The Alpha-Gal Syndrome Story: How Researchers Traced a Red-Meat Allergy to Ticks

During the early 2000s, Thomas Platts-Mills, an allergist and immunologist at the University of Virginia (UVA), had a handful of patients visit his allergy clinic with a rather unusual complaint: They had suddenly developed an allergic reaction to red meat. He recalled his first patient, an older woman who said she became covered in hives four hours after consuming pork. Platts-Mills was skeptical. “I didn't believe her; it doesn't make sense.” He added, “People don't become allergic to red meat in the middle of their life.” Other patients reported additional symptoms, including gastrointestinal issues, nausea, shortness of breath, and in some cases, anaphylaxis. Platts-Mills was sure there must be another explanation for their symptoms, but he didn’t know where to look.

I didn't believe her; it doesn't make sense. People don't become allergic to red meat in the middle of their life.
—Thomas Platts-Mills, University of Virginia

Around the same time, oncologists at his university reached out for help solving a cancer-drug allergy mystery. Little did he know that this cancer conundrum would provide clues to solve the mystery of the unusual allergy—now known as alpha-gal syndrome.

A Sweet Discovery Uncovers Alpha-Gal

In the 2000s, cancer centers across the US were administering the newly-approved cancer drug cetuximab, a chimeric mouse-human immunoglobulin G1 (IgG₁) recombinant monoclonal antibody. Soon, they noticed something odd: An unusually high number of patients experienced anaphylaxis following their first infusion of the drug. “The prevalence of reactions was extraordinary,” said Platts-Mills. Typically, less than one percent of patients have such a severe reaction to a monoclonal antibody, but at some centers, cetuximab triggered reactions in more than 20 percent of patients.¹

Oncologists working at UVA, one of the cancer centers with a high number of hypersensitive patients, turned to their colleague Platts-Mills, an allergy specialist, for help. Platts-Mills worked with the team to develop an ImmunoCAP assay— commonly used in allergy diagnostics to measure the amount of allergen-specific immunoglobulin E (IgE) antibodies—specifically for cetuximab. When the team tested pretreatment serum samples, they discovered that patients who exhibited severe reactions to cetuximab already had IgEs specific to the drug in their system. How was that possible when they had never been exposed to the drug before?

Researchers at ImClone Systems had also started looking into the chemical makeup of the drug for clues. When they analyzed post-translational glycosylation patterns they found that the specific mouse myeloma cell line they were using to produce cetuximab decorated the drug with an unusually high amount of the sugar galactose-α-1,3-galactose, or alpha-gal for short.²

We started to wonder, ‘gosh, why would you have one protein in beef that you're allergic to all of a sudden, and another one in pork, and a third one in lamb? What if this is all alpha-gal?’
—Scott Commins, University of North Carolina

Curious whether this sugar coating the cetuximab was triggering the adverse drug responses, Platts-Mills and his colleagues returned to the blood samples and found that patients with hypersensitivity to the drug had alpha-gal-specific IgE antibodies in their blood prior to treatment, whereas those who responded well to the infusion did not. “It proved beyond doubt that having IgE to this molecule before you're treated predicted whether you'd get a reaction or not,” said Platts-Mills. “That was a big deal.” He added, “This was the first time the issue of a cell line glycosylating a molecule had influenced the results of a clinical trial.”

In fact, this finding triggered another cascade of events. It got Platts-Mills wondering whether this mammalian sugar was also central to the meat allergy mystery.

Scott Commins, an allergy immunologist at the University of North Carolina, studies alpha-gal syndrome and the role of resident immune cells in allergic immune responses.

