What the Mystery of the Tick-Borne Meat Allergy Could Reveal - New York Timeshttps://doximity-res.cloudinary.com/image/upload/t_public_profile_photo_320x320/v1392483518/kmnszubxlvjiupg7lhy8.jpg
Until meat allergy was recognized, the prevailing medical wisdom held that an allergic reaction to meat from mammals was extremely unusual. Unlike that from shellfish, say, meat from mammals was thought by some allergists to be too similar to human flesh for the immune system to attack it with the full fury of the allergic arsenal. In this and other respects, meat allergy is upending longstanding assumptions about how allergies work. Its existence suggests that other allergies could be initiated by arthropod bites or unexpected exposures. It also raises the possibility that other symptoms often reported by patients that clinicians might dismiss because they don’t fit into established frameworks — gluten intolerance, for example, or mucus production after drinking milk — could, similarly, be conditions that scientists simply don’t understand yet. Mammalian-meat allergy “really has the potential to revolutionize our understanding of food allergy, because it doesn’t fall under the umbrella of our paradigm,” Dr. Maya R. Jerath, a professor of medicine at Washington University School of Medicine, in St. Louis, told me. “Maybe our paradigm is wrong.”
The meat-allergy story begins somewhat obliquely, with a new drug for metastatic colon cancer called cetuximab. In 2006, Thomas Platts-Mills, an allergist at the University of Virginia School of Medicine, received a phone call from a colleague. Oncologists testing cetuximab were baffled to find that nearly one in four patients had severe anaphylactic reactions to the drug. A few patients even died. The caller urged Platts-Mills to look into the mystery. He agreed and began by comparing the blood from those who had an allergic response to cetuximab with the blood from those who didn’t. The patients who reacted, he discovered, had allergic antibodies to a complex sugar called galactose-alpha-1,3-galactose, or alpha-gal for short. Most mammals produce alpha-gal; it’s a component of their cell membranes. The exceptions are African and Asian apes and monkeys. As primates of African origin, we do not produce alpha-gal, either. That makes the human immune system unusual: It can learn to see alpha-gal, present in the beef and pork and other mammalian meat we eat, as foreign and threatening, thereby allowing for an allergic response. Cetuximab contained alpha-gal, it turned out; the sugar came from the genetically modified mice used to manufacture the drug.
While Platts-Mills had identified the molecule in the drug causing these severe allergic reactions, he didn’t yet know why those patients were allergic to it. How had their immune systems become sensitized to it? Humans aren’t born allergic to anything; allergy is like a bad habit the immune system needs to learn. Many scientists suspect that our allergic machinery — the swelling of tissues, mucus production, the coughing and sneezing — served an important purpose in our evolutionary past. It probably helped us to fight off parasites. But in allergic disorders, the body unleashes this ancient anti-parasite response inappropriately against molecules that aren’t obviously dangerous (beyond their role in causing a reaction) — against cat dander or pollens or peanuts. The mystery of any allergy is how and why the immune system is first led to make this mistake.
EDITORS’ PICKS
The A.C.L.U. vs. Trump: 170 Legal Actions (So Far)
It’s 4 A.M. The Baby’s Coming. But the Hospital Is 100 Miles Away.
Young Jean Lee’s Unsafe Spaces
ADVERTISEMENT
What had primed the patients to be allergic to the alpha-gal sugar? The oncologists did have one clue: They noticed that allergic patients tended to come from the Southeast. Initially Platts-Mills thought that maybe intestinal parasites or even a mold from the region was sensitizing patients to alpha-gal. But a technician in his lab pointed out that the geographical distribution of cases matched the reported distribution of a tick-borne disease called Rocky Mountain spotted fever. That got Platts-Mills thinking about ticks.
At the same time, he was seeing a growing number of patients in his allergy clinic, many of them hunters and outdoorsy types, complaining about what was apparently a strange reaction to eating meat. They suffered stomach pains and rashes hours later. When Platts-Mills analyzed their blood, he found that, like the cancer patients who had an allergic reaction to cetuximab, they also had allergic antibodies for alpha-gal. And when he and his colleague Scott P. Commins surveyed the patients, they found that more than 80 percent of them reported having had strong reactions to tick bites.
