that perhaps the immune system isn’t the first responder to an allergen. Maybe it’s the nervous system.
We then tested this hypothesis and found that sensory neurons can directly detect a wide range of allergens.
These neurons then relay signals to the immune system, effectively acting as the first line of detection.
This discovery reframed our understanding of allergies as a two-system interaction—between the nervous and immune systems—and opened entirely new avenues of research.
Q: What inspired you to pursue research in allergies and how did you end up at Massachusetts General Hospital (MGH)?
I’ve always been fascinated by why we have allergies and what makes them worse.
Why would the immune system devote an entire arm to reacting against things like pollen or food—substances that are harmless or could even be beneficial?
That question led me to explore what makes certain substances allergenic and why some people react while others don’t.
When I began this work, I was surprised by how little we actually knew about allergies, despite how common and life-altering they are.
That gap in understanding motivated me to dig deeper into how allergic responses begin.
I started asking these questions as a graduate student. I trained as an MD/PhD at Yale University, and although I knew I wanted to focus on science, I also wanted the best possible clinical training.
From the moment I interviewed at MGH for residency, I knew it was the right place.
I completed my residency in internal medicine, followed by allergy and immunology training, did my postdoctoral research fellowship here, and eventually started my lab. I’ve been here ever since.
Q: What happens in the body during an allergic reaction?
Let’s start with the easy stuff and then we’ll get to the harder stuff.
So, first, let’s talk about things like bee venom, birch pollen—stuff like that.
What we’ve seen is that if you’ve never been exposed to these before, the allergens can have toxic activity.
For example, bee venom starts flip-flopping molecules in our cell membranes, and cells really don’t like that.
With dust mites, the allergen chews up proteins, which also freaks cells out—they lose their connections with other cells.
What’s wild is that our sensory neurons, which are everywhere in the body, can somehow detect that damage.
We don’t know exactly how just yet, but they do, and that leads to them getting activated, which causes itch or pain and the release of neuropeptides that then activate immune cells.
Then things escalate: Your immune system kicks in, starts producing antibodies specific to those allergens, and those antibodies coat these cells called mast cells in your skin and tissues.
Mast cells are like little bombs—once the antibodies get cross-linked by allergens like dust mite or cat dander, boom, they go off and dump out all these mediators that make you itchy, make you swell, make you sneeze—all the classic allergy stuff.
That’s the “easy” part, even though there’s still a ton we don’t know.
The hard part is stuff like peanut allergies and other food allergens. And honestly, we don’t really know how that works.
What we do know is that food allergens tend to be heat-stable and acid-stable, so they don’t break down easily and they often carry small molecules with them like cargo and it may be that this cargo-carrying ability that makes them allergenic.
Q: If everyone has sensory nerves and are exposed to allergens, why do only some people develop allergies?
That’s exactly the question we were looking to answer in one of our recent Nature papers: If we all have sensory nerves and are constantly exposed to allergens, why do only about 30% of people develop allergies?
We hypothesized that an immune cell might be tuning the sensitivity of sensory neurons—essentially acting as a dial that makes nerves more or less reactive.
We were surprised to find that gamma/delta T cells—an ancient population of innate-like cells that bridges innate and adaptive immunity—are essential for normal sensory nerve responses to allergens.
In mice, applying an allergen to the cheek triggers itch and an immune response, but in gamma/delta T cell-deficient mice, there’s no reaction at all.
We discovered a subset of these cells in the epidermis, closely associated with free nerve endings, that secrete IL-3 in response to an environmental signal we’re still trying to identify.
IL-3 lowers the activation threshold of sensory nerves, making them more responsive to even tiny amounts of allergen.
Without IL-3 or its receptor, the allergic response disappears entirely.
What’s exciting is that this might be relevant in humans too. Humans have epidermal gamma/delta T cells, though their function has been unclear.
We also know that high IL-3 levels can correlate with itch. Interestingly, some patients with atopic dermatitis don’t respond to targeted therapies such as dupilumab but do improve with broad immunosuppressants.
So now we’re asking: could the allergies in these patients be driven by the IL-3 pathway?
And if so, could targeting IL-3 offer a more effective treatment? That’s what we’re working to find out.
Q: What’s the big-picture goal your lab is working toward over the next years?
I’m a physician-scientist, and while my lab focuses on basic science, my ultimate goal is to bring those insights back to people and make a real impact on patients.
One of the big next steps for us is understanding how gamma/delta T cells get activated.
We have some early evidence suggesting that the skin microbiome, which is all the normal bacteria that live on our skin, might be playing a role in directing or influencing that activation.
So we’re trying to figure out exactly what triggers these cells, because if we can understand that we can start thinking about ways to modulate their activity in people.
If we think about treatments, especially for atopic dermatitis, the landscape has changed a lot over the past decade.
We now have therapies like dupilumab, which even kids can take. And for patients who don’t respond to dupilumab, there are now JAK inhibitors.
The challenge is that while JAK inhibitors can help with itch, they come with a lot of side effects, particularly around cell development and immune function.
That’s why we’re really interested in the possibility of targeting the IL-3 pathway more specifically.
The first step is figuring out whether the IL-3 pathway is actually active in humans. To study this, I’m collaborating with two physicians at Brigham and Women’s Hospital—Matthew P. Giannetti, MD, from the division of Allergy and Clinical Immunology, and Rachel E. Meltzer, MD, MPH, from the department of Dermatology.
Together, we’re collecting samples from both atopic dermatitis patients and healthy controls to begin investigating this pathway in a clinical context.
It’s early, but we’re hopeful that this could open up a new, more targeted therapeutic avenue.
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