Brain Strickland

Most non-primate mammals produce alpha-gal, but humans do not.³ However, most humans have IgG antibodies—not to be confused with the IgE isotope—against alpha-gal. IgG production is an important part of the normal immune response to food, and it allows humans to tolerate food antigens, including alpha-gal. This is why most humans can eat mammalian products without triggering an allergic response. Yet, for many affected by the unusual adult-onset allergy, foods they had enjoyed all their lives—a juicy steak, a lamb dinner, and a sizzling bacon sandwich—suddenly became triggers for a life-threatening reaction. “We started to wonder, ‘gosh, why would you have one protein in beef that you're allergic to all of a sudden, and another one in pork, and a third one in lamb? What if this is all alpha-gal?’,” said Scott Commins, an allergy immunologist at the University of North Carolina at Chapel Hill who worked in Platts-Mills’ team at the time. He added, “So we had this awareness of sugars and carbohydrates and glycosylation that allergists typically almost ignored because so much of allergy had, up until that point, been predicated on protein-based responses.”

Using the alpha-gal ImmunoCAP assay they already had on hand, Commins started testing blood from their patients with the red meat allergy.⁴ Lo and behold, the patients had IgE antibodies to alpha-gal in their sera. “That's how the story starts to come together,” said Commins. Over time, the condition came to be known as alpha-gal syndrome. But there remained another mystery: How did the patients receiving cetuximab or reporting the red meat allergy acquire the alpha-gal specific IgE in the first place?

The Culprit Behind Alpha-Gal Syndrome: Lone Star Tick

While oncologists were trying to determine why so many patients were experiencing such severe reactions to cetuximab, they noticed an unusual pattern in the data. The allergic reactions seemed to be occurring only at cancer centers in the Southeast of the US. One study found that 22 percent of patients who were treated in Tennessee and North Carolina had severe hypersensitivity reactions to cetuximab but less than one percent of patients at centers in the Northeast showed such responses.⁵ "No one had ever seen a drug reaction so brilliantly separated geographically,” said Platts-Mills.

When they looked at control blood samples from the Vanderbilt University and Harvard University sites, they found that 17 percent of the Southeast controls have IgE to alpha-gal, compared to less than one percent of those from the Northeast.¹ “That is a fantastic difference,” said Platts-Mills. “So, having this antibody had nothing to do with cancer, it had everything to do with rural Tennessee.”

There were several possible regional exposures, such as a fungus or a parasite, that could be sensitizing the patients, so Platts-Mills tasked one of his lab members with scouring the web for distribution maps that matched the southeastern patterns of cases. One map from the CDC stuck out: It showed the distribution of Rocky Mountain Spotted Fever (RMSF), an acute febrile tick-borne illness. “[The distribution] overlapped really perfectly with some of the cetuximab and alpha gal syndrome patients that we were hearing about and finding,” said Commins.

Photo of a lone star tick, with a white dot on his back, in a dish with a pair of tweezers approaching the tick. — After scoring the web for pathogens or diseases that showed a similar geographic distribution to the cetuximab reactions, Platts-Mill, Commins, and their team landed on the lone star tick, named for the distinctive white dot on its back.
Scott Commin

Platts-Mills and his team started to wonder if a tick was to blame for their cetuximab and red meat allergy mysteries. By this point, the team had already enrolled 130 meat allergy patients for a study. “We had never asked anyone, ‘Oh, have you been bitten by a tick before?’,” said Platts-Mills. So, Commins went back and called each of the patients to ask about their tick bite history. To their surprise, more than 90 percent indicated some history of tick bites. Platts-Mills remembers the first patient he asked—a deer hunter—who rolled up his trousers to reveal his leg covered in tick bites. In time, they narrowed in on the lone star tick as the alpha-gal spreader. “As I say, the tick was out of the bag,” said Platts-Mills.

Over the last decade, the evidence linking tick bites to alpha-gal IgE has been growing.⁶ “It's tough to prove,” said Commins. “It really wasn't until 2023 where we did a case control study with the CDC and demonstrated the association of tick bites creating this incredible odds ratio for the development of alpha gal syndrome,” said Commins. Although Platts-Mills and Commins had made a connection to ticks, there were still a lot of unknowns, starting with how the alpha-gal sugars were transmitted.