Independent of the research Platts-Mills was doing, in 2007 an Australian allergist named Sheryl van Nunen described 24 cases of meat allergy associated with tick bites. Colleagues were skeptical of her claims, she told me. They didn’t think an allergy to meat from mammals was very likely. And she hadn’t identified what the immune system was specifically attacking, the molecule in meat that was attracting the onslaught. That discovery fell to Platts-Mills, Commins and their colleagues. They posited that alpha-gal as the allergen that made people sick hours after eating hamburgers (or, in Australia, kangaroo steaks). And they proposed tick bites as the trigger. Ticks could explain the two seemingly disparate phenomena: why people who reacted to cetuximab came from the Southeast and why most cases of meat allergy occurred in the same region. The Southeastern lone-star tick was exposing and thus sensitizing people to the sugar through its bites. Some subset of the ectoparasite’s victims would thereafter react to alpha-gal whenever they encountered it, including in meat and cetuximab.
Platts-Mills still lacked definitive proof that a tick bite initiated the allergy. He hadn’t conducted an experiment in which, for example, he deliberately induced meat allergy in human volunteers. But one day in August 2007, he took a hike in the nearby Blue Ridge Mountains. When he got home, he discovered hundreds of larval-stage ticks feeding on his ankles. (He spent the evening removing them with a knife and Scotch tape.) Platts-Mills doesn’t eat red meat often — he had a heart attack in 2005 — but a few months after that hike, on a trip to Europe, he ate two lamb chops and had a glass of red wine. “Six hours later I was in a hotel, covered in hives, itching like crazy and laughing at myself,” he told me. By then, he thought he knew what was happening: The ticks had made him allergic to those chops.
In 2013, on a hike and a picnic with some friends in the Blue Ridge Mountains, Platts-Mills was again swarmed by larval ticks. By this time he was already monitoring his alpha-gal antibody levels, so he was able to compare how much antibody he had circulating before and after these ticks fed on him. Post-picnic, the allergic antibodies directed at alpha-gal in his bloodstream surged more than tenfold, direct evidence that tick bites had provoked the allergic response to alpha-gal. It seemed he had cracked the case, and others around the world took note. Sheryl van Nunen, now at the University of Sydney, told me this understanding of the precise cause of mammalian-meat allergy makes it unique. “This is really allergy in a kit — how to get it and how to lose it,” van Nunen said. “There’s really nothing else like it.”
Image
Until meat allergy was recognized, the prevailing medical wisdom held that an allergic reaction to meat from mammals was extremely unusual.CreditPhoto Illustration by Daan Brand
Mammalian-meat allergy differs from most other food allergies in several important ways. One is the delayed reaction; it’s not uncommon for sufferers to wake up in the middle of the night, hours after a steak dinner, covered with hives and struggling to breathe. By contrast, those with food allergies to peanuts usually develop symptoms within minutes after ingesting the offending food. And whereas in most cases of allergy, the immune system pursues a protein, meat allergy is set off by a sugar.
ADVERTISEMENT
Another unusual aspect of meat allergy is that it can emerge after a lifetime spent eating meat without problems. In other food allergies, scientists think that children’s immune systems may never learn to tolerate the food in the first place. But in meat allergy, the tick seems to break an already established tolerance, causing the immune system to attack what it previously ignored. One way to understand how the parasite pulls this off is to consider its bite as a kind of inadvertent vaccine. A vaccine teaches an immune system to pursue a pathogen it otherwise wouldn’t by exposing it to weakened versions of that pathogen — an attenuated measles virus, say — or bits and pieces of dead pathogen. Vaccines also often contain a substance called an adjuvant, which is designed to spur the immune system into action.
In similar fashion, when the lone-star tick feeds, alpha-gal leaks from its mouth into the wound, exposing the victim’s immune system to the sugar, prompting the immune system to remember and pursue alpha-gal. But exposure to alpha-gal alone probably doesn’t achieve this feat. Commins, who is at the University of North Carolina, at Chapel Hill, has identified a candidate, an enzyme in the tick’s saliva called dipeptidyl-peptidase that works as an adjuvant. It’s also common in bee and wasp venom. This enzyme, Commins argues, is what tells your immune system to see alpha-gal as the type of threat that warrants the itching and swelling of the allergic response.