From Bite to Body: How Alpha-Gal Enters the System

It was long thought that a tick acquires the alpha-gal sugar through a bloodmeal from a dog or deer and then transmits it to humans. While this may still be one mode of transmission, Commins noted, “It seems like they can produce the alpha-gal sugar themselves.” Shahid Karim, a molecular entomologist at the University of Southern Mississippi, discovered the alpha-gal antigen in the salivary glands and saliva of the lone star tick.⁷ “We were a little disheartened when we found that,” said Commins. “It now probably means that the risk of developing alpha-gal [syndrome] from a lone star tick bite is probably higher than we thought, because they tend to make it themselves.”

Regardless of how a tick acquires alpha-gal, scientists still don't fully understand the immune mechanisms driving alpha-gal-specific IgE production in humans. Soon after Platts-Mills and his team published their findings on cetuximab and alpha-gal syndrome, he was on a trip to London one November when he started to experience the very condition he had been studying in patients. He recalled having a lovely lamb dinner before heading back to his hotel. “[At] three in the morning I'm itching, covered in hives,” he said. It turns out that Platts-Mills had developed alpha-gal syndrome after being bitten by a bunch of baby lone star ticks while hiking a couple of months before. In fact, he had been testing himself for alpha-gal IgE throughout this period. “My antibodies went up each week for two months, and by November, I had high levels [of IgE].”

White lint roller paper with hundreds of tiny brown larvae with a dime for scale. — All stages of the lone star tick can trigger sensitivity to alpha-gal, including the larval hordes, also called “tick bombs.”
Patrick Roden-Reynolds

For many humans, exposure to alpha-gal via the gut drives production of IgG, IgM, and IgA, but not IgE.⁸ This suggests that there may be something unique about transmission via the skin, possibly bringing in innate and adaptive immune pathways. Another possibility is that there is something in the tick saliva that promotes immunoglobulin class switching, whereby B cells change their production of immunoglobulin from one class to another, such as an IgM to an IgE.

Another oddity with alpha-gal syndrome is the delay in symptom onset. Traditional IgE-mediated food allergies, such as to peanuts, cause a reaction shortly after consumption, whereas patients with alpha-gal syndrome experience reactions anywhere from two to six hours after eating meat.⁹ What’s happening during this waiting period? Platts-Mills said that the only thing that makes sense to him is that the alpha-gal is hitchhiking on fats, which are abundant in certain meats. Fats take a while to get broken down in the gut into smaller (200 to 1,000 nanometers) chylomicrons, which continue to break down into smaller and smaller lipid particles before becoming low-density lipoproteins, which are only 22 to 28 nanometers, small enough to make it into the bloodstream where it now has access to tissues to cause hives. “That's been the argument now for five or six years, but no one's proved it,” said Platts-Mills.

The Lone Star Tick Brings Alpha-Gal to the North

On Martha’s Vineyard, an island off the coast of Massachusetts, Patrick Roden-Reynolds, a public health biologist and director of the island’s Tick-Borne Illness Reduction Initiative, is beginning his fourth tick season. As part of the tick program on Martha’s Vineyard, Roden-Reynolds surveys residential yards by slowly dragging a white cloth attached to the end of a broom handle along the edge of a mowed lawn. Ticks that have ventured from their brushy habitats in search of a host, a behavior called “questing”, are sitting, waiting to cling onto a passing host. “Drag sampling is just taking advantage of that questing behavior,” said Roden-Reynolds. Every few steps, he stops, plucks the ticks off the sheet, sticks them to a lint roller hanging off his belt, and continues with his survey.

Photo of a lone star tick sitting in a questing position, with its arms out, one a blade of grass. — When the lone star tick is seeking a host it goes “questing” where they crawl onto vegetation, extend their front legs, and wait for a passing host to brush against them
Patrick Roden-Reynolds

Since 2011, just over a decade before Roden-Reynolds moved to the island, the Martha’s Vineyard Tick Program has been running such island-wide surveys to track the population abundance and distribution of ticks. There are currently three human-biting tick species on the island: deer tick (also known as the black legged tick), the American dog tick, and the lone star tick. Roden-Reynolds said that deer tick has long been the most worrying of the tick species as it is responsible for Lyme disease and babesiosis, which affects the island’s population the most. But over the last decade, the lone star tick has been making a name for itself.

The 2011 survey was the first documented occurrence of the lone star tick on the island, but Roden-Reynolds noted that they had likely been on the island for at least a few years based on established breeding populations, and historical newspaper articles noted observations of a single lone star tick back in the 1980s. But since the survey began, their populations have skyrocketed. “They become abundant pretty quickly. They're much more prolific than deer ticks,” said Roden-Reynolds. He said that the 2011 drag surveys would maybe turn up a handful of lone star ticks in someone's yard. “Fast forward to the surveys that I do—I find anywhere from two ticks to 200 ticks in people's yards,” said Roden-Reynolds.

[Alpha-gal syndrome] went from low on my radar to probably the number one thing I talk about most.
—Patrick Roden-Reynolds, Martha's Vineyard Program

Over the last decade the ticks have also made their way across the island.¹⁰ Early surveys found them exclusively in the southwestern and southeastern corners of the triangle-shaped island. “But since 2015, we've seen this slow kind of northerly march of the lone star tick,” said Roden-Reynolds. “Now I can find them clear across the island.”

As the lone star tick population boomed, Martha’s Vineyard started seeing an increase in the number of people sickened by the diseases and conditions they cause, including alpha-gal syndrome. When he first got to the island, Roden-Reynolds admitted that he didn’t care too much about alpha-gal syndrome. After all, for Martha’s Vineyard and much of the Northeast, there were other tick-borne diseases like Lyme disease causing serious problems for a lot of the population. “I thought it was an allergy that went away pretty quickly,” said Roden-Reynolds. “I was like, ‘Okay, you can't eat a cheeseburger; you can't eat bacon for six months, but then you go back to a regular diet.’” But soon he realized that it was more than just a short-term nuisance, adding, “It's quite a life changing allergy.”

Map of Martha’s Vineyard with dots of different sizes and colors that represent the average number of ticks in each area. — For more than a decade, the Martha’s Vineyard Tick Program has surveyed ticks in residential yards across the island. Over the last few years, the lone star tick population has increased and spread across the island.
Patrick Roden-Reynolds

Although mammalian meat is the most common trigger, some patients with alpha-gal syndrome can also develop allergic reactions to a range of other products.¹¹ Dairy products, foods, medicines, and vaccines that contain gelatin, and prosthetic heart valves from cows and pigs are just a handful of products that patients may need to avoid. Worries about cross-contamination can also cause an entire household to change their diet and lifestyle.

For some people, their symptoms, and alpha-gal IgE levels, dissipate after a few years. Meanwhile, others, including Platts-Mills, have dealt with the syndrome for more than a decade. “I don't think I'm ever going to get rid of it now,” he said. Currently, treatment options are very limited and largely center on avoiding food triggers and new tick bites, which can trigger another wave of alpha-gal IgE.

“[Alpha-gal syndrome] went from low on my radar to probably the number one thing I talk about most,” said Roden-Reynolds, who runs tick education events across the island. “So many people are turning up positive with alpha-gal, especially in the last three years.” He added, “Everyone knows someone that has alpha-gal [syndrome].”

Martha’s Vineyard is not alone in its experiences with the lone star tick and alpha-gal syndrome. Other regions in the Northeast, particularly Long Island, have seen reports of alpha-gal syndrome for more than a decade now. “Over the past 15 years, it's gone from a southern thing to a largely continental US thing,” said Commins, although cases are still more common in the Southeast. Nor is alpha-gal syndrome a US-specific problem. “Several people in the world had already noticed that some people getting tick bites became allergic to red meat, but they hadn't a hope in hell of working out what the sugar was,” said Platts-Mills. “The cetuximab gave us the advantage.” For example, around the time that Platts-Mills and Commins reported their findings, Sheryl van Nunen, an allergy specialist at Royal North Shore Hospital in Sydney, Australia, reported that some patients seemed to develop a red meat allergy after having a reaction to a bite from a paralysis tick.¹² Today, the mammalian meat allergy has been reported on all human dwelling continents, but the tick culprit differs from place to place.¹³ “It's a different tick in every place, but it's always ticks,” said Platts-Mills.