Once sensitized, some victims find that they can no longer tolerate beef, pork, lamb — even milk or butter, foodstuffs with only very small amounts of alpha-gal. Several factors can also affect the severity of the allergic reaction, or if there is an allergic reaction at all. Grilled meat is less allergenic than other methods of preparation that preserve more of its fat. Fatty meat leads to more alpha-gal crossing a person’s gut barrier into his or her circulatory system, triggering a stronger immune reaction than leaner cuts. A study of German patients also found that alcohol imbibed with meat can push people toward an allergic reaction, as can exercise; both actions make the gut more permeable, exposing the immune system to more alpha-gal.
As it happens, an immune response to alpha-gal is also what drives, in part, the rejection of tissue transplanted from animals to people. Scientists have developed genetically modified pigs meant to supply parts that can be grafted onto human bodies without eliciting an anti-alpha-gal immune reaction. Now, as awareness of the meat allergy spreads, there has been talk of using such alpha-gal-free pigs for food — pork chops your doctor can prescribe if you find yourself allergic to meat.
A recent study by scientists at the National Institutes of Health, which included Commins and Platts-Mills as co-authors, linked allergic sensitization to alpha-gal with a greater risk of arterial plaques, a hallmark of heart disease. It’s unclear whether having alpha-gal antibodies specifically increases your risk of developing plaques or whether some other factor increases a person’s risk of heart disease and sensitization to alpha-gal. But if it turns out that meat allergy pushes people toward cardiac arrest, it would imply that encounters with the lone-star tick contribute to the leading cause of death in the United States.
The big, unanswered question is why meat allergy is on the rise today. Commins estimates that at least 5,000 cases have been diagnosed in the United States, and many more probably remain undiagnosed. In some tick-heavy regions, the prevalence of meat allergy is estimated to be at least 1 percent of the population. Ticks are not new. Neither is the human consumption of meat. Why the sudden problem for so many? One possibility is that the ticks have changed somehow. Maybe they’ve acquired a pathogen we don’t understand yet, and this infection is causing the allergy. Or perhaps, Commins says, changes to the insect’s microbiome, the collection of symbiotic microbes that it carries in its body, have somehow made its bites more allergenic.
The idea is plausible and could nicely explain how an arachnid that has been around for a long time could begin causing a new set of complications. Scientists have long debated where the alpha-gal in the tick originates: Does it come from the blood a tick sucks from other mammals and then regurgitates as it feeds on people, or does it come from the tick itself? Shahid Karim, a vector biologist at the University of Southern Mississippi, in Hattiesburg, told me that the answer might be neither; the sugar probably comes from the microbes that the tick carries within it. So it’s entirely possible, he said, that changes in its microbiome could, by increasing the amount of alpha-gal humans are exposed to in tick bites, make the lone-star tick more likely to induce meat allergy.
ADVERTISEMENT
What such an account fails to address, however, is why the meat allergy has increased in other parts of the world, like Australia and Europe. (Van Nunen says that in the tick country around Sydney, people are now more likely to carry EpiPens, which contain a shot of adrenaline, for meat allergy than for better-known peanut allergies.) Other tick species are linked with meat allergy in those regions, not the lone-star tick. And it seems very unlikely that the microbiomes of all these ticks on different continents have changed in similar ways at the same time. “I don’t for the life of me have a unifying hypothesis for why it’s happening everywhere,” Commins told me, although he added that pesticides could be one factor changing tick microbiomes globally.
It may simply be that an increase in the number of ticks has turned a problem once so rare that it went scientifically unnoticed into an observable epidemic. “I think we’ve got far more tick bites today than people had as recently as 35 years ago,” Platts-Mills told me. He lays the blame for the growing spread of ticks on newly abundant deer. In Virginia, he thinks new laws requiring dogs to remain on leashes have emboldened deer, which then bring ticks closer to people. People aren’t necessarily venturing deeper into the forests than in the past, he says. More than half the patients he sees with the allergy were bitten on their own lawns.
His leash theory is anecdotal, but it’s certainly true that the current ecological state of Eastern forests is probably encouraging ticks to multiply. After having been cleared in the Colonial era, the forests have partly grown back. Deer and turkey, which the lone-star tick likes to feed on, are abundant again. They thrive in the new-growth forests, now fragmented by roads and suburbs. Large predators are mostly absent. And the rise of tick-borne disease generally has been linked with the decline (or absence) of predators that eat the animals ticks feed on. In Australia, for example, van Nunen points to the eradication of foxes, an introduced species there, as one factor in the increase of ticks and the rise of meat allergy.
We might label this the disturbed ecosystem theory of meat allergy. Forests ecosystems have recovered partially — lots of animal hosts for ticks but not enough predators to keep those hosts in check — and this imbalance has fostered an exponential growth in the number of ticks. In some ways, this is the most probable explanation for the rise of meat allergy. Climate change may be aiding the lone-star tick’s move northward too, Rick Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies, told me. Hundreds of cases of meat allergy have been diagnosed on Long Island in recent years, which wasn’t part of the tick’s range in recent history. The tick has been spotted as far north as Maine.
But what’s happening in the American East can’t account for the full extent of the phenomenon elsewhere in the world. In Northern Europe, ticks are proliferating as forests recover and the climate becomes warmer. But in Spain and Southern Europe, the rising incidence of meat allergy has not been accompanied by an increase in tick numbers, according to José de la Fuente, a professor at the Institute of Game and Wildlife Research in Ciudad Real, Spain. For him, the mystery of meat allergy is captured in one question: If a tick bites two genetically similar people, why might only one develop the meat allergy?
Onyinye Iweala, an assistant professor who works with Scott Commins’s lab at the University of North Carolina, echoes this uncertainty. Why are some people sensitized to alpha-gal — meaning they have allergic antibodies directed at the sugar in their blood stream — but never have an allergic reaction to it? This can happen in all allergies. You can have antibodies to, say, cat dander, yet never wheeze or sneeze around cats. Iweala suspects that sensitization to alpha-gal isn’t new. What’s changing is the proportion of people who, after sensitization, proceed to overt allergy. Something else in the environment, she told me, is likely pushing people toward full-blown meat allergy. Perhaps shifts in the microbes that live within us have somehow made us more easily sensitized by tick bite. As a model of how this might work, Iweala points to intriguing research on the interaction between malaria and the human microbiome that centers on alpha-gal.
OUR DISTANT ANCESTORS once made alpha-gal. Understanding why humans don’t could shed light on the meat-allergy mystery. Like other mammals, South American monkeys produce alpha-gal. Only Old World monkeys and apes (and humans) have lost the ability to make the sugar. Hence scientists deduce that the change most likely happened after New and Old World primates diverged from each other around 40 million years ago. One explanation for the disappearance of alpha-gal is that it was driven by some catastrophe, a deadly infection that afflicted Old World primates, perhaps, and as a result maybe these distant relatives of ours stopped being able to produce the sugar because doing so conferred an evolutionary advantage. The mutation that eliminated alpha-gal could have improved a primate’s ability to fight off an infection by enabling its immune system to more easily distinguish between its own body and some pathogen with alpha-gal.
ADVERTISEMENT
What could this pathogen have been? In the late 2000s, Miguel Soares, a scientist at the Instituto Gulbenkian de Ciência in Oeiras, Portugal, began to suspect the plasmodium parasite that causes malaria. Because the protozoan is so deadly and has historically been so widespread in warmer climes, geneticists often say that malaria has been the single greatest force shaping the human genome in our recent evolutionary history. The parasite remains a leading cause of death in the developing world. And it’s coated in alpha-gal. More: https://www.nytimes.com/2018/07/24/magazine/what-the-mystery-of-the-tick-borne-meat-allergy-could-reveal.html?hootPostID=184d3d6893cf17abbb622c9a6e8347fd